WO2025238236A1

WO2025238236A1 - Polyplexes of nucleic acids and targeted conjugates comprising polyethyleneimine and polyethylene glycol

Info

Publication number: WO2025238236A1
Application number: PCT/EP2025/063599
Authority: WO
Inventors: Maya ZIGLER; Alexei Shir; Eric Kitas; Esteban Pombo-Villar
Original assignee: Targimmune Therapeutics AG
Current assignee: Targimmune Therapeutics AG
Priority date: 2024-05-16
Filing date: 2025-05-16
Publication date: 2025-11-20
Anticipated expiration: 2026-11-16

Abstract

The present invention provides targeting polyplexes comprised of (i) nucleic acids, in particular nucleic acids encoding pharmaceutically active peptides or proteins, and (ii) targeting conjugates comprising LPEI and PEG fragments that are connected by discrete linkages formed through defined, chemoselective reactions. Thus, the LPEI fragment is bonded in a linear end- to-end fashion to a single PEG fragment. The linear conjugates are further conjugated to a targeting fragment to enable selective interaction with a particular cell type. The polyplexes selectively deliver the nucleic acids to the targeted cells resulting in high expression and efficient protein translation as well as secretion of the encoded pharmaceutically active proteins.

Description

_{P6797PC00 – 1 –} POLYPLEXES OF NUCLEIC ACIDS AND TARGETED CONJUGATES COMPRISING POLYETHYLENEIMINE AND POLYETHYLENE GLYCOL RELATED ART CRISPR/Cas9 has considerable potential to treat and even cure human diseases, including genetic diseases. However, there remain challenges associated with the safe and effective delivery of CRISPR/Cas9 gene editing components to patients. Finn et al., 2018, Cell Reports 22, 2227-2235. SUMMARY OF THE INVENTION T_{he present invention provides polyplexes comprising (i) targeting conjugates} comprising LPEI and PEG fragments; and (ii) components for gene editing using CRISPR/Cas9. In preferred embodiments, the components for gene editing include an mRNA _{encoding a Cas protein, preferably Cas9; and preferably a guide RNA and optionally template} DNA. In preferred embodiments, the conjugates are connected by discrete linkages formed through defined, chemoselective reactions instead of through random and uncontrolled bonding of an electrophilic PEG fragment to multiple nucleophiles of an LPEI backbone fragment. Thus, the present invention provides homogenous targeting conjugates with defined chemical structures. The discrete linkages not only ensure consistent and predictable ratios of LPEI to PEG fragments, but further ensure defined linear instead of random branched conjugates. Thus, _{the LPEI fragment is bonded in a linear end-to-end fashion to a single PEG fragment. The} conjugates further comprise targeting fragments linked to the PEG fragments which allow them to target a particular cell type and to facilitate the uptake of the inventive compositions and pharmaceutically active nucleic acids in said particular cell type. Thus, preferred embodiments comprise targeting fragments such as hEGF, DUPA or folate specifically connected to the LPEI-PEG diconjugates to target the corresponding receptors such hEGFR, PSMA or folate receptor on the particular cell types, e.g., cancer cell types, on which said receptors show high expression and are overexpressed. T_{he inventive targeted polyplexes described herein can efficiently and selectively} deliver the components necessary for CRISPR/Cas9 gene editing to a patient in need of treatment. In one aspect, the present invention provides a composition comprising a first polyplex, wherein said first polyplex comprises a first conjugate and a first nucleic acid, and _{P6797PC00 – 2 –} wherein said first conjugate comprises: a linear polyethyleneimine fragment comprising an alpha terminus and an omega terminus; wherein the alpha terminus of said polyethyleneimine fragment is an initiation residue; a polyethylene glycol fragment comprising a first terminal end and a second terminal end; and wherein the omega terminus of the polyethyleneimine fragment is connected to the first terminal end of the polyethylene glycol fragment by a divalent covalent linking group -Z-X¹-, _{wherein -Z-X1- is not a single bond and -Z- is not an amide; and} wherein the second terminal end of the polyethylene glycol fragment is connected to a targeting fragment by a divalent covalent linking moiety X², and wherein said first nucleic acid is a nucleic acid encoding a Cas protein, preferably wherein said Cas protein is Cas9. In one aspect, the present invention provides a composition comprising a first polyplex, wherein said first polyplex comprises a first conjugate and a first nucleic acid, and wherein said first conjugate comprises: a linear polyethyleneimine fragment comprising an alpha terminus and an omega terminus; wherein the alpha terminus of said polyethyleneimine fragment is an initiation residue; a polyethylene glycol fragment comprising a first terminal end and a second terminal end; and wherein the omega terminus of the polyethyleneimine fragment is connected to the first terminal end of the polyethylene glycol fragment by a divalent covalent linking group -Z-X¹-, _{wherein -Z-X1- is not a single bond and -Z- is not an amide; and} wherein the second terminal end of the polyethylene glycol fragment is connected to a targeting fragment by a divalent covalent linking moiety X², and wherein said first nucleic acid is an mRNA encoding a Cas protein, preferably wherein said Cas protein is Cas9. In one aspect, the present disclosure provides a composition as described herein, for use _{in a method of inserting, altering, or modifying a gene and/or altering or modifying its} expression in a subject. _{P6797PC00 – 3 –} In one aspect, the present disclosure provides a method of altering gene expression in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a composition as described herein. In one aspect, the present disclosure provides a composition as described herein for use in a method of treating a disease in a subject. In one aspect, the present disclosure provides a method of treating a disease in a subject, the method comprising administering to the subject a therapeutically effective amount of a composition as described herein. In one aspect, the present disclosure provides the use of a composition as described herein in the manufacture of a medicament for treating a disease in a subject. In one aspect, the present disclosure relates to a kit of parts comprising: (i) a first container comprising a first polyplex comprising a first conjugate and a first nucleic acid; (ii) a second container comprising a second nucleic acid; (iii) optionally a third container comprising a third nucleic acid; and (_{iii) optionally instructions for combining the contents of said first container with said} second container and optionally the contents of said third container. In preferred embodiments, said first nucleic acid is an mRNA encoding a Cas protein, preferably wherein said Cas protein is Cas9. In preferred embodiments, said second nucleic acid is a gRNA. In preferred embodiments, said third nucleic acid is a template DNA. In preferred embodiments, said conjugate is a conjugate of Formula I, preferably LPEI-l- [N₃:DBCO]-PEG₃₆-hEGF. I_{n one aspect, the present disclosure relates to a kit of parts comprising:} (i) a first container comprising a first polyplex comprising a first conjugate and a first nucleic acid; (ii) a second container comprising a second polyplex comprising a second conjugate and a second nucleic acid; (iii) optionally a third container comprising a third polyplex comprising a third conjugate and a third nucleic acid; and (iii) optionally instructions for combining the contents of said first container with said _{second container and optionally the contents of said third container.} In preferred embodiments, said first nucleic acid is an mRNA encoding a Cas protein, preferably wherein said Cas protein is Cas9. In preferred embodiments, said second nucleic _{P6797PC00 – 4 –} acid is a gRNA. In preferred embodiments, said third nucleic acid is a template DNA. In preferred embodiments, said first conjugate is a conjugate of Formula I, preferably LPEI-l- [N3:DBCO]-PEG36-hEGF. In preferred embodiments, said second conjugate is a conjugate of _{Formula I, preferably LPEI-l-[N3:DBCO]-PEG36-hEGF. In preferred embodiments, said third} conjugate is a conjugate of Formula I, preferably LPEI-l-[N₃:DBCO]-PEG₃₆-hEGF. Additional features and advantages of the present technology will be apparent to one of _{skill in the art upon reading the Detailed Description of the Invention, below and further aspects} and embodiments of the present invention will be become apparent as this description continues. B_{RIEF DESCRIPTION OF THE FIGURES} _{FIG 1A is a DLS back scatter plot of polyplexes generated with LPEI-l-[N3:DBCO]-} PEG₃₆-hEGF, Cas9 mRNA and mouse sgTTR at 0.25 mg/mL and N/P 6. FIG 1B is a DLS back scatter plot of polyplexes generated with LPEI-l-[N3:DBCO]- _{PEG36-hEGF, Cas9 mRNA and mouse sgTTR at 0. 5 mg/mL and N/P 8} FIG 2 shows Cas9 expression in RENCA parental and RESC cells using polyplexes _{prepared at a concentration of 0.25 mg/mL and 0.5 mg/mL.} _{FIG 3 is a plot of percent cell survival in RENCA parental cells and RESC cells treated} for 48h with LPEI-l-[N3:DBCO]-PEG36-hEGF polyplexes comprising Cas9 mRNA and mTTR sgRNA at N/P ratios of 6 and 8. F_{IG 4 is a bar graph showing the fold-change in frameshift mutations in RENCA EGFR} _{cells vs. RENCA parental cells following treatment with the inventive polyplexes after 24 h} and 48 h. F_{IG 5A is a Western Blot assay showing the expression of the Cas9 protein after delivery} _{of LPEI-l-[N3:DBCO]-PEG36-hEGF:Cas9 mRNA polyplexes in RENCA parental and RESC} cells. F_{IG 5B is a Western Blot assay showing the expression of the Cas9 protein after delivery} _{of LPEI-l-[N3:DBCO]-PEG36-hEGF:Cas9 mRNA polyplexes in RESC cells.} _{DETAILED DESCRIPTION OF THE INVENTION} Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art to which this invention _{belongs. The herein described and disclosed embodiments, preferred embodiments and very} _{P6797PC00 – 5 –} preferred embodiments should apply to all aspects and other embodiments, preferred embodiments and very preferred embodiments irrespective of whether is specifically again referred to. Definitions Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art to which this disclosure belongs. The articles “a” and “an” are used in this disclosure to refer to one or more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element. The term “and/or” is used in this disclosure to mean either “and” or “or” unless indicated otherwise. T_{he term “about”, as used herein shall have the meaning of +/- 10%. For example about} _{50% shall mean 45% to 55%. Preferably, the term “about”, as used herein shall have the} _{meaning of +/- 5%. For example about 50% shall mean 47.5% to 52.5%.} The phrase "between number X and number Y", as used herein, shall refer to include _{the number X and the number Y. For example, the phrase "between 0.01 ^mol and 50 ^mol”} _{refers to 0.01 ^mol and 50 ^mol and the values in between. The same applies to the phrase} "between about number X and about number Y”. The term “optionally substituted” is understood to mean that a given chemical moiety (e.g. an alkyl group) can (but is not required to) be bonded to other substituents (e.g. heteroatoms). For instance, an alkyl group that is optionally substituted can be a fully saturated alkyl chain (i.e. a pure hydrocarbon). Alternatively, the same optionally substituted alkyl group can have substituents different from hydrogen. For instance, it can, at any point along the chain be bounded to a halogen atom, an alkoxy group, or any other substituent described herein. Thus the term “optionally substituted” means that a given chemical moiety has the potential to contain other functional groups, but does not necessarily have any further functional groups. The term “optionally replaced” is understood to refer to situations in which the carbon _{atom of a methylene group (i.e., -CH2-) can be, but is not required to be, replaced by a} _{heteroatom (e.g., -NH-, -O-). For example, a C3 alkylene (i.e., propylene) group wherein one} _{of the methylene groups is “optionally replaced” can have the structure -CH2-O-CH2- or -O-} CH₂-CH₂-. It will be understood by one of skill in the art that a methylene group cannot be _{P6797PC00 – 6 –} _{replaced when such replacement would result in an unstable chemical moiety. For example,} _{one of skill in the art will understand that four methylene groups cannot simultaneously be} replaced by oxygen atoms. Thus, in some preferred embodiments, when one methylene group of an alkylene fragment is replaced by a heteroatom, one or both of the neighboring carbon atoms are not replaced by a heteroatom. T_{he term “aryl” refers to cyclic, aromatic hydrocarbon groups that have 1 to 2 aromatic} rings, including monocyclic or bicyclic groups such as phenyl, biphenyl or naphthyl. A C6-C10 aryl group contains between 6 and 10 carbon atoms. When containing two aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group may be joined at a single point (e.g., biphenyl), or fused (e.g., naphthyl). The aryl group may be optionally substituted by one or more substituents, e.g., 1 to 5 substituents, at any point of attachment. The substituents can themselves be optionally substituted. Furthermore, when containing two fused rings, the aryl groups herein defined may have an unsaturated or partially saturated ring fused with a fully saturated ring. Exemplary ring systems of these aryl groups include indanyl, indenyl, tetrahydronaphthalenyl, and tetrahydrobenzoannulenyl. In some preferred embodiments, the aryl group is a phenyl group. Unless otherwise specifically defined, “heteroaryl” means a monovalent monocyclic _{aromatic ring of 5 to 24 ring atoms or a polycyclic aromatic ring, containing one or more ring} heteroatoms selected from N, S, P, or O, the remaining ring atoms being C. A 5-10 membered heteroaryl group contains between 5 and 10 atoms. Heteroaryl as herein defined also means a bicyclic heteroaromatic group wherein the heteroatom is selected from N, S, P, or O. The aromatic radical is optionally substituted independently with one or more substituents described herein. Examples include, but are not limited to, furyl, thienyl, pyrrolyl, pyridyl, pyrazolyl, pyrimidinyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl, thiophen-2-yl, quinolyl, benzopyranyl, isothiazolyl, thiazolyl, thiadiazole, indazole, benzimidazolyl, _{thieno[3,2-b]thiophene, triazolyl, triazinyl, imidazo[1,2-b]pyrazolyl, furo[2,3-c]pyridinyl,} imidazo[1,2-a]pyridinyl, indazolyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrazolo[3,4-c]pyridinyl, thieno[3,2-c]pyridinyl, thieno[2,3-c]pyridinyl, thieno[2,3- _{b]pyridinyl, benzothiazolyl, indolyl, indolinyl, indolinonyl, dihydrobenzothiophenyl,} dihydrobenzofuranyl, benzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, dihydrobenzoxanyl, quinolinyl, isoquinolinyl, 1,6-naphthyridinyl, benzo[de]isoquinolinyl, pyrido[4,3-b][1,6]naphthyridinyl, thieno[2,3-b]pyrazinyl, quinazolinyl, tetrazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, isoindolyl, pyrrolo[2,3- _{P6797PC00 – 7 –} b]pyridinyl, pyrrolo[3,4-b]pyridinyl, pyrrolo[3,2-b]pyridinyl, imidazo[5,4-b]pyridinyl, _{pyrrolo[1,2-a]pyrimidinyl, tetrahydro pyrrolo[1,2-a]pyrimidinyl, 3,4-dihydro-2H-1λ2-} pyrrolo[2,1-b]pyrimidine, dibenzo[b,d]thiophene, pyridin-2-one, furo[3,2-c]pyridinyl, furo[2,3-c]pyridinyl, 1H-pyrido[3,4-b][1,4]thiazinyl, benzooxazolyl, benzoisoxazolyl, furo[2,3-b]pyridinyl, benzothiophenyl, 1,5-naphthyridinyl, furo[3,2-b]pyridine, [1,2,4]triazolo[1,5-a]pyridinyl, benzo [1,2,3]triazolyl, imidazo[1,2-a]pyrimidinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazole, 1,3- dihydro-2H-benzo[d]imidazol-2-one, 3,4-dihydro-2H-pyrazolo[1,5-b][1,2]oxazinyl, 4,5,6,7- tetrahydropyrazolo[1,5-a]pyridinyl, thiazolo[5,4-d]thiazolyl, imidazo[2,1- b][1,3,4]thiadiazolyl, thieno[2,3-b]pyrrolyl, 3H-indolyl, and derivatives thereof. Furthermore, when containing two fused rings, the heteroaryl groups herein defined may have an unsaturated or partially saturated ring fused with a fully saturated ring. Exemplary ring systems of these heteroaryl groups include indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, 3,4-dihydro-1H-- isoquinolinyl, 2,3-dihydrobenzofuran, indolinyl, indolyl, and dihydrobenzoxanyl. The term “alkyl” refers to a straight or branched chain saturated hydrocarbon. C1-C6 alkyl groups contain 1 to 6 carbon atoms. Examples of a C1-C6 alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl and neopentyl. The term “alkylene” refers to a straight or branched chain saturated and bivalent hydrocarbon fragment. C0-C6 alkyl groups contain 0 to 6 carbon atoms. Examples of a C0-C6 alkylene group include, but are not limited to, methylene, ethylene, propylene, butylene, pentylene, isopropylene, isobutylene, sec-butylene, tert-butylene, isopentylene, and neopentylene. The term “C1-C6-alkoxy”, as used herein, refers to a substituted hydroxyl of the formula (-OR'), wherein R' is an optionally substituted C1-C6 alkyl, as defined herein, and the oxygen moiety is directly attached to the parent molecule, and thus the term “C1-C6 alkoxy”, as used herein, refers to straight chain or branched C₁-C₆ alkoxy which may be, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, straight or branched pentoxy, straight or branched hexyloxy. Preferred are C1-C4 alkoxy and C1-C3 alkoxy. The term “cycloalkyl” means monocyclic or polycyclic saturated carbon rings _{containing 3-18 carbon atoms. A C3-C8 cycloalkyl contains between 3 and 8 carbon atoms.} Examples of cycloalkyl groups include, without limitations, cyclopropyl, cyclobutyl, _{P6797PC00 – 8 –} cyclopentyl, cyclohexyl, cycloheptanyl, cyclooctanyl, norboranyl, norborenyl, bicyclo[2.2.2]octanyl, or bicyclo[2.2.2]octenyl. A C₃-C₈ cycloalkyl is a cycloalkyl group containing between 3 and 8 carbon atoms. The term “cycloalkenyl” means monocyclic, non-aromatic unsaturated carbon rings _{containing 5-18 carbon atoms. Examples of cycloalkenyl groups include, without limitation,} cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, and norborenyl. A C5-C8 cycloalkenyl is a cycloalkenyl group containing between 5 and 8 carbon atoms. The terms “heterocyclyl” or “heterocycloalkyl” or “heterocycle” refer to monocyclic or polycyclic 3 to 24-membered rings containing carbon and heteroatoms taken from oxygen, nitrogen, or sulfur and wherein there is not delocalized π electrons (aromaticity) shared among the ring carbon or heteroatoms. A 3-10 membered heterocycloalkyl group contains between 3 and 10 atoms. Heterocyclyl rings include, but are not limited to, oxetanyl, azetadinyl, tetrahydrofuranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, and homotropanyl. The term “heterocycloalkenyl” refers to monocyclic or polycyclic 3 to 24-membered rings containing carbon and heteroatoms taken from oxygen, nitrogen, or sulfur and wherein there is not delocalized π electrons (aromaticity) shared among the ring carbon or heteroatoms, but there is at least one element of unsaturation within the ring. A 3-10 membered heterocycloalkenyl group contains between 3 and 10 atoms. As used herein, the term “halo” or “halogen” means fluoro (F), chloro (Cl), bromo (Br), or iodo (I). The term “carbonyl” refers to a functional group composing a carbon atom double- bonded to an oxygen atom. It can be abbreviated herein as “oxo”, as C(O), or as C═O. The term "polyplex" as used herein refers to a complex of a polymer and a nucleic acid typically and preferably formed via electrostatic interactions. In particular, the term "polyplex" as used herein refers to a complex of a conjugate as described herein for the present invention and a nucleic acid preferably wherein said nucleic is an mRNA encoding a Cas protein, preferably Cas9. In preferred embodiments, said nucleic acid is a gRNA and/or a template DNA, wherein said gRNA and/or a template DNA are polyplexed to the same conjugate as the mRNA encoding a Cas protein, or are individually polyplexed to a different conjugate. The term "polyplex" further typically and preferably refers to a vector, in particular a polymeric _{P6797PC00 – 9 –} _{non-viral triconjugate vector as described herein for the present invention useful for carrying} and delivering nucleic acids to the desired targeted cells. Conjugate(s) of Formula I: As used herein, when referring to conjugate(s) of Formula as defined and although the N-N=N fragment of the bicyclic ring in Formula I and corresponding formulae are typically drawn herein using one single bond and one double bond for simplicity, one of skill in the art knows that Formula I and associated conjugate structures as depicted herein can alternatively be drawn as shown with dotted lines over the three nitrogen atoms. Such depictions and descriptions of Formula I are interchangeably used herein: R² I. Thus, the R² represents two different regioisomeric attachments of the fragment , wherein the wavy lines represent formulae as drawn herein encompass two regioisomeric embodiments, i.e., wherein the LPEI fragment R¹(NR²CH2CH2)n i_{s bonded at the top nitrogen atom in the structures above or at the bottom nitrogen atom in the} structures above, but not at the middle nitrogen atom. Thus, the skilled in the art knows that Formula I and corresponding formulae as drawn herein related to and comprising substituted 1,2,3-triazole moieties encompass two regioisomeric embodiments, wherein the LPEI fragment R_{1(NR2CH2CH2)n is bonded – depending on numbering of the nitrogen N atoms in the triazole} _{ring - at the 1-N nitrogen atom in the structures and at the 3-Nitrogen atom in the structures,} but not at the 2-N nitrogen atom. In addition the skilled in the art further knows that the same a_{pplies to other formulae herein, including Formula IA, Formula IB, Formula IC, Formula ID,} Formula IE, Formula IH, Formula IJ, Formula IK and the like. _{P6797PC00 – 10 –} _{The term “overexpression” refers to gene or protein expression within a cell or in a cell} _{surface that is increased relative to basal or normal expression. In a preferred embodiment, said} targeting fragment is capable of binding to a cell overexpressing a cell surface receptor. In one embodiment, said cell overexpressing a cell surface receptor means that the level of said cell surface receptor expressed in said cell of a certain tissue is elevated in comparison to the level of said cell surface receptor as measured in a normal healthy cell of the same type of tissue under analogous conditions. In one embodiment, said cell overexpressing a cell surface receptor refers to an increase in the level of said cell surface receptor in a cell relative to the level in the same cell or closely related non-malignant cell under normal physiological conditions. T_{he term “polyanion”, as used herein, refers to a polymer, preferably a biopolymer,} _{having more than one site carrying a negative charge. Typically and preferably, the term} _{“polyanion”, as used herein, refers to a polymer, preferably a biopolymer, made up of repeating} _{units comprising residues capable of bearing negative charge. In further embodiments, a} _{polyanion is a polymer, preferably a biopolymer, made up of repeating units comprising} _{negatively charged residues.} _{The term “nucleic acid” as used herein, comprises deoxyribonucleic acid (DNA) and/or} _{ribonucleic acid (RNA) or a combination thereof. In a preferred embodiment, the term “nucleic} acid” refers to an mRNA encoding a Cas protein, preferably Cas9. In preferred embodiments, said nucleic acid is a gRNA. In other preferred embodiments, said nucleic acid is a template DNA. In some embodiments, “nucleic acid” refers to recombinantly prepared and chemically synthesized molecules. A nucleic acid may be in the form of a single stranded or double- stranded (preferably single stranded), and may comprise a chemical derivatization of a nucleic acid on a nucleotide base, on the sugar or on the phosphate, and may contain non-natural nucleotides and nucleotide analogs. The term “dispersity” (abbreviated as D), as used herein refers to the distribution of the molar mass in a given polymeric sample such as in polymeric fragments as used herein for the _{inventive conjugates and polyplexes. It is defined herein as D = (Mw/Mn), wherein D is} dispersity; M_w is the weight average molecular weight of the polymeric sample or polymeric fragment; and Mn is the number average molecular weight of the polymeric sample or polymeric fragment. The term "weight average molecular weight", as used herein refers to the sum of the products of the weight fraction for a given molecule in the mixture times the mass of the molecule for each molecule in the mixture and is typically and preferably represented by the _{P6797PC00 – 11 –} _{symbol Mw. Typically and preferably, the weight average molecular weight for a given} polymeric, typically and preferably for a given polymeric sample of the polymeric LPEI fragments and polymeric PEG fragments, as used herein for the inventive conjugates, is determined by GPC or DLS, further typically and preferably by GPC. T_{he term "number average molecular weight", as used herein refers to the total weight} of a mixture divided by the number of molecules in the mixture and is typically and preferably represented by the symbol Mn. The term “LPEI fragment”, as used herein, typically and preferably refers to moieties _{having the chemical formula –[NR2-CH2-CH2]n–, wherein n represents the number of} monomeric and repeating units, and preferably the term “LPEI fragment”, as used herein, refers to linear polyethyleneimine (LPEI) moieties having the chemical formula –[NH-CH₂-CH₂]_n–, wherein n represents the number of monomeric and repeating units. When characterizing the LPEI fragments herein by way of its molecular weight it is, unless indicated differently, referred _{to weight average molecular weight even though it may be referred to “molecular weight” for} the sake of simplicity. The terms “PEG fragment”, as used herein refers to polyethylene glycol moieties having _{the chemical formula –[CH2-CH2-O]m–, wherein m represents the number of monomeric units.} The term “repeating units” as used herein and referring to the LPEI fragment and/or the PEG fragment or parts thereof, shall refer to the number of repeating units of the LPEI fragment and/or the PEG fragment or parts thereof, which is typically associated with abbreviations such _{as “m”, “n” and the like and which values are expressed as integers. In case of polymeric LPEI} fragments and/or polymeric PEG fragments or parts thereof, the referral to “repeating units” _{and to the associated abbreviations such as “m”, “n” and the like typically and preferably refers} to “weight average repeating units” even if it is solely referred herein to as “repeating units” for the sake of simplicity. Such “weight average repeating units” correspond to and are calculated _{based on the "weight average molecular weight" of the LPEI fragment and/or the PEG} fragments or parts thereof as defined and determined herein. In case of non-polymeric PEG fragments, the term repeating units is typically used with the further clarification referring to a _{discrete number of repeating units or even to a discrete number of contiguous repeating units.} _{The term “polydispersity index” (abbreviated as PDI) as used herein refers to the} polydispersity index in dynamic light scattering measurements of polyplex nanoparticles such as the polyplexes in accordance with the present invention. This index is a number calculated _{from a simple 2 parameter fit to the correlation data (the cumulants analysis). The polydispersity} _{P6797PC00 – 12 –} index is dimensionless and scaled such that values smaller than 0.05 are rarely seen other than with highly monodisperse standards. Values greater than 0.7 indicate that the sample has a very broad size distribution and is probably not suitable for the dynamic light scattering (DLS) technique. The various size distribution algorithms work with data that falls between these two _{extremes. The zeta-average diameter (z-average diameter) and polydispersity index of the} inventive polyplexes are determined by Dynamic Light Scattering (DLS), based on the assumption that said polyplexes are isotropic and spherically shaped. The calculations for these _{parameters are defined and determined according to ISO standard document ISO 22412:2017.} The term “amino acid residue” refers to a divalent residue derived from an organic compound containing the functional groups amine (-NH2) and carboxylic acid (-COOH), typically and preferably, along with a side chain specific to each amino acid. In a preferred embodiment of the present invention, an amino acid residue is divalent residue derived from an organic compound containing the functional groups amine (-NH₂) and carboxylic acid (- _{COOH), wherein said divalence is effected with said amine and said carboxylic acid functional} _{group, and thus by –NH- and –CO- moieties. In alternative preferred embodiment of the present} invention, an amino acid residue is a divalent residue derived from an organic compound containing the functional groups amine (-NH2) and carboxylic acid (-COOH), wherein said divalence is effected with said amine or said carboxylic acid functional group, and with a further functional group present in said amino acid residue. By way of a preferred example and embodiment, an amino acid residue in accordance with the present invention derived from cysteine includes the divalent structure –S-(CH2)-CH(COOH)-NH-, wherein said divalence is effected by the amino functionality and the comprised thiol functionality. The term “amino acid residue”, as used herein typically and preferably includes amino acid residues derived from naturally occurring or non-naturally occurring amino acids. Furthermore, the term “amino acid _{residue”, as used herein, typically and preferably also includes amino acid residues derived} _{from unnatural amino acids that are chemically synthesized including alpha-(α-), beta-(β-),} gamma-(γ-) or delta-(δ-) etc. amino acids as well as mixtures thereof in any ratio. In addition, the term “amino acid residue”, as used herein, typically and preferably also includes amino acid residues derived from alpha amino acids including any isomeric form thereof, in particular its D-stereoisomers and L-stereoisomers (alternatively addressed by the (R) and (S) nomenclature), as well as mixtures thereof in any ratio, preferably in a racemic ratio of 1:1. The term “D-stereoisomer”, “L-stereoisomer”, “D-amino acid” or “L-amino acid” refers to the chiral alpha carbon of the amino acids. Thus, in a preferred embodiment, said amino acid _{P6797PC00 – 13 –} residue is a divalent group of the structure -NH-CHR-C(O)-, wherein R is an amino acid side chain. Two or more consecutive amino acid residues preferably form peptide (i.e., amide) bonds at both the amine portion and the carboxylic acid portion of the amino acid residues _{respectively. When di, tri or polypeptides are described herein as amino acid residues, typically} _{as (AA)a, the provided sequence is depicted from left to right in the N-C direction. Thus, and} by way of example the (AA)a being Trp-Trp-Gly should refer to an amino acid residue, wherein _{Trp corresponds to the N-terminus of said tripeptide with a –NH- valence, and wherein Gly} _{corresponds to the C-terminus of said tripeptide with a –CO- valence.} _{The terms “peptide”, “polypeptide” and “protein”, as used herein refers to substances} which comprise about two or more consecutive amino acid residues linked to one another via peptide bonds. The terms "peptide," "polypeptide," and "protein" are used interchangeably _{herein to refer to polymers of amino acid residues of any length. In one embodiment, the term} "protein" refers to large peptides, in particular peptides having at least about 151 amino acids, while in one embodiment, the term "peptide" refers to substances which comprise about two or _{more, about 3 or more, about 8 or more, or about 20 or more, and up to about 50, about 100 or} about 150. The term "disease-associated antigen", as used herein, refers in its broadest sense to refer to any antigen associated with a disease. A disease-associated antigen is a molecule which contains epitopes that will stimulate a host's immune system to make a cellular antigen-specific immune response and/or a humoral antibody response against the disease. The disease- associated antigen or an epitope thereof may therefore be used for therapeutic purposes. Disease-associated antigens may be associated with infection by microbes, typically microbial antigens, or associated with cancer, typically tumors. The term "viral antigen", as used herein, refers to any viral component having antigenic properties, i.e. being able to provoke an immune response in an individual. The viral antigen may be a viral ribonucleoprotein or an envelope protein. The term "bacterial antigen", as used herein, refers to any bacterial component having antigenic properties, i.e. being able to provoke an immune response in an individual. The bacterial antigen may be derived from the cell wall or cytoplasm membrane of the bacterium. The term "epitope", as used herein, refers to a part or fragment of a molecule such as an _{antigen that is recognized by the immune system. For example, the epitope may be recognized} by T cells, B cells or antibodies. An epitope of an antigen preferably comprises a continuous or discontinuous portion of said protein and is preferably between 5 and 100, preferably between _{P6797PC00 – 14 –} 5 and 50, more preferably between 8 and 30, most preferably between 10 and 25 amino acids _{in length, for example, the epitope may be preferably 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,} _{20, 21, 22, 23, 24, or 25 amino acids in length. In one embodiment, an epitope is between about} 10 and about 25 amino acids in length. The term "epitope" includes T cell epitopes. The term "T cell epitope", as used herein, refers to a part or fragment of a protein that is recognized by a T cell when presented in the context of MHC molecules. The term "major histocompatibility complex" and the abbreviation "MHC" includes MHC class I and MHC class II molecules and relates to a complex of genes which is present in all vertebrates. MHC proteins or molecules are important for signaling between lymphocytes and antigen presenting cells or diseased cells in immune reactions, wherein the MHC proteins or molecules bind peptide epitopes and present them for recognition by T cell receptors on T cells. The proteins encoded by the MHC are expressed on the surface of cells, and display both self-antigens (peptide fragments from the cell itself) and non-self-antigens (e.g., fragments of invading microorganisms) to a T cell. The term “antibody” refers to any immunoglobulin, whether natural or wholly or partially synthetically produced and to derivatives thereof and characteristic portions thereof. An antibody may be monoclonal or polyclonal. An antibody may be a member of any immunoglobulin class, including any of the human classes: IgG, IgM, IgA, IgD, and IgE. As used herein, an antibody fragment (i.e. characteristic portion of an antibody) refers to any _{derivative of an antibody which is less than full-length. In general, an antibody fragment retains} at least a signiﬁcant portion of the full-length antibody’s speciﬁc binding ability. Examples of antibody fragments include, but are not limited to, single chain and double strain fragments, Fab, Fab’, F(ab’)2, scFv, Fv, dsFv diabody, and Fd fragments. An antibody fragment may be produced by any means. For example, an antibody fragment may be enzymatically or chemically produced by fragmentation of an intact antibody and/or it may be recombinantly produced from a gene encoding the partial antibody sequence. Alternatively or additionally, an antibody fragment may be wholly or partially synthetically produced. An antibody fragment may optionally comprise a single chain antibody fragment. Alternatively or additionally, an antibody fragment may comprise multiple chains which are linked together, for example, by disulﬁde linkages. An antibody fragment may optionally comprise a multimolecular complex. A functional antibody fragment will typically comprise at least about 50 amino acids and more typically will comprise at least about 200 amino acids. In some embodiments, antibodies may include chimeric (e.g. “humanized”) and single chain (recombinant) antibodies. In some embodiments, antibodies may have reduced effector functions and/or bispeciﬁc molecules. In _{P6797PC00 – 15 –} some embodiments, antibodies may include fragments produced by a Fab expression library. Single-chain Fvs (scFvs) are recombinant antibody fragments consisting of only the variable light chain (VL) and variable heavy chain (VH) covalently connected to one another by a polypeptide linker. Either VL or VH may comprise the NH2-terminal domain. The polypeptide linker may be of variable length and composition so long as the two variable domains are bridged without signiﬁcant steric interference. Typically, linkers primarily comprise stretches of glycine and serine residues with some glutamic acid or lysine residues interspersed for solubility. Diabodies are dimeric scFvs. Diabodies typically have shorter peptide linkers than most scFvs, and they often show a preference for associating as dimers. An Fv fragment is an antibody fragment which consists of one VH and one VL domain held together by noncovalent _{interactions. The term “dsFv” as used herein refers to an Fv with an engineered intermolecular} disulﬁde bond to stabilize the VH-VL pair. A F(ab’)2 fragment is an antibody fragment essentially equivalent to that obtained from immunoglobulins by digestion with an enzyme pepsin at pH 4.0-4.5. The fragment may be recombinantly produced. A Fab’ fragment is an antibody fragment essentially equivalent to that obtained by reduction of the disulﬁde bridge or bridges joining the two heavy chain pieces in the F(ab’)2 fragment. The Fab’ fragment may be recombinantly produced. l. A Fab fragment is an antibody fragment essentially equivalent to that obtained by digestion of immunoglobulins with an enzyme (e.g. papain). The Fab fragment may be recombinantly produced. The heavy chain segment of the Fab fragment is the Fd sub- fragment. The term “alpha terminus of the linear polyethyleneimine fragment” (^-terminus of LPEI fragment), as used herein, refers to the terminal end of the LPEI fragment where initiation of polymerization occurs using electrophilic initiators as further described below for the term “initiation residue”. The term “omega terminus of the linear polyethyleneimine fragment” (^-terminus of _{LPEI fragment) as used herein, refers to the terminal end of the LPEI fragment where} termination of polymerization occurs using nucleophiles such as azides, thiol and other _{nucleophiles as described herein.} The term “organic residue” refers to any suitable organic group capable of binding to _{the nitrogen atoms embedded within LPEI fragments. In preferred embodiments the organic} residue is connected to the nitrogen atom via a carbonyl group to form an amide linkage. _{Without wishing to be bound by theory, said organic residue is incorporated on the nitrogen} _{atoms of poly(2-oxazoline) during ring-opening polymerization 2-oxazoline (see, e.g., Glassner} _{P6797PC00 – 16 –} et al., (2018), Poly(2-oxazoline)s: A comprehensive overview of polymer structures and their _{physical properties. Polym. Int, 67: 32-45. https://doi.org/10.1002/pi.5457). Typically and} _{preferably, said organic residue is cleaved (i.e., typically said amide is cleaved) from the poly(2-} _{oxazoline) to yield LPEI and LPEI fragments and thus -(NH-CH2-CH2)–moieties embedded} _{within the conjugates of the present invention. However, in case said cleavage reaction is not} _{complete a fraction of said organic residue is not cleaved. Thus, in preferred embodiments of} the invention at least 80%, preferably 90% of R² in the R¹-(NR²-CH2-CH2)n–moieties of the conjugates of the present invention including the ones of Formula I* and I is H, preferably at least 91%, more preferably 92%, more preferably 93%, more preferably 94%, more preferably _{95%, more preferably 96%, more preferably 97%, more preferably 98%, and most preferably} 99%, of R² in the R¹-(NR²-CH₂-CH₂)_n–moieties of the conjugates of the present invention including the ones of Formula I* or I is H. T_{he term “initiation residue” refers to the residue present in the LPEI fragment and the} R¹-(NR²-CH2-CH2)n–moieties of the conjugates of the present invention, which residue derives from any initiator, typically and preferably any electrophilic initiator, capable of initiating the _{polymerization of poly(2-oxazoline) from 2-oxazoline. As set forth in Glassner et al., (2018),} Poly(2-oxazoline)s: A comprehensive overview of polymer structures and their physical properties. Polym. Int, 67: 32-45. https://doi.org/10.1002/pi.5457, “different initiator systems _{can be used including toluenesulfonic acid (TsOH) or alkyl sulfonates such as methyl p-} toluenesulfonate (MeOTs), which is most frequently found in literature, p- _{nitrobenzenesulfonates (nosylates) and trifluoromethanesulfonates (triflates), alkyl, benzyl and} acetyl halides, oxazolinium salts and lewis acids.” Accordingly, although in preferred embodiments R¹ is -H or -CH3, one of skill in the art will understand that R¹ can also include _{but is not limited to other suitable residues such as a Cn alkyl group wherein n is greater than 1,} typically a C1-6 alkyl group, a benzyl group, or an acetyl group. T_{he present invention provides targeting polyplexes comprising (i) nucleic acids,} wherein said nucleic acids encode components for gene editing using CRISPR/Cas9, preferably _{mRNA encoding the Cas9 protein, and (ii) targeting conjugates, preferably comprising LPEI} and PEG fragments that are connected by discrete linkages formed through defined, chemoselective reactions instead of through random and uncontrolled bonding of an electrophilic PEG fragment to multiple nucleophiles of an LPEI backbone fragment. The discrete linkages not only ensure consistent and predictable ratios of LPEI to PEG fragments, _{but further ensure defined linear instead of random branched conjugates. Thus, the LPEI} _{P6797PC00 – 17 –} fragment is bonded in a linear end-to-end fashion to a single PEG fragment. The chemoselective bonding of the LPEI fragments to the PEG fragments can take place using any suitable chemical precursors that can form a chemoselective bond. In preferred embodiments, the chemoselective bonding of LPEI fragments to PEG fragments takes place by means of a [3+2] cycloaddition between an azide and an alkyne or alkene. Alternatively, said chemoselective bonding is by means of a thiol-ene reaction between a thiol and an alkene. When the chemoselective bond is between an azide and an alkyne or alkene, the resulting linkage is a 1,2,3-triazole (when an alkyne is coupled) or a 4,5-dihydro-1H-[1,2,3]triazole (when an alkene is coupled). When the chemoselective bond is between a thiol and an alkene, the resulting linkage is a thioether. The conjugates further comprise targeting fragments linked to the PEG fragments which allow to target a particular cell type and to facilitate the uptake of the inventive compositions and pharmaceutically active nucleic acids in said particular cell type. Thus, preferred embodiments comprise targeting fragments such as hEGF, DUPA or folate specifically connected to the LPEI-PEG diconjugates to target the corresponding receptors such hEGFR, PSMA or folate receptor on the particular cell types, typically cancer cell types, on which said receptors show high expression and are overexpressed. Further advantageously and surprisingly, the inventors have found that the resulting preferred conjugates and polyplexes in accordance with the present invention which have a significant reduced heterogeneity due to the defined chemoselective bonding of the LPEI _{fragments to the PEG fragments, and thus, which have a significant reduced number of} potentially biologically active conjugates and polyplexes, not only form polyplexes of suitable size, but also are expected to maintain or even increase their overall biological activity such as highly selective targeted delivery of the nucleic acid components for gene editing using CRISPR/Cas9. Thus, the inventive compositions and polyplexes do not only selectively deliver nucleic acid components for gene editing using CRISPR/Cas9 (e.g., mRNA encoding a Cas _{protein such as Cas9) to the targeted cells, in particular cancer cells, but furthermore, said} _{delivery is expected to result in high expression of the Cas protein and efficient gene editing} using CRISPR/Cas9. Moreover, it is expected that the polyplexes disclosed herein can comprise various nucleic acids (e.g., mRNA encoding a Cas protein such as Cas9; a gRNA; and or a template _{DNA) in various combinations with no loss of efficacy. For example, as set forth below, a} composition can comprise a polyplex comprising more than one nucleic acid (e.g., mRNA _{encoding a Cas protein such as Cas9; a gRNA; and optionally a template DNA). Accordingly,} _{P6797PC00 – 18 –} in some embodiments, a single polyplex can comprise all of the necessary nucleic acids necessary to carry out gene editing using CRISPR/Cas9. I_{n other embodiments, a composition can comprise multiple polyplexes containing} _{different nucleic acids, wherein the polyplexes are prepared individually and mixed together.} For instance, a composition can comprise a first polyplex comprising a first conjugate and an mRNA encoding a Cas protein such as Cas9, and a second polyplex comprising a second conjugate and a gRNA. The composition can optionally comprise a third polyplex comprising _{a third conjugate and a template DNA. In preferred embodiments, when multiple polyplexes} are used, the conjugates comprising the conjugates all comprise the same targeting fragment and are thus all targeted to the same cell type. In preferred embodiments, when multiple polyplexes are used, the various polyplexes can be mixed together prior to administration (e.g., to a subject or a cell). In some embodiments, when multiple polyplexes are used, the various polyplexes can be co-administered to a subject or a cell. I_{n some embodiments, said nucleic acid capable of eliciting gene editing or said nucleic} _{acid encoding a protein capable of gene eliciting editing is a small nuclear RNA (snRNa); a} _{nucleic acid encoding a base editor; a transcription activator-like effector nuclease (TALEN);} a zinc-finger nuclease (ZFN); or a combination thereof. In some embodiments, said first nucleic acid can be a nucleic acid encoding a Cas protein, e.g., a DNA encoding a Cas protein such as Cas9. In some embodiments, said first nucleic acid is an RNA encoding a Cas protein, e.g., Cas9. In one aspect, the present invention provides a composition comprising a polyplex, wherein said polyplex comprises a first conjugate, a first polyanion, and a second polyanion; wherein said first conjugate comprises: a linear polyethyleneimine fragment comprising an alpha terminus and an omega terminus; wherein the alpha terminus of said polyethyleneimine fragment is an initiation residue; a polyethylene glycol fragment comprising a first terminal end and a second terminal _{end; and} wherein the omega terminus of the polyethyleneimine fragment is connected to the first terminal end of the polyethylene glycol fragment by a divalent covalent linking group -Z-X¹-, _{wherein -Z-X1- is not a single bond and -Z- is not an amide; and} wherein the second terminal end of the polyethylene glycol fragment is connected to a targeting fragment by a divalent covalent linking moiety X². In some embodiments, said first _{P6797PC00 – 19 –} polyanion is a nucleic acid. In some embodiments, said second polyanion is a nucleic acid. In some embodiments, the first conjugate is a conjugate of the Formula I. In one aspect, the present disclosure provides a composition comprising a first polyplex, wherein said first polyplex comprises a first conjugate and a first nucleic acid, and wherein said first conjugate comprises: a linear polyethyleneimine fragment comprising an alpha terminus and an omega terminus; wherein the alpha terminus of said polyethyleneimine fragment is an initiation residue; a polyethylene glycol fragment comprising a first terminal end and a second terminal end; and wherein the omega terminus of the polyethyleneimine fragment is connected to the first terminal end of the polyethylene glycol fragment by a divalent covalent linking group -Z-X¹-, _{wherein -Z-X1- is not a single bond and -Z- is not an amide; and} wherein the second terminal end of the polyethylene glycol fragment is connected to a targeting fragment by a divalent covalent linking moiety X², and wherein said first nucleic acid is an mRNA encoding a Cas protein, preferably wherein _{said Cas protein is Cas9. In preferred embodiments, said first nucleic acid is preferably non-} covalently bound to said conjugate. In some embodiments, said first conjugate is of the Formula I* or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or enantiomer thereof R_{1-(NR2-CH2-CH2)n-Z-X1-(O-CH2-CH2)m-X2-L (Formula I*);} wherein n is any integer between 1 and 1500; m is any integer between 1 and 200; R¹ is an initiation residue, wherein preferably R¹ is -H or -CH3; R² is independently -H or an organic residue, wherein at least 80%, preferably 90%, of _{said R2 in said -(NR2-CH2-CH2)n- is H;} X¹ and X² are independently divalent covalent linking moieties; Z is a divalent covalent linking moiety wherein Z is not a single bond and Z is not - NHC(O)-; L is a targeting fragment, wherein preferably said targeting fragment is capable of binding to a cell. _{P6797PC00 – 20 –} In some embodiments, said first conjugate is of the Formula I, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or enantiomer thereof. As used herein, Formula I is understood as: R² L wherein: i_{s a single bond or a double bond, preferably a double bond;} n is any integer between 1 and 1500; m is any integer between 1 and 200; R¹ is an initiation residue, wherein preferably R¹ is -H or -CH3; R² is independently -H or an organic residue, wherein at least 80%, preferably wherein at _{least 90%, of said R2 in said -(NR2-CH2-CH2)n– is H, further preferably said R2 is H;} Ring A is a 5 to 10-membered cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl, optionally substituted with one or more R^A1; R^A1 is independently selected from C1-C6 alkyl, C1-C6 alkoxy, oxo, or halogen; or two R^A1, together with the atoms to which they are attached, can combine to form one or more fused C₆-C₁₀ aryl, C₅-C₆ heteroaryl, or C₃- C6 cycloalkyl rings, wherein each fused aryl, heteroaryl, or cycloalkyl is optionally substituted with one or more R^A2; R^A2 is independently selected from C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen - SO3H, or -OSO3H; X¹ is a divalent covalent linking moiety; X² is a divalent covalent linking moiety; and L is a targeting fragment, wherein preferably said targeting fragment is capable of binding to a cell. I_{n some embodiments of Formula I or Formula I*, said -(O-CH2-CH2)m-moiety consists} of a discrete number of repeating units m of 4 to 60, wherein preferably said discrete number _{m of repeating -(O-CH2-CH2)- units is 36.} In preferred embodiments, said conjugate of Formula I (e.g., said first, second or third conjugate) is LPEI-l-[N3:DBCO]-PEG36-hEGF, preferably wherein said LPEI-l-[N3:DBCO]- PEG₃₆-hEGF has the structure: _{P6797PC00 – 21 –} H _{O O} O L ; H _{O O} O L hEGF, preferably wherein said LPEI-l-[N3:DBCO]-PEG36-hEGF has the structure: H _{O O} O ; _the regioisomers: H _{O O} O _{P6797PC00 – 22 –} _{O O} O . second nucleic acid is a gRNA. In some embodiments, a ratio of said first nucleic acid to said second nucleic acid is 1:1 (w/w). In some embodiments, the first polyplex comprises a first conjugate, a first nucleic acid and a second nucleic acid. In preferred embodiments, the first nucleic acid is an mRNA encoding a Cas protein, preferably wherein said Cas protein is Cas9. In preferred embodiments, the second nucleic acid is a guide RNA (gRNA). In preferred embodiments, said conjugate is LPEI-l-[N₃:DBCO]-PEG₃₆-hEGF. In some embodiments, a ratio of the first nucleic acid to the second nucleic acid within the polyplex is in a range from about 1:10 to about 10:1. In some embodiments, a ratio of the first nucleic acid to the second nucleic acid within the polyplex is 1:10 (w/w). In some embodiments, a ratio of the first nucleic acid to the second nucleic acid within the polyplex is 2:10 (w/w). In some embodiments, a ratio of the first nucleic acid to the second nucleic acid within the polyplex is 3:10 (w/w). In some embodiments, a ratio of the first nucleic acid to the second nucleic acid within the polyplex is 4:10 (w/w). In some embodiments, a ratio of the first nucleic acid to the second nucleic acid within the polyplex is 5:10 (w/w). In some _{embodiments, a ratio of the first nucleic acid to the second nucleic acid within the polyplex is} 6:10 (w/w). In some embodiments, a ratio of the first nucleic acid to the second nucleic acid within the polyplex is 7:10 (w/w). In some embodiments, a ratio of the first nucleic acid to the second nucleic acid within the polyplex is 8:10 (w/w). In some embodiments, a ratio of the first nucleic acid to the second nucleic acid within the polyplex is 9:10 (w/w). In some embodiments, a ratio of the first nucleic acid to the second nucleic acid within the polyplex is 1:1 (w/w). In some embodiments, a ratio of the first nucleic acid to the second nucleic acid within the polyplex is 10:9 (w/w). In some embodiments, a ratio of the first nucleic acid to the second nucleic acid within the polyplex is 10:8 (w/w). In some embodiments, a ratio of the first nucleic acid to the second nucleic acid within the polyplex is 10:7 (w/w). In some embodiments, a ratio of the first nucleic acid to the second nucleic acid within the polyplex is _{P6797PC00 – 23 –} 10:6 (w/w). In some embodiments, a ratio of the first nucleic acid to the second nucleic acid within the polyplex is 10:5 (w/w). In some embodiments, a ratio of the first nucleic acid to the second nucleic acid within the polyplex is 10:4 (w/w). In some embodiments, a ratio of the first nucleic acid to the second nucleic acid within the polyplex is 10:3 (w/w). In some embodiments, a ratio of the first nucleic acid to the second nucleic acid within the polyplex is 10:2 (w/w). In some embodiments, a ratio of the first nucleic acid to the second nucleic acid within the polyplex is 10:1 (w/w). In some embodiments, said first polyplex comprises a third nucleic acid, preferably wherein said third nucleic acid is a template DNA. In preferred embodiments, the first nucleic acid is an mRNA encoding a Cas protein, preferably wherein said Cas protein is Cas9. In preferred embodiments, the second nucleic acid is a guide RNA (gRNA). In preferred embodiments, the third nucleic acid is a template DNA. In preferred embodiments, said conjugate is LPEI-l-[N₃:DBCO]-PEG₃₆-hEGF. In some embodiments, a ratio of said first nucleic acid to said second nucleic acid to said third nucleic acid is 1:1:1 (w/w). In some embodiments, the first polyplex comprises a first conjugate, a first nucleic acid, a second nucleic acid, and a third nucleic acid. In some embodiments, a ratio of the first nucleic acid to the second nucleic acid within the polyplex is in a range from about 1:10 to about 10:1. In some embodiments, a ratio of the first nucleic acid to the second nucleic acid within the polyplex is 1:10 (w/w). In some embodiments, a ratio of the first nucleic acid to the second nucleic acid within the polyplex is 2:10 (w/w). In some embodiments, a ratio of the first nucleic acid to the second nucleic acid within the polyplex is 3:10 (w/w). In some embodiments, a ratio of the first nucleic acid to the second nucleic acid within the polyplex is 4:10 (w/w). In some embodiments, a ratio of the first nucleic acid to the second nucleic acid within the polyplex is 5:10 (w/w). In some embodiments, a ratio of the first nucleic acid to the second nucleic acid within the polyplex is 6:10 (w/w). In some embodiments, a ratio of the first nucleic acid to the second nucleic acid within the polyplex is 7:10 (w/w). In some embodiments, a ratio of the first nucleic acid to the second nucleic acid within the polyplex is 8:10 (w/w). In some _{embodiments, a ratio of the first nucleic acid to the second nucleic acid within the polyplex is} 9:10 (w/w). In some embodiments, a ratio of the first nucleic acid to the second nucleic acid within the polyplex is 1:1 (w/w). In some embodiments, a ratio of the first nucleic acid to the second nucleic acid within the polyplex is 10:9 (w/w). In some embodiments, a ratio of the first nucleic acid to the second nucleic acid within the polyplex is 10:8 (w/w). In some _{P6797PC00 – 24 –} embodiments, a ratio of the first nucleic acid to the second nucleic acid within the polyplex is 10:7 (w/w). In some embodiments, a ratio of the first nucleic acid to the second nucleic acid within the polyplex is 10:6 (w/w). In some embodiments, a ratio of the first nucleic acid to _{the second nucleic acid within the polyplex is 10:5 (w/w). In some embodiments, a ratio of} the first nucleic acid to the second nucleic acid within the polyplex is 10:4 (w/w). In some embodiments, a ratio of the first nucleic acid to the second nucleic acid within the polyplex is 10:3 (w/w). In some embodiments, a ratio of the first nucleic acid to the second nucleic acid within the polyplex is 10:2 (w/w). In some embodiments, a ratio of the first nucleic acid to the second nucleic acid within the polyplex is 10:1 (w/w). In some embodiments, a ratio of the second nucleic acid to the third nucleic acid within the polyplex is in a range from about 1:10 to about 10:1. In some embodiments, a ratio of the second nucleic acid to the third nucleic acid within the polyplex is 1:10 (w/w). In some embodiments, a ratio of the second nucleic acid to the third nucleic acid within the polyplex is 2:10 (w/w). In some embodiments, a ratio of the second nucleic acid to the third nucleic acid within the polyplex is 3:10 (w/w). In some embodiments, a ratio of the second nucleic acid to the third nucleic acid within the polyplex is 4:10 (w/w). In some embodiments, a ratio of the second nucleic acid to the third nucleic acid within the polyplex is 5:10 (w/w). In some embodiments, a ratio of the second nucleic acid to the third nucleic acid within the polyplex is 6:10 (w/w). In some embodiments, a ratio of the second nucleic acid to the third nucleic acid within the polyplex is 7:10 (w/w). In some embodiments, a ratio of the second nucleic acid to the third nucleic acid within the polyplex is 8:10 (w/w). In some embodiments, a ratio of the second nucleic acid to the third nucleic acid within the polyplex is 9:10 (w/w). In some embodiments, a ratio of the second nucleic acid to _{the third nucleic acid within the polyplex is 1:1 (w/w). In some embodiments, a ratio of the} second nucleic acid to the third nucleic acid within the polyplex is 10:9 (w/w). In some embodiments, a ratio of the second nucleic acid to the third nucleic acid within the polyplex is 10:8 (w/w). In some embodiments, a ratio of the second nucleic acid to the third nucleic acid within the polyplex is 10:7 (w/w). In some embodiments, a ratio of the second nucleic acid to the third nucleic acid within the polyplex is 10:6 (w/w). In some embodiments, a ratio of the second nucleic acid to the third nucleic acid within the polyplex is 10:5 (w/w). In some embodiments, a ratio of the second nucleic acid to the third nucleic acid within the polyplex is 10:4 (w/w). In some embodiments, a ratio of the second nucleic acid to the third nucleic acid within the polyplex is 10:3 (w/w). In some embodiments, a ratio of the second nucleic acid to _{P6797PC00 – 25 –} the third nucleic acid within the polyplex is 10:2 (w/w). In some embodiments, a ratio of the second nucleic acid to the third nucleic acid within the polyplex is 10:1 (w/w). In one aspect, said composition comprises a second polyplex, wherein said second polyplex comprises a second conjugate and a second nucleic acid, wherein said second conjugate comprises: a linear polyethyleneimine fragment comprising an alpha terminus and an omega terminus; wherein the alpha terminus of said polyethyleneimine fragment is an initiation residue; a polyethylene glycol fragment comprising a first terminal end and a second terminal _{end; and} wherein the omega terminus of the polyethyleneimine fragment is connected to the first terminal end of the polyethylene glycol fragment by a divalent covalent linking group -Z-X¹-, _{wherein -Z-X1- is not a single bond and -Z- is not an amide; and} wherein the second terminal end of the polyethylene glycol fragment is connected to a targeting fragment by a divalent covalent linking moiety X², and wherein said second nucleic acid is a gRNA. In some embodiments, the second conjugate is of the Formula I*, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or enantiomer thereof. In some embodiments, the second conjugate is of the Formula I, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or enantiomer thereof. In some embodiments, said -(O-CH2-CH2)m-moiety of said second conjugate of Formula I* or Formula I consists of a discrete number of repeating units m of 4 to 60, wherein _{preferably said discrete number m of repeating -(O-CH2-CH2)- units is 36.} In some embodiments, said conjugate of Formula I is LPEI-l-[N₃:DBCO]-PEG₃₆-hEGF, preferably wherein said LPEI-l-[N3:DBCO]-PEG36-hEGF has the structure: H _{O O} O ; the regioisomers: _{P6797PC00 – 26 –} H _{O O} O . conjugate and a first nucleic acid; and a second polyplex comprising a second conjugate and a _{second nucleic acid.} In preferred embodiments, the first nucleic acid is an mRNA encoding a Cas protein, preferably wherein said Cas protein is Cas9. In preferred embodiments, the second nucleic acid is a guide RNA (gRNA). In preferred embodiments, said first conjugate is LPEI-l-[N3:DBCO]- PEG₃₆-hEGF. In preferred embodiments, said second conjugate is LPEI-l-[N₃:DBCO]-PEG₃₆- hEGF. In some embodiments, a ratio of the first nucleic acid to the second nucleic acid is 1:1 (w/w). In preferred embodiments, a ratio of the first nucleic acid in said first polyplex to the second nucleic acid in said second polyplex is 1:1 (w/w). In some embodiments, a ratio of the first nucleic acid to the second nucleic acid within the composition is in a range from about 1:10 to about 10:1. In some embodiments, a ratio of the first nucleic acid to the second nucleic acid within the composition is 1:10 (w/w). In some embodiments, a ratio of the first nucleic _{acid to the second nucleic acid within the composition is 2:10 (w/w). In some embodiments, a} ratio of the first nucleic acid to the second nucleic acid within the composition is 3:10 (w/w). In some embodiments, a ratio of the first nucleic acid to the second nucleic acid within the _{composition is 4:10 (w/w). In some embodiments, a ratio of the first nucleic acid to the second} nucleic acid within the composition is 5:10 (w/w). In some embodiments, a ratio of the first nucleic acid to the second nucleic acid within the composition is 6:10 (w/w). In some embodiments, a ratio of the first nucleic acid to the second nucleic acid within the composition is 7:10 (w/w). In some embodiments, a ratio of the first nucleic acid to the second nucleic acid within the composition is 8:10 (w/w). In some embodiments, a ratio of the first nucleic acid _{P6797PC00 – 27 –} to the second nucleic acid within the composition is 9:10 (w/w). In some embodiments, a ratio of the first nucleic acid to the second nucleic acid within the composition is 1:1 (w/w). In _{some embodiments, a ratio of the first nucleic acid to the second nucleic acid within the} composition is 10:9 (w/w). In some embodiments, a ratio of the first nucleic acid to the second nucleic acid within the composition is 10:8 (w/w). In some embodiments, a ratio of the first _{nucleic acid to the second nucleic acid within the composition is 10:7 (w/w). In some} embodiments, a ratio of the first nucleic acid to the second nucleic acid within the composition is 10:6 (w/w). In some embodiments, a ratio of the first nucleic acid to the second nucleic acid within the composition is 10:5 (w/w). In some embodiments, a ratio of the first nucleic acid to the second nucleic acid within the composition is 10:4 (w/w). In some embodiments, _{a ratio of the first nucleic acid to the second nucleic acid within the composition is 10:3 (w/w).} In some embodiments, a ratio of the first nucleic acid to the second nucleic acid within the composition is 10:2 (w/w). In some embodiments, a ratio of the first nucleic acid to the second nucleic acid within the composition is 10:1 (w/w). In some embodiments, said first polyplex comprises a third nucleic acid, wherein said third nucleic acid is a template DNA. In preferred embodiments, the first nucleic acid is an mRNA encoding a Cas protein, preferably wherein said Cas protein is Cas9. In preferred embodiments, the second nucleic acid is a guide RNA (gRNA). In preferred embodiments, said third nucleic acid is template DNA. In preferred embodiments, said first conjugate is LPEI-l-[N3:DBCO]-PEG36-hEGF. In preferred embodiments, said second conjugate is LPEI-l-[N3:DBCO]-PEG36-hEGF. In some embodiments, the composition comprises a first polyplex comprising a first conjugate and a first nucleic acid; a second polyplex comprising a second conjugate and a second nucleic acid; and wherein said first polyplex further comprises a third nucleic acid. In some embodiments, a ratio of the first nucleic acid to the second nucleic acid within the composition is in a range from about 1:10 to about 10:1. In some embodiments, a ratio of the first nucleic acid to the second nucleic acid within the composition is 1:10 (w/w). In some embodiments, a ratio of the first nucleic acid to the second nucleic acid within the composition is 2:10 (w/w). In some embodiments, a ratio of the first nucleic acid to the second nucleic acid within the composition is 3:10 (w/w). In some embodiments, a ratio of the first nucleic acid to the second nucleic acid within the composition is 4:10 (w/w). In some embodiments, a ratio of the first nucleic acid to the second nucleic acid within the composition is 5:10 (w/w). In some embodiments, a ratio of the first nucleic acid to the second nucleic acid within the _{P6797PC00 – 28 –} composition is 6:10 (w/w). In some embodiments, a ratio of the first nucleic acid to the second nucleic acid within the composition is 7:10 (w/w). In some embodiments, a ratio of the first nucleic acid to the second nucleic acid within the composition is 8:10 (w/w). In some embodiments, a ratio of the first nucleic acid to the second nucleic acid within the composition is 9:10 (w/w). In some embodiments, a ratio of the first nucleic acid to the second nucleic acid within the composition is 1:1 (w/w). In some embodiments, a ratio of the first nucleic acid to _{the second nucleic acid within the composition is 10:9 (w/w). In some embodiments, a ratio} of the first nucleic acid to the second nucleic acid within the composition is 10:8 (w/w). In some embodiments, a ratio of the first nucleic acid to the second nucleic acid within the composition is 10:7 (w/w). In some embodiments, a ratio of the first nucleic acid to the second nucleic acid within the composition is 10:6 (w/w). In some embodiments, a ratio of the first nucleic acid to the second nucleic acid within the composition is 10:5 (w/w). In some embodiments, a ratio of the first nucleic acid to the second nucleic acid within the composition is 10:4 (w/w). In some embodiments, a ratio of the first nucleic acid to the second nucleic acid within the composition is 10:3 (w/w). In some embodiments, a ratio of the first nucleic acid to the second nucleic acid within the composition is 10:2 (w/w). In some embodiments, a ratio of the first nucleic acid to the second nucleic acid within the composition is 10:1 (w/w). In some embodiments, a ratio of the second nucleic acid to the third nucleic acid within the composition is in a range from about 1:10 to about 10:1. In some embodiments, a ratio of the second nucleic acid to the third nucleic acid within the composition is 1:10 (w/w). In some embodiments, a ratio of the second nucleic acid to the third nucleic acid within the composition is 2:10 (w/w). In some embodiments, a ratio of the second nucleic acid to the third nucleic acid within the composition is 3:10 (w/w). In some embodiments, a ratio of the second nucleic acid to the third nucleic acid within the composition is 4:10 (w/w). In some embodiments, a ratio of the second nucleic acid to the third nucleic acid within the composition is 5:10 (w/w). In some embodiments, a ratio of the second nucleic acid to the third nucleic acid within the composition is 6:10 (w/w). In some embodiments, a ratio of the second nucleic acid to the third nucleic acid within the composition is 7:10 (w/w). In some embodiments, a ratio of the second nucleic acid to the third nucleic acid within the composition is 8:10 (w/w). In some embodiments, a ratio of the second nucleic acid to the third nucleic acid within the composition is 9:10 (w/w). In some embodiments, a ratio of the second nucleic acid to the third nucleic acid within the composition is 1:1 (w/w). In some embodiments, a ratio of the second nucleic acid to the third nucleic acid within the composition is 10:9 (w/w). In some embodiments, a ratio _{P6797PC00 – 29 –} _{of the second nucleic acid to the third nucleic acid within the composition is 10:8 (w/w). In} some embodiments, a ratio of the second nucleic acid to the third nucleic acid within the composition is 10:7 (w/w). In some embodiments, a ratio of the second nucleic acid to the third nucleic acid within the composition is 10:6 (w/w). In some embodiments, a ratio of the second nucleic acid to the third nucleic acid within the composition is 10:5 (w/w). In some embodiments, a ratio of the second nucleic acid to the third nucleic acid within the composition is 10:4 (w/w). In some embodiments, a ratio of the second nucleic acid to the third nucleic acid within the composition is 10:3 (w/w). In some embodiments, a ratio of the second nucleic acid to the third nucleic acid within the composition is 10:2 (w/w). In some embodiments, a ratio of the second nucleic acid to the third nucleic acid within the composition is 10:1 (w/w). In some embodiments, said second polyplex comprises a third nucleic acid, wherein said third nucleic acid is a template DNA. In preferred embodiments, the first nucleic acid is an mRNA encoding a Cas protein, preferably wherein said Cas protein is Cas9. In preferred embodiments, the second nucleic acid _{is a guide RNA (gRNA). In some embodiments, said third nucleic acid is template DNA. In} preferred embodiments, said first conjugate is LPEI-l-[N3:DBCO]-PEG36-hEGF. In preferred embodiments, said second conjugate is LPEI-l-[N3:DBCO]-PEG36-hEGF. In some embodiments, the composition comprises a first polyplex comprising a first conjugate and a first nucleic acid; a second polyplex comprising a second conjugate and a _{second nucleic acid and third nucleic acid. In some embodiments, a ratio of the first nucleic} acid to the second nucleic acid within the composition is in a range from about 1:10 to about 10:1. In some embodiments, a ratio of the first nucleic acid to the second nucleic acid within the composition is 1:10 (w/w). In some embodiments, a ratio of the first nucleic acid to the second nucleic acid within the composition is 2:10 (w/w). In some embodiments, a ratio of the first nucleic acid to the second nucleic acid within the composition is 3:10 (w/w). In some embodiments, a ratio of the first nucleic acid to the second nucleic acid within the composition is 4:10 (w/w). In some embodiments, a ratio of the first nucleic acid to the second nucleic acid within the composition is 5:10 (w/w). In some embodiments, a ratio of the first nucleic acid to the second nucleic acid within the composition is 6:10 (w/w). In some embodiments, a ratio of the first nucleic acid to the second nucleic acid within the composition is 7:10 (w/w). In some embodiments, a ratio of the first nucleic acid to the second nucleic acid within the composition is 8:10 (w/w). In some embodiments, a ratio of the first nucleic acid to the second nucleic acid within the composition is 9:10 (w/w). In some embodiments, a ratio of the first _{P6797PC00 – 30 –} nucleic acid to the second nucleic acid within the composition is 1:1 (w/w). In some embodiments, a ratio of the first nucleic acid to the second nucleic acid within the composition is 10:9 (w/w). In some embodiments, a ratio of the first nucleic acid to the second nucleic acid within the composition is 10:8 (w/w). In some embodiments, a ratio of the first nucleic acid to the second nucleic acid within the composition is 10:7 (w/w). In some embodiments, a ratio of the first nucleic acid to the second nucleic acid within the composition is 10:6 (w/w). In some embodiments, a ratio of the first nucleic acid to the second nucleic acid within the composition is 10:5 (w/w). In some embodiments, a ratio of the first nucleic acid to the second nucleic acid within the composition is 10:4 (w/w). In some embodiments, a ratio of the first nucleic acid to the second nucleic acid within the composition is 10:3 (w/w). In some embodiments, a ratio of the first nucleic acid to the second nucleic acid within the composition is 10:2 (w/w). In some embodiments, a ratio of the first nucleic acid to the second nucleic acid within the composition is 10:1 (w/w). In some embodiments, a ratio of the second nucleic acid to the third nucleic acid within the composition is in a range from about 1:10 to about 10:1. _{In some embodiments, a ratio of the second nucleic acid to the third nucleic acid within the} composition is 1:10 (w/w). In some embodiments, a ratio of the second nucleic acid to the third nucleic acid within the composition is 2:10 (w/w). In some embodiments, a ratio of the second nucleic acid to the third nucleic acid within the composition is 3:10 (w/w). In some embodiments, a ratio of the second nucleic acid to the third nucleic acid within the composition _{is 4:10 (w/w). In some embodiments, a ratio of the second nucleic acid to the third nucleic} acid within the composition is 5:10 (w/w). In some embodiments, a ratio of the second nucleic acid to the third nucleic acid within the composition is 6:10 (w/w). In some embodiments, a ratio of the second nucleic acid to the third nucleic acid within the composition is 7:10 (w/w). In some embodiments, a ratio of the second nucleic acid to the third nucleic acid within the composition is 8:10 (w/w). In some embodiments, a ratio of the second nucleic acid to the third nucleic acid within the composition is 9:10 (w/w). In some embodiments, a ratio of the second nucleic acid to the third nucleic acid within the composition is 1:1 (w/w). In some embodiments, a ratio of the second nucleic acid to the third nucleic acid within the composition is 10:9 (w/w). In some embodiments, a ratio of the second nucleic acid to the third nucleic acid within the composition is 10:8 (w/w). In some embodiments, a ratio of the second nucleic acid to the third nucleic acid within the composition is 10:7 (w/w). In some embodiments, a ratio of the second nucleic acid to the third nucleic acid within the composition is 10:6 (w/w). In some embodiments, a ratio of the second nucleic acid to the third nucleic acid within the _{P6797PC00 – 31 –} composition is 10:5 (w/w). In some embodiments, a ratio of the second nucleic acid to the third nucleic acid within the composition is 10:4 (w/w). In some embodiments, a ratio of the second nucleic acid to the third nucleic acid within the composition is 10:3 (w/w). In some embodiments, a ratio of the second nucleic acid to the third nucleic acid within the composition is 10:2 (w/w). In some embodiments, a ratio of the second nucleic acid to the third nucleic acid within the composition is 10:1 (w/w). In one aspect, said composition comprises a third polyplex, wherein said third polyplex comprises a third conjugate and a third nucleic acid, wherein said third conjugate comprises: a linear polyethyleneimine fragment comprising an alpha terminus and an omega terminus; wherein the alpha terminus of said polyethyleneimine fragment is an initiation residue; a polyethylene glycol fragment comprising a first terminal end and a second terminal end; and w_{herein the omega terminus of the polyethyleneimine fragment is connected to the first} terminal end of the polyethylene glycol fragment by a divalent covalent linking group -Z-X¹-, _{wherein -Z-X1- is not a single bond and -Z- is not an amide; and} wherein the second terminal end of the polyethylene glycol fragment is connected to a targeting fragment by a divalent covalent linking moiety X², and wherein said third nucleic acid is a template DNA. In some embodiments, the third conjugate is of the Formula I*, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or enantiomer thereof. In some embodiments, the third conjugate is of the Formula I, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or enantiomer thereof. In some embodiments, said -(O-CH₂-CH₂)_m-moiety of said third conjugate of Formula I* or Formula I consists of a discrete number of repeating units m _{of 4 to 60, wherein preferably said discrete number m of repeating -(O-CH2-CH2)- units is 36.} In some embodiments, said third conjugate is LPEI-l-[N3:DBCO]-PEG36-hEGF, preferably wherein said LPEI-l-[N₃:DBCO]-PEG₃₆-hEGF has the structure: H _{O O} O ; _{P6797PC00 – 32 –} preferably wherein said LPEI-l-[N3:DBCO]-PEG36-hEGF is a mixture of the regioisomers: . to said third nucleic acid is 1:1:1 (w/w). In some embodiments, the composition comprises a first polyplex comprising a first conjugate and a first nucleic acid; a second polyplex comprising a second conjugate and a second nucleic acid; and a third polyplex comprising a third conjugate and a third nucleic acid. In preferred embodiments, the first nucleic acid is an mRNA encoding a Cas protein, preferably wherein said Cas protein is Cas9. In preferred embodiments, the second nucleic acid _{is a guide RNA (gRNA). In preferred embodiments, said third nucleic acid is template DNA.} In preferred embodiments, said first conjugate is LPEI-l-[N₃:DBCO]-PEG₃₆-hEGF. In preferred embodiments, said second conjugate is LPEI-l-[N3:DBCO]-PEG36-hEGF. In preferred embodiments, said third conjugate is LPEI-l-[N₃:DBCO]-PEG₃₆-hEGF. In some embodiments, a ratio of the first nucleic acid to the second nucleic acid within the composition is in a range from about 1:10 to about 10:1. In some embodiments, a ratio of the first nucleic acid to the second nucleic acid within the composition is 1:10 (w/w). In some embodiments, a ratio of the first nucleic acid to the second nucleic acid within the composition is 2:10 (w/w). In some embodiments, a ratio of the first nucleic acid to the second nucleic acid within the composition is 3:10 (w/w). In some embodiments, a ratio of the first nucleic acid to the second nucleic acid within the composition is 4:10 (w/w). In some embodiments, a ratio of the first nucleic acid to the second nucleic acid within the composition is 5:10 (w/w). In some embodiments, a ratio of the first nucleic acid to the second nucleic acid within the composition is 6:10 (w/w). In some embodiments, a ratio of the first nucleic acid to the second _{P6797PC00 – 33 –} nucleic acid within the composition is 7:10 (w/w). In some embodiments, a ratio of the first nucleic acid to the second nucleic acid within the composition is 8:10 (w/w). In some embodiments, a ratio of the first nucleic acid to the second nucleic acid within the composition is 9:10 (w/w). In some embodiments, a ratio of the first nucleic acid to the second nucleic acid within the composition is 1:1 (w/w). In some embodiments, a ratio of the first nucleic acid to the second nucleic acid within the composition is 10:9 (w/w). In some embodiments, a ratio of the first nucleic acid to the second nucleic acid within the composition is 10:8 (w/w). In some embodiments, a ratio of the first nucleic acid to the second nucleic acid within the composition is 10:7 (w/w). In some embodiments, a ratio of the first nucleic acid to the second nucleic acid within the composition is 10:6 (w/w). In some embodiments, a ratio of the first nucleic acid to the second nucleic acid within the composition is 10:5 (w/w). In some embodiments, a ratio of the first nucleic acid to the second nucleic acid within the composition is 10:4 (w/w). In some embodiments, a ratio of the first nucleic acid to the second nucleic acid within the composition is 10:3 (w/w). In some embodiments, a ratio of the first nucleic acid to the second nucleic acid within the composition is 10:2 (w/w). In some embodiments, a ratio of the first nucleic acid to the second nucleic acid within the composition is 10:1 (w/w). In some embodiments, a ratio of the second nucleic acid to the third nucleic acid within the composition is in a range from about 1:10 to about 10:1. In some embodiments, a ratio of the second nucleic acid to the third nucleic acid within the composition is 1:10 (w/w). In some embodiments, a ratio of the second nucleic acid to the third nucleic acid within the composition is 2:10 (w/w). In some embodiments, a ratio of the second nucleic acid to the third nucleic acid within the composition is 3:10 (w/w). In some embodiments, a ratio of the second nucleic acid to the third nucleic acid within the composition is 4:10 (w/w). In some embodiments, a ratio of the second nucleic acid to the third nucleic acid within the composition is 5:10 (w/w). In some embodiments, a ratio of the second nucleic acid to the third nucleic acid within the composition is 6:10 (w/w). In some embodiments, a ratio of the second nucleic acid to the third nucleic acid within the composition is 7:10 (w/w). In some embodiments, a ratio of the second nucleic acid to the third nucleic acid within the composition is 8:10 (w/w). In some embodiments, a ratio of the second nucleic acid to the third nucleic acid within the composition is 9:10 (w/w). In some embodiments, a ratio of the second nucleic acid to the third nucleic acid within the composition is 1:1 (w/w). In some embodiments, a ratio of the second nucleic acid to the third nucleic acid within the composition is 10:9 (w/w). In some embodiments, a ratio of the second nucleic acid to the third nucleic acid within the composition is 10:8 (w/w). In _{P6797PC00 – 34 –} some embodiments, a ratio of the second nucleic acid to the third nucleic acid within the composition is 10:7 (w/w). In some embodiments, a ratio of the second nucleic acid to the third nucleic acid within the composition is 10:6 (w/w). In some embodiments, a ratio of the second nucleic acid to the third nucleic acid within the composition is 10:5 (w/w). In some embodiments, a ratio of the second nucleic acid to the third nucleic acid within the composition is 10:4 (w/w). In some embodiments, a ratio of the second nucleic acid to the third nucleic acid within the composition is 10:3 (w/w). In some embodiments, a ratio of the second nucleic acid to the third nucleic acid within the composition is 10:2 (w/w). In some embodiments, a ratio of the second nucleic acid to the third nucleic acid within the composition is 10:1 (w/w). In some embodiments, the N/P ratio of the compositions is from about 3 to about 12. In some embodiments, the N/P ratio of the compositions is from about 4 to about 8. In some embodiments, the N/P ratio of the compositions is from about 4 to about 6. I_{n some embodiments, an N/P ratio of the composition is about 4 or about 6. In some} embodiments, the N/P ratio of the composition is about 3. In some embodiments, the N/P ratio of the composition is about 4. In some embodiments, the N/P ratio of the composition is about _{5. In some embodiments, the N/P ratio of the composition is about 6. In some embodiments,} the N/P ratio of the composition is about 7. In some embodiments, the N/P ratio of the composition is about 8. In some embodiments, the N/P ratio of the composition is about 9. In some embodiments, the N/P ratio of the composition is about 10. In some embodiments, the N/P ratio of the composition is about 11. In some embodiments, the N/P ratio of the composition is about 12. In some embodiments, the composition comprises a first polyplex comprising a first conjugate and a first nucleic acid, preferably wherein said first nucleic acid is an mRNA _{encoding a Cas protein, preferably Cas9, and wherein the N/P ratio of said first polyplex is 4.} In some embodiments, the composition comprises a first polyplex comprising a first conjugate, a first nucleic acid, and a second nucleic acid, preferably wherein said first nucleic acid is an mRNA encoding a Cas protein, preferably Cas9; wherein said second nucleic acid is a gRNA; and wherein the N/P ratio of said first polyplex is 4. In some embodiments, the composition comprises a first polyplex comprising a first conjugate, a first nucleic acid, a second nucleic acid, and a third nucleic acid; preferably wherein said first nucleic acid is an mRNA encoding a Cas protein, preferably Cas9; wherein said second nucleic acid is a gRNA; wherein said third nucleic acid is a template DNA; and wherein the N/P ratio of said first polyplex is 4. _{P6797PC00 – 35 –} In some embodiments, the composition comprises a first polyplex comprising a first conjugate and a first nucleic acid, preferably wherein said first nucleic acid is an mRNA encoding a Cas protein, preferably Cas9, and wherein the N/P ratio of said first polyplex is 6. In some embodiments, the composition comprises a first polyplex comprising a first conjugate, a first nucleic acid, and a second nucleic acid, preferably wherein said first nucleic acid is an mRNA encoding a Cas protein, preferably Cas9; wherein said second nucleic acid is a gRNA; and wherein the N/P ratio of said first polyplex is 6. In some embodiments, the composition comprises a first polyplex comprising a first conjugate, a first nucleic acid, a second nucleic acid, and a third nucleic acid; preferably wherein said first nucleic acid is an mRNA encoding a Cas protein, preferably Cas9; wherein said second _{nucleic acid is a gRNA; wherein said third nucleic acid is a template DNA; and wherein the} N/P ratio of said first polyplex is 6. In some embodiments, the composition comprises a polyplex comprising a second _{conjugate and a second nucleic acid, wherein said nucleic acid is gRNA, and wherein the N/P} ratio of said first polyplex is 4. In some embodiments, the composition comprises a polyplex comprising a third _{conjugate and a third nucleic acid, wherein said nucleic acid is template DNA, and wherein the} N/P ratio of said first polyplex is 4. In some embodiments, the composition comprises a polyplex comprising a second conjugate and a second nucleic acid, wherein said nucleic acid is gRNA, and wherein the N/P ratio of said first polyplex is 6. In some embodiments, the composition comprises a polyplex comprising a third conjugate and a third nucleic acid, wherein said nucleic acid is template DNA, and wherein the N/P ratio of said first polyplex is 6. In one aspect, the present disclosure provides a composition as described herein, for use _{in a method of inserting, altering, or modifying a gene and/or altering or modifying its} expression in a subject. In one aspect, the present disclosure provides a method of altering gene expression in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a composition as described herein. In one aspect, the present disclosure provides a composition as described herein for use in a method of treating a disease in a subject. _{P6797PC00 – 36 –} In one aspect, the present disclosure provides a method of treating a disease in a subject, the method comprising administering to the subject a therapeutically effective amount of a composition as described herein. In one aspect, the present disclosure provides the use of a composition as described herein in the manufacture of a medicament for treating a disease in a subject. In one aspect, the present disclosure relates to a kit of parts comprising: (i) a first container comprising a first polyplex comprising a first conjugate and a first nucleic acid; (ii) a second container comprising a second nucleic acid; (iii) optionally a third container comprising a third nucleic acid; and (_{iii) optionally instructions for combining the contents of said first container with said} second container and optionally the contents of said third container. In preferred embodiments, said first nucleic acid is an mRNA encoding a Cas protein, preferably wherein said Cas protein is Cas9. In preferred embodiments, said second nucleic acid is a gRNA. In preferred embodiments, said third nucleic acid is a template DNA. In preferred embodiments, said conjugate is a conjugate of Formula I, preferably LPEI-l- [N3:DBCO]-PEG36-hEGF. In one aspect, the present disclosure relates to a kit of parts comprising: (_{i) a first container comprising a first polyplex comprising a first conjugate and a first} nucleic acid; (ii) a second container comprising a second polyplex comprising a second conjugate and a second nucleic acid; (iii) optionally a third container comprising a third polyplex comprising a third conjugate and a third nucleic acid; and (_{iii) optionally instructions for combining the contents of said first container with said} _{second container and optionally the contents of said third container.} In preferred embodiments, said first nucleic acid is an mRNA encoding a Cas protein, preferably wherein said Cas protein is Cas9. In preferred embodiments, said second nucleic acid is a gRNA. In preferred embodiments, said third nucleic acid is a template DNA. In preferred embodiments, said first conjugate is a conjugate of Formula I, preferably LPEI-l- _{[N3:DBCO]-PEG36-hEGF. In preferred embodiments, said second conjugate is a conjugate of} Formula I, preferably LPEI-l-[N3:DBCO]-PEG36-hEGF. In preferred embodiments, said third conjugate is a conjugate of Formula I, preferably LPEI-l-[N₃:DBCO]-PEG₃₆-hEGF. _{P6797PC00 – 37 –} In a preferred embodiment of this aspect, said composition consists of said first polyplex. In a preferred embodiment of this aspect, said composition consists of said first _{polyplex and said second polyplex. In a preferred embodiment of this aspect, said composition} consists of said first polyplex, said second polyplex, and said third polyplex. In a preferred embodiment, linear polyethyleneimine fragment of said conjugate of Formula I or Formula I* is of the formula R¹-(NR²-CH2-CH2)n-, n is any integer between 1 and 1500. In a further preferred embodiment, said R¹-(NR²-CH2-CH2)n-moiety is a disperse polymeric moiety with between about 115 and about 1150 repeating units n and a dispersity of about 5 or less, preferably between about 280 and about 700 repeating units n with a dispersity of about 3 or less, and further preferably between about 350 and about 630 repeating units n with a dispersity of about 2 or less, and wherein preferably R¹ is -H or -CH₃. In preferred embodiments of any of the aspects described herein, the nucleic acid (e.g., a first nucleic acid encoding a Cas protein; a second nucleic acid wherein said second nucleic _{acid is a gRNA; and/or a third nucleic acid wherein said third nucleic acid is a template DNA)} is non-covalently bound to said conjugate (e.g., said conjugate of Formula I). In some embodiments, the conjugate (e.g., the first conjugate, the second conjugate, and/or a subsequent conjugate) is a conjugate of the Formula I, or a pharmaceutically acceptable _{salt, solvate, hydrate, tautomer or enantiomer thereof as shown below:} R² L wherein: i_{s a single bond or a double bond, preferably a double bond;} n is any integer between 1 and 1500, preferably any integer between 2 and 1500; m is any integer between 1 and 200, preferably any integer between 2 and 200, and further preferably any integer between 2 and 100; R¹ is an initiation residue, wherein preferably R¹ is -H or -CH3; R² is independently -H or an organic residue, wherein at least 80%, preferably wherein _{at least 90%, of said R2 in said -(NR2-CH2-CH2)n– is H, further preferably said R2 is H;} Ring A is a 5 to 10-membered cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl, optionally substituted at any position with one or more R^A1; R^A1 is _{P6797PC00 – 38 –} independently selected from C1-C6 alkyl, C1-C6 alkoxy, oxo, or halogen; or two R^A1, together with the atoms to which they are attached, can combine to form one or more fused C₆-C₁₀ aryl, C5-C6 heteroaryl, or C3-C6 cycloalkyl rings, wherein each fused aryl, heteroaryl, or cycloalkyl is optionally substituted with one or more R^A2; R^A2 is independently selected from C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen -SO₃H, or -OSO₃H; X¹ is a divalent covalent linking moiety; X² is a divalent covalent linking moiety; and L is a targeting fragment, wherein preferably said targeting fragment is capable of binding to a cell, and wherein further preferably said targeting fragment is capable of binding to a cell surface receptor. In some embodiments, the conjugate (e.g., the first conjugate, the second conjugate, and/or a subsequent conjugate) is a conjugate of the Formula I, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or enantiomer thereof: R² L wherein: i_{s a single bond or a double bond, preferably a double bond;} n is any integer between 1 and 1500, preferably any integer between 2 and 1500; m is any integer between 1 and 200, preferably m is any integer between 2 and 200, preferably any integer between 1 and 100, and further preferably any integer between 2 and 100; R¹ is an initiation residue, wherein preferably R¹ is -H or -CH3; R² is independently -H or an organic residue, wherein at least 80%, preferably 90% of said R² in said -(NR²-CH2-CH2)n–moieties is H; Ring A is a 5 to 10-membered cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl, optionally substituted at any position with one or more R^A1; R^A1 is independently selected from C₁-C₆ alkyl, C₁-C₆ alkoxy, oxo, or halogen; or two R^A1, together with the atoms to which they are attached, can combine to form one or more fused C₆-C₁₀ aryl, C₅-C₆ heteroaryl, or C₃-C₆ cycloalkyl rings, wherein each fused aryl, heteroaryl, or cycloalkyl is optionally substituted with one or more R^A2; _{P6797PC00 – 39 –} R^A2 is independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen -SO3H, or - OSO₃H; X_{1 is a linking moiety of the formula –(Y1)p–, wherein p is an integer between 1 and 20,} and each occurrence of Y¹ is independently selected from a chemical bond, -CR¹¹R¹²-, -C(O)-, -O-, -S-, -NR¹³-, an amino acid residue, a divalent phenyl moiety, a divalent heterocycle moiety, and a divalent heteroaryl moiety, wherein each divalent phenyl or heteroaryl is optionally substituted with one or more R¹³, and each divalent heterocycle is optionally substituted with one or more R¹⁴; wherein R¹¹, R¹² and R¹³ are independently, at each occurrence, H or C₁-C₆ alkyl; and wherein R¹⁴ is independently, at each occurrence, H, C₁-C₆ alkyl, or oxo; X² is a linking moiety of the formula –(Y²)q–, wherein q is an integer between 1 and 50, and each occurrence of Y² is independently selected from a chemical bond, -CR²¹R²²-, NR²³-, -O-, -S-, -C(O)-, an amino acid residue, a divalent phenyl moiety, a divalent heterocycle moiety, and a divalent heteroaryl moiety, wherein each divalent phenyl and divalent heteroaryl is _{optionally substituted with one or more R23, and wherein each divalent heterocycle moiety is} optionally substituted with one or more R²⁴; wherein R^21, R^22, and R²³ are each independently, at each occurrence, -H, -CO2H, or C1-C6 alkyl, wherein each C1-C6 alkyl is optionally substituted with one or more -OH, oxo, C6-C10 aryl, or 5 to 8-membered heteroaryl; and wherein R²⁴ is independently, at each occurrence, -H, -CO₂H, C₁-C₆ alkyl, or oxo; and L is a targeting fragment preferably capable of binding to a cell, and wherein preferably said targeting fragment is capable of binding to a cell surface receptor. I_{n some embodiments, the conjugate of a polyplex as described herein (e.g., the first,} _{second or subsequent polyplex) is a conjugate of the Formula I, or a pharmaceutically} acceptable salt, solvate, hydrate, tautomer or enantiomer thereof: R² L wherein: i_{s a single bond or a double bond, preferably a double bond;} n is any integer between 1 and 1500, preferably any integer between 2 and 1500; m_{is any discrete number of repeating -(O-CH2-CH2)- units of 25 to 100, preferably of} 25 to 60, wherein preferably said discrete number m is a discrete number of contiguous _{P6797PC00 – 40 –} _{repeating -(O-CH2-CH2)- units, and wherein said discrete number of contiguous repeating -(O-} _{CH2-CH2)- units) is any discrete number of 25 to 100, preferably of 25 to 60;} R¹ is an initiation residue, wherein preferably R¹ is -H or -CH3; R² is independently -H or an organic residue, wherein at least 80%, preferably wherein _{at least 90%, of said R2 in said -(NR2-CH2-CH2)n– is H, further preferably said R2 is H;} Ring A is a 5 to 10-membered cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl, optionally substituted at any position with one or more R^A1; R^A1 is independently selected from C₁-C₆ alkyl, C₁-C₆ alkoxy, oxo, or halogen; or two R^A1, together with the atoms to which they are attached, can combine to form one or more fused C₆-C₁₀ aryl, C5-C6 heteroaryl, or C3-C6 cycloalkyl rings, wherein each fused aryl, heteroaryl, or cycloalkyl is optionally substituted with one or more R^A2; R^A2 is independently selected from C₁-C₆ alkyl, C1-C6 alkoxy, halogen -SO3H, or -OSO3H; X¹ is a divalent covalent linking moiety; X² is a divalent covalent linking moiety; and L is a targeting fragment, wherein preferably said targeting fragment is capable of binding to a cell, and wherein further preferably said targeting fragment is capable of binding to a cell surface receptor. In some embodiments, the conjugate of a polyplex as described herein (e.g., the first, second or subsequent polyplex) is a conjugate of the Formula I, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or enantiomer thereof: R² L wherein: i_{s a single bond or a double bond, preferably a double bond;} n is any integer between 1 and 1500, preferably any integer between 2 and 1500; m_{is a discrete number of repeating -(O-CH2-CH2)- units of 36, wherein preferably said} _{discrete number m is a discrete number of contiguous repeating -(O-CH2-CH2)- units, and} _{wherein said discrete number of contiguous repeating -(O-CH2-CH2)- units) is 36;} R¹ is an initiation residue, wherein preferably R¹ is -H or -CH₃; _{P6797PC00 – 41 –} R² is independently -H or an organic residue, wherein at least 80%, preferably wherein _{at least 90%, of said R2 in said -(NR2-CH2-CH2)n– is H, further preferably said R2 is H;} _{Ring A is a 5 to 10-membered cycloalkyl, cycloalkenyl, heterocycloalkyl, or} heterocycloalkenyl, optionally substituted at any position with one or more R^A1; R^A1 is independently selected from C₁-C₆ alkyl, C₁-C₆ alkoxy, oxo, or halogen; or two R^A1, together with the atoms to which they are attached, can combine to form one or more fused C6-C10 aryl, C5-C6 heteroaryl, or C3-C6 cycloalkyl rings, wherein each fused aryl, heteroaryl, or cycloalkyl is optionally substituted with one or more R^A2; R^A2 is independently selected from C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen -SO₃H, or -OSO₃H; X¹ is a divalent covalent linking moiety; X² is a divalent covalent linking moiety; and L is a targeting fragment, wherein preferably said targeting fragment is capable of _{binding to a cell, and wherein further preferably said targeting fragment is capable of binding} to a cell surface receptor. In some embodiments, the conjugate of a polyplex as described herein (e.g., the first, second or subsequent polyplex) is a conjugate of the Formula I, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or enantiomer thereof: R² L wherein: i_{s a single bond or a double bond, preferably a double bond;} n is any integer between 1 and 1500, preferably any integer between 2 and 1500; m_{is a discrete number of repeating -(O-CH2-CH2)- units of 36, wherein preferably said} _{discrete number m is a discrete number of contiguous repeating -(O-CH2-CH2)- units, and} _{wherein said discrete number of contiguous repeating -(O-CH2-CH2)- units) is 36;} R¹ is an initiation residue, wherein preferably R¹ is -H or -CH3; R² is independently -H or an organic residue, wherein at least 80%, preferably wherein _{at least 90%, of said R2 in said -(NR2-CH2-CH2)n– is H, further preferably said R2 is H;} Ring A is a 5 to 10-membered cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl, optionally substituted at any position with one or more R^A1; R^A1 is _{P6797PC00 – 42 –} independently selected from C1-C6 alkyl, C1-C6 alkoxy, oxo, or halogen; or two R^A1, together with the atoms to which they are attached, can combine to form one or more fused C₆-C₁₀ aryl, C5-C6 heteroaryl, or C3-C6 cycloalkyl rings, wherein each fused aryl, heteroaryl, or cycloalkyl is optionally substituted with one or more R^A2; R^A2 is independently selected from C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen -SO₃H, or -OSO₃H; X¹ is a linking moiety of the formula –(Y¹)p–, wherein p is an integer between 1 and 20, _{and each occurrence of Y1 is independently selected from a chemical bond, -CR11R12-, -C(O)-,} -O-, -S-, -NR¹³-, an amino acid residue, a divalent phenyl moiety, a divalent carbocycle moiety, a divalent heterocycle moiety, and a divalent heteroaryl moiety, wherein each divalent phenyl or heteroaryl is optionally substituted with one or more R¹³, and each divalent heterocycle is optionally substituted with one or more R¹⁴; wherein R¹¹, R¹² and R¹³ are independently, at each occurrence, H, -SO3H, -NH2, -CO2H, or C1-C6 alkyl, wherein each alkyl is optionally substituted with -CO₂H or -NH₂; and wherein R¹⁴ is independently, at each occurrence, H, C₁- C6 alkyl, or oxo, C6-C10 aryl, or 5 to 8-membered heteroaryl; X² is a linking moiety of the formula –(Y²)_q–, wherein q is an integer between 1 and 50, and each occurrence of Y² is independently selected from a chemical bond, -CR²¹R²²-, NR²³-, -O-, -S-, -C(O)-, an amino acid residue, a divalent phenyl moiety, a divalent carbocycle moiety a divalent heterocycle moiety, and a divalent heteroaryl moiety, wherein each divalent phenyl and divalent heteroaryl is optionally substituted with one or more R²³, and wherein each divalent heterocycle moiety is optionally substituted with one or more R²⁴; wherein R^21, R^22, and R²³ are each independently, at each occurrence, -H, -SO3H, -NH2, -CO2H, or C1-C6 alkyl, wherein each C₁-C₆ alkyl is optionally substituted with one or more -OH, oxo, -CO₂H, -NH₂, _{C6-C10 aryl, or 5 to 8-membered heteroaryl; and wherein R24 is independently, at each} occurrence, -H, -CO₂H, C₁-C₆ alkyl, or oxo; and L is a targeting fragment, wherein preferably said targeting fragment is capable of binding to a cell, and wherein further preferably said targeting fragment is capable of binding to a cell surface receptor. Although the N-N=N fragment of bicyclic ring in Formula I is typically drawn herein using one single bond and one double bond for simplicity, one of skill in the art knows that Formula I and associated conjugate structures as depicted herein can alternatively be drawn as shown below. Such depictions and descriptions of Formula I are interchangeably used herein: _{P6797PC00 – 43 –} R² R² N , wherein the wavy lines represent chemical herein encompasses two regioisomeric embodiments, i.e., wherein the fragment R¹(NR²CH2CH2)n is bonded at the top nitrogen atom in the structures above or at the bottom nitrogen atom in the structures above, but not at the middle nitrogen atom. One of skill in the art knows that the same applies to other formulae herein, including Formula IA, Formula IB, Formula IC, Formula ID, Formula IE, Formula IH, Formula IJ, Formula IK and the like. I_{n some embodiments, at least 60%, at least 70%, at least 80%, at least 90%, at least} 95% or at least 99% of the LPEI in the composition is connected to the PEG fragment by a single covalent linking moiety, preferably wherein the covalent linking moiety produces a linear end-to-end linkage between the LPEI fragment and the PEG fragment. In some embodiments, a_{t least 60% at least 70%, or at least 80%, at least 90%, at least 95% or at least 99% of the LPEI} fragments comprised in the composition are comprised by said conjugate, as preferably d_{etermined by UV spectroscopy or mass spectrometry. In some embodiments, at least 60% at} least 70%, or at least 80%, at least 90%, at least 95% or at least 99% of the LPEI comprised in the composition are comprised by said conjugate, as preferably determined by UV spectroscopy or mass spectrometry. In some embodiments, at least 60% of the LPEI in the composition is connected to a single PEG fragment by a single covalent linking moiety Z, preferably wherein the covalent linking moiety Z produces a linear end-to-end linkage between the LPEI fragment and the PEG _{P6797PC00 – 44 –} fragment. In some embodiments, at least 60% of the LPEI fragments comprised in the _{composition are linked to the PEG fragment by a single triazole linker, as preferably determined} _{by UV spectroscopy or mass spectrometry. In some embodiments, at least 70% of the LPEI in} the composition is connected to the PEG fragment by a single covalent linking moiety Z, preferably wherein the covalent linking moiety Z produces a linear end-to-end linkage between the LPEI fragment and the PEG fragment. In some embodiments, at least 70% of the LPEI fragments comprised in the composition are comprised by said conjugate, as preferably determined by UV spectroscopy or mass spectrometry. In some embodiments, at least 80% of _{the LPEI in the composition is connected to the PEG fragment by a single covalent linking} moiety Z, preferably wherein the covalent linking moiety Z produces a linear end-to-end linkage between the LPEI fragment and the PEG fragment. In some embodiments, at least 80% of the LPEI fragments comprised in the composition are comprised by said conjugate, as preferably determined by UV spectroscopy or mass spectrometry. In some embodiments, at least 90% of the LPEI in the composition is connected to the PEG fragment by a single covalent linking moiety Z, preferably wherein the covalent linking moiety Z produces a linear end-to- end linkage between the LPEI fragment and the PEG fragment. In some embodiments, at least 90% of the LPEI fragments comprised in the composition are comprised by said conjugate, as preferably determined by UV spectroscopy or mass spectrometry. In some embodiments, at least 95% of the LPEI in the composition is connected to the PEG fragment by a single covalent linking moiety Z, preferably wherein the covalent linking moiety Z produces a linear end-to- end linkage between the LPEI fragment and the PEG fragment. In some embodiments, at least 95% of the LPEI fragments comprised in the composition are comprised by said conjugate, as preferably determined by UV spectroscopy or mass spectrometry. In some embodiments, at least 99% of the LPEI in the composition is connected to the PEG fragment by a single covalent linking moiety Z, preferably wherein the covalent linking moiety Z produces a linear end-to- end linkage between the LPEI fragment and the PEG fragment. In some embodiments, at least 99% of the LPEI fragments comprised in the composition are comprised by said conjugate, as preferably determined by UV spectroscopy or mass spectrometry. In some embodiments, said composition consists essentially of said conjugate. In some embodiments, said composition consists of said conjugate. In some embodiments, the LPEI fragment does not comprise substitution beyond its first terminal end and second terminal end. In some embodiments, the covalent linking moiety Z comprises a triazole. _{P6797PC00 – 45 –} _{In some embodiments, the Formula I* does not comprise the structure: R1-(NH-CH2-} _{CH2)n-NHC(O)-(CH2-CH2-O)m-X2-L. In some embodiments, the Formula I* does not comprise} the structure R¹-(NR²-CH2-CH2)n-NHC(O)-X¹-(O-CH2-CH2)m-X²-L. In some embodiments, the composition does not comprise a conjugate of the structure R¹-(NH-CH₂-CH₂)_n-NHC(O)- X¹-(O-CH₂-CH₂)_m-X²-L. In some embodiments, the composition does not comprise a conjugate of the structure R¹-(NR²-CH2-CH2)n-NHC(O)-(CH2-CH2-O)m-X²-L. In some embodiments, R¹ is -H. In some embodiments, at least 80% of the R² in the composition is -H. In some embodiments, at least 85%, preferably 90%, preferably 95%, more preferably 99% of the R² in _{the composition is -H. In a preferred embodiment, R2 is independently -H or an organic residue,} wherein at least 85%, preferably 90% of said R² in said -(NR²-CH₂-CH₂)_n–moieties is H. In another preferred embodiment, R² is independently -H or an organic residue, wherein at least 90% of said R² in said -(NR²-CH₂-CH₂)_n–moieties is H. In another preferred embodiment, R² _{is independently -H or an organic residue, wherein at least 90% of said R2 in said -(NR2-CH2-} _{CH2)n–moieties is H. In another preferred embodiment, R2 is independently -H or an organic} residue, wherein at least 91%, preferably at least 92%, more preferably 93%, of said R² in said -(NR²-CH2-CH2)n–moieties is H. In another preferred embodiment, R² is independently -H or an organic residue, wherein at least 94%, preferably at least 95%, more preferably 96%, of said _{R2 in said -(NR2-CH2-CH2)n–moieties is H. In another preferred embodiment, R2 is} independently -H or an organic residue, wherein at least 95%, preferably wherein at least 97%, further preferably at least 98%, more preferably 99%, of said R² in said -(NR²-CH2-CH2)n– moieties is H. In some embodiments, Ring A is an 8-membered cycloalkenyl, 5-membered _{heterocycloalkyl, or 7- to 8-membered heterocycloalkenyl, wherein each cycloalkenyl,} heterocycloalkyl or heterocycloalkenyl is optionally substituted at any position with one or more R^A1. I_{n some embodiments, Ring A is cyclooctene, maleimide, or 7- to 8-membered} heterocycloalkenyl, wherein the heterocycloalkyl or heterocycloalkenyl does not comprise heteroatoms other than N, O and S, and wherein each cyclooctene, heterocycloalkyl or heterocycloalkenyl is optionally substituted at any position with one or more R^A1. I_{n some embodiments, Ring A is cyclooctene, maleimide, or 7- to 8-membered} heterocycloalkenyl, wherein the heterocycloalkyl or heterocycloalkenyl comprises one or more heteroatoms, preferably one or two heteroatoms selected from N, O and S, and wherein each _{P6797PC00 – 46 –} cyclooctene, heterocycloalkyl or heterocycloalkenyl is optionally substituted at any position with one or more R^A1. I_{n some embodiments, Ring A is cyclooctene, maleimide, or an 8- membered} heterocycloalkene, wherein the heterocycloalkene comprises exactly one heteroatom selected from N, O, and S, wherein each cyclooctene or heterocycloalkene is optionally substituted with one or more R^A1. I_{n some embodiments, RA1 is -H, oxo or fluorine, or two RA1 combine to form one or} more fused phenyl rings, preferably one or two fused phenyl rings, and wherein each phenyl ring is optionally substituted with one or more -OSO₃H or -SO₃H. I_{n some embodiments, Ring A is cyclooctene, maleimide, or an 8- membered} heterocycloalkene, wherein the heterocycloalkene comprises exactly one heteroatom selected from N, O, and S, wherein each cyclooctene or heterocycloalkene is optionally substituted with one or more R^A1, wherein R^A1 is oxo or fluorine, or wherein two R^A1 combine to form one or more fused phenyl rings, preferably one or two fused phenyl rings. I_{n some embodiments, Ring A is cyclooctene, maleimide, or an 8- membered} heterocycloalkene, wherein the heterocycloalkene comprises exactly one heteroatom selected from N, wherein each cyclooctene or heterocycloalkene is optionally substituted with one or two R^A1. In some embodiments, R^A1 is -H, oxo or fluorine, or two R^A1 combine to form one or more fused phenyl rings, preferably one or two fused phenyl rings, and wherein each phenyl ring is optionally substituted with one or more R^A2. I_{n some embodiments, Ring A is cyclooctene, maleimide, or an 8- membered} heterocycloalkene, wherein the heterocycloalkene comprises exactly one heteroatom selected from N, wherein each cyclooctene or heterocycloalkene is optionally substituted with one or two R^A1, wherein R^A1 is -H, oxo or fluorine, or wherein two R^A1 combine to form one or more fused phenyl rings, preferably one or two fused phenyl rings, and wherein each phenyl ring is optionally substituted with one or more -OSO3H or -SO3H. I_{n some preferred embodiments, Ring A is cyclooctene, maleimide, or an 8- membered} heterocycloalkene, wherein the heterocycloalkene comprises exactly one heteroatom selected from N, wherein each cyclooctene or heterocycloalkene is optionally substituted with one or two R^A1, wherein R^A1 is -H, or wherein two R^A1 combine to form one or more fused phenyl rings, preferably one or two fused phenyl rings, and wherein each phenyl ring is optionally substituted with one or more -OSO₃H or -SO₃H. _{P6797PC00 – 47 –} _{Preparation of Linear Conjugates} _{The conjugates of the invention can be prepared in a number of ways well known to} those skilled in the art of polymer synthesis. By way of example, compounds of the present _{invention can be synthesized using the methods described below, together with synthetic} methods known in the art of polymer chemistry, or variations thereon as appreciated by those skilled in the art. The methods include, but are not limited to, those methods described below. _{The conjugates of the present invention can be synthesized by following the steps outlined in} _{General Schemes 1, 2, 3, 4, 5, 6, 7 and 8, as described herein and in WO2023/079142,} WO2024100040, WO2024100044, WO2024100046, the specific disclosures thereof _{incorportated herein by way of reference, or can be prepared using alternate sequences of} assembling intermediates without deviating from the present invention. The conjugates of the _{present invention can also be synthesized using slight variations on the steps outlined below.} _{For example, where Scheme 3 shows the use of a tetrafluorophenyl ester as an electrophilic} functional group for coupling with hEGF, one of skill in the art will recognize other suitable electrophilic functional groups that can be used for the same purpose. In some preferred embodiments, the LPEI fragment and the PEG fragment are coupled via a [3+2] cycloaddition between an azide and an alkene or alkyne to form a 1,2,3 triazole or a 4,5-dihydro-1H-[1,2,3]triazole. In some preferred embodiments, the LPEI fragment _{comprises the azide functional group and the PEG fragment comprises the alkene or alkyne} functional group. The conjugates of the present invention can be prepared as described in the Examples below, in particular for preferred conjugates of the present invention. Moreover, the conjugates of the present invention can be prepared as described in the prior art such as in WO2004/045491, WO2010/073247, WO2015/173824, WO2019/063705, WO2023/079142, WO2024100040, WO2024100044, WO2024100046, the entire disclosures thereof incorportated herein by way of reference, including the methods known by the skill in the art. LPEI Fragment The conjugates of the present invention can comprise LPEI fragments and PEG _{fragments. Linear polyethyleneimine (LPEI) has the chemical formula –[NH-CH2-CH2]–.} Thus, linear polyethyleneimine (LPEI) has the chemical formula of repeating units n of –[NH- CH2-CH2]–. LPEI can be synthesized according to a number of methods known in the art, including in particular the polymerization of a 2-oxazoline, followed by hydrolysis of the _{P6797PC00 – 48 –} _{pendant amide bonds (see e.g., Brissault et al., Bioconjugate Chem., 2003, 14, 581-587). As} noted above, the polymerization of poly(2-oxazolines) (i.e., a suitable precursor for LPEI) from 2-oxazolines can be initiated with any suitable initiator. In some embodiments, the initiator leaves an initiation residue at the alpha terminus of the poly(2-oxazoline). In a preferred embodiment, the initiation residue (i.e., R¹ of Formula I* or Formula I) is a hydrogen atom or a C1-C6 alkyl, preferably a hydrogen or C1-C4 alkyl, more preferably a hydrogen or methyl group; most preferably a hydrogen atom. In a preferred embodiment, the initiation residue R¹ of Formula I is a hydrogen atom or a C₁-C₆ alkyl, preferably a hydrogen or C₁-C₄ alkyl, more _{preferably a hydrogen or methyl group; most preferably a hydrogen atom. In preferred} embodiments, the initiation residue (i.e., R¹ of Formula I* or Formula I) is -H or -CH3, most preferably -H. In a preferred embodiment, said initiation residue R¹ of Formula I* is -H. In a preferred embodiment, said initiation residue R¹ of Formula I is -H. In a preferred embodiment, said initiation residue R¹ of Formula I* is -CH₃. In a preferred embodiment, said initiation _{residue R1 of Formula I is -CH3. However, one of skill in the art will understand that the} initiation residue can be the residue left from any suitable initiator capable of initiating the polymerization of poly(2-oxazolines) from 2-oxazolines. In some embodiments, the LPEI fragment can be coupled to the PEG fragment via a _{[3+2] cycloaddition between an azide and an alkene or alkyne to form a 1, 2, 3 triazole or a 4,5-} _{dihydro-1H-[1,2,3]triazole wherein the LPEI fragment comprises the azide (-N3) functional} _{group at the omega terminus of the chain. In some preferred embodiments, the LPEI fragment} _{is not further substituted except for a single substitution at the alpha terminus. For example, in} some preferred embodiments, the LPEI fragment comprises the repeating formula –[NH-CH₂- _{CH2]– and is substituted at the omega terminus with an azide group which can be coupled to an} alkyne or alkene substituent on a PEG fragment. In some preferred embodiments, the alpha terminus of the LPEI fragment can be substituted with a hydrogen atom or a C1-C6 alkyl, preferably a hydrogen or C1-C4 alkyl, more preferably a hydrogen or methyl group; most preferably a hydrogen atom. F_{or example, in some preferred embodiments, the LPEI fragment can be substituted at} _{the alpha terminus with a hydrogen atom or a C1-C6 alkyl, preferably a hydrogen atom or C1-} _{C4 alkyl, more preferably a hydrogen atom or methyl group and at the omega terminus with an} azide group; in some preferred embodiments, there is no additional substitution present on the LPEI fragment. For example, conjugates of the present invention can be prepared from LPEI fragments of the following formula: _{P6797PC00 – 49 –} 1 H R N 3 _{wherein R1 can be any a hydrogen or C1-C6} _alkyl, _{preferably hydrogen or C1-C4 alkyl, more preferably hydrogen or methyl, most preferably a} hydrogen. In some embodiments, the LPEI fragment can be terminated with a thiol group, thus, in some embodiments, the omega terminus of said LPEI fragment comprises, preferably is, a thiol _{group, which can be coupled to a reactive alkene group on the PEG fragment by a thiol-ene} _{reaction. Accordingly, in some embodiments conjugates of the present invention can be} prepared from LPEI fragments of the following formula: H N w_{herein R1 can be any} _{preferably hydrogen or methyl,} preferably a hydrogen. In some embodiments, the LPEI fragment can be terminated with an alkene group, thus, in some embodiments, the omega terminus of said LPEI fragment comprises, preferably is, a alkene group, which can be coupled to a reactive thiol group on the PEG fragment by a thiol- _{ene reaction. Accordingly, in some embodiments, conjugates of the present invention can be} prepared from LPEI fragments of the following formula: H N wherein R¹ can be preferably hydrogen or methyl, preferably a hydrogen. The LPEI fragment can comprise a range of lengths (i.e., repeating units represented _{above by the variable “n”). For example, the LPEI fragment can comprise between 1 and 1000} _{repeating units (i.e., -NH-CH2-CH2-). In some embodiments, the LPEI fragment can be present} _{as a disperse polymeric moiety and does not comprise a discrete number of -NH-CH2-CH2-} repeating units. For example, the LPEI fragment can be present as a disperse polymeric moiety with a molecular weight of between about 5 and 50 KDa, preferably with a dispersity of about _{5 or less, preferably of about 4 or less, preferably of about 3 or less, preferably of about 2 or} less, preferably of about 1.5 or less. In some embodiments, the LPEI fragment can be present _{as a disperse polymeric moiety with a molecular weight of between about 10 and 40 KDa with} a dispersity of about 4 or less, preferably of about 3 or less, preferably of about 2 or less, _{P6797PC00 – 50 –} _{preferably of about 1.5 or less. In some embodiments, the LPEI fragment can be present as a} _{disperse polymeric moiety with a molecular weight of between about 12 and 30 KDa with a} dispersity of about 3 or less, preferably of about 2 or less, preferably of about 1.5 or less. In _{some embodiments, the LPEI fragment can be present as a disperse polymeric moiety with a} molecular weight of between about 15 and 27 KDa with a dispersity of about 2 or less, preferably of about 1.5 or less. In some embodiments, the LPEI fragment can be present as a _{disperse polymeric moiety with a molecular weight of between about 17 and 25 KDa, with a} dispersity of about 1.2 or less. For example, the LPEI fragment can be present as a disperse polymeric moiety comprising between about 115 and 1150 repeating units, preferably with a dispersity of about 5 or less, preferably of about 4 or less, preferably of about 3 or less, preferably of about 2 or less, preferably of about 1.5 or less. In some embodiments, the LPEI fragment can be present _{as a disperse polymeric moiety comprising between about 230 and 930 repeating units with a} dispersity of about 4 or less, preferably of about 3 or less, preferably of about 2 or less, preferably of about 1.5 or less. In some embodiments, the LPEI fragment can be present as a _{disperse polymeric moiety comprising between about 280 and 700 repeating units with a} dispersity of about 3 or less, preferably of about 2 or less, preferably of about 1.5 or less. In some embodiments, the LPEI fragment can be present as a disperse polymeric moiety _{comprising between about 350 and 630 repeating units with a dispersity of about 2 or less,} preferably of about 1.5 or less. In some embodiments, the LPEI fragment can be present as a _{disperse polymeric moiety comprising between about 400 and 580 repeating units, with a} _{dispersity of about 1.2 or less.} In some embodiments, said R¹-(NR²-CH2-CH2)n-moiety is a disperse polymeric moiety _{with between 115 and 1150 repeating units n and a dispersity of about 5 or less, wherein} preferably said R¹-(NR²-CH2-CH2)n-moiety is a disperse polymeric moiety with between 280 and 700 repeating units n and a dispersity of about 3 or less, and wherein further preferably said R¹-(NR²-CH2-CH2)n-moiety is a disperse polymeric moiety with between 350 and 630 repeating units n and a dispersity of about 2 or less, and again further preferably wherein said R¹-(NR²-CH2-CH2)n-moiety is a disperse polymeric moiety with between 400 and 580 repeating units n and a dispersity of about 1.2 or less. In a preferred embodiment, said polyethyleneimine fragment is a disperse polymeric moiety with between about 115 and about 1150 repeating units and a dispersity of about 5 or less, preferably between about 230 and about 930 repeating units with a dispersity of about 4 _{P6797PC00 – 51 –} or less; more preferably between about 280 and about 700 repeating units with a dispersity of about 3 or less; again more preferably between about 350 and about 630 repeating units with a dispersity of about 2 or less; yet more preferably between about 400 and about 580 repeating units, with a dispersity about 1.2 or less. In a preferred embodiment, said polyethyleneimine fragment is a disperse polymeric moiety with between about 115 and about 1150 repeating units and a dispersity of about 5 or less, preferably of about 4 or less, preferably of about 3 or less, preferably of about 2 or less, preferably of about 1.5 or less. In a preferred embodiment, said polyethyleneimine fragment is a disperse polymeric moiety with between about 230 and about 930 repeating units with a dispersity of about 4 or less, preferably of about 3 or less, preferably of about 2 or less, _{preferably of about 1.5 or less. In a preferred embodiment, said polyethyleneimine fragment is} a disperse polymeric moiety with between about 280 and about 700 repeating units with a dispersity of about 3 or less, preferably of about 2 or less, preferably of about 1.5 or less. In a preferred embodiment, said polyethyleneimine fragment is a disperse polymeric moiety with between about 350 and about 630 repeating units with a dispersity of about 2 or less, preferably of about 1.5 or less. In a preferred embodiment, said polyethyleneimine fragment is a disperse polymeric moiety with between about 400 and about 580 repeating units, with a dispersity about 1.2 or less. As noted above, one of skill in the art will understand that in some embodiments, the _{LPEI fragment may include organic residues, (i.e., pendant amide groups) connected at the} nitrogen atoms embedded within the LPEI chain. One of skill in the art will understand that _{such organic residues (i.e., amide groups) can be formed during the ring-opening} polymerization of 2-oxazolines to form a poly(2-oxazoline). Without wishing to be bound by theory, LPEI can be formed from a poly(2-oxazoline) by cleavage of the amide groups (e.g., using an acid such as HCl). However, in some cases not every amide linkage may be cleaved under these conditions. Accordingly, in some embodiments about 5% or less of the nitrogen _{atoms in the LPEI fragment may be connected to an organic residue to form an amide. In some} embodiments, about 4% or less, about 3% or less, about 2% or less, about 1% or less, about 0.5% or less, about 0.4% or less, about 0.3% or less, about 0.2% or less, or about 0.1% or less _{of the nitrogen atoms in the LPEI fragment may be connected to an organic residue to form an} amide. One of skill in the art will understand that the molecular weight of the LPEI fragment includes the percentage of LPEI fragment that is bonded to an organic residue as an amide. Moreover, one of skill in the art will understand that although chemical structures drawn herein _{P6797PC00 – 52 –} _{show repeating -NH-CH2-CH2- fragments, trace amounts of residual organic residue such as} _{pendant amide groups (e.g., those defined above) may still be present in the resulting} triconjugates or polyplexes of the present disclosure. The term “triconguate”, as occasionally used herein, shall refer to the inventive conjugate. The prefix “tri-” is caused by the three _{components comprised by the inventive conjugates, namely the LPEI fragment, the PEG} fragment and the targeting fragment. PEG Fragment P_{olyethylene glycol (PEG) has the chemical formula –[O-CH2-CH2]–. Thus,} polyethylene glycol (PEG) has the chemical formula of repeating units m of –[O-CH₂-CH₂]–. _{In some preferred embodiments, the PEG fragment can be coupled to the LPEI fragment via a} [3+2] cycloaddition between an azide and an alkene or alkyne to form a 1,2,3 triazole or a 4,5- dihydro-1H-[1,2,3]triazole, wherein the respective reactive precursor molecule comprising the _{PEG fragment further comprises the alkene or alkyne functional group. For example, in some} preferred embodiments, the reactive precursor molecule comprising the PEG fragment _{comprises the repeating formula –[O-CH2-CH2]– and is substituted at a first end (i.e., terminus)} with an alkene or alkyne group (e.g., via a linking moiety “X¹” as discussed herein) which can be coupled to the azide group of a corresponding respective reactive precursor molecule comprising the LPEI fragment. I_{n some preferred embodiments, said alkene or alkyne group is an activated alkene or} alkyne group capable of spontaneously reacting with an azide (e.g., without the addition of a catalyst such as a copper catalyst). For example, an activated alkyne group can be incorporated _{into a 7- or 8-membered ring, resulting in a strained species that reacts spontaneously with the} azide group of the LPEI fragment. An activated alkene can include a maleimide moiety, wherein the alkene is activated by conjugation to the neighboring carbonyl groups. In some preferred embodiments, the second end (i.e., terminus) of the PEG fragment can be substituted with a _{targeting fragment (e.g., hEGF, HER2, folate, or DUPA) (e.g., via a linking moiety “X2” as} discussed herein). T_{he PEG fragment can comprise a range of lengths (i.e., repeating units represented by} _{the variable “m”). In other embodiments, the PEG fragment can comprise a discrete number of} _{repeating -O-CH2-CH2- units and is not defined in terms of an average chain length. In a} _{preferred embodiment, said said -(O-CH2-CH2)m- is a disperse polymeric moiety. In a preferred} embodiment, said -(O-CH2-CH2)m-moiety comprises, preferably consists of, a discrete number _{P6797PC00 – 53 –} of repeating units m. In a preferred embodiment, said -(O-CH2-CH2)m-moiety comprises, preferably consists of, a discrete number of contiguous repeating units m. I_{n some preferred embodiments, the PEG fragment is a disperse polymeric moiety} _{comprising between about 1 and about 200 repeating units, preferably between about 1 and} about 200 repeating units. In some preferred embodiments, the PEG fragment can comprise _{between 1 and 100 repeating units (i.e., -O-CH2-CH2-). Preferably the PEG fragments of the} present invention comprise between about 1 and about 100 repeating units, between about 1 and about 90 repeating units, between about 1 and about 80 repeating units, between about 1 and about 70 repeating units, between about 1 and about 60 repeating units, between about 1 _{and about 50 repeating units, between about 1 and about 50 repeating units, between about 1} _{and about 40 repeating units, between about 1 and about 30 repeating units, or between about} 1 and about 20 repeating units. In some other preferred embodiments, the PEG fragments comprise a discrete number of repeating units m, preferably 12 repeating units or 24 repeating units. In some embodiment, said polyethylene glycol fragment is a disperse polymeric moiety with between about 2 and about 80 repeating units and a dispersity of about 2.0 or less, preferably of about 1.8 or less, further of about 1.5 or less; preferably between about 2 and about 70 repeating units with a dispersity of about 1.8 or less, preferably of about 1.5 or less; more preferably between about 2 and about 50 repeating units with a dispersity of about 1.5 or less. In some embodiment, said -(O-CH₂-CH₂)_m-moiety is a disperse polymeric moiety with between about 2 and about 80 repeating units and a dispersity of about 2.0 or less, preferably between about 2 and about 70 repeating units with a dispersity of about 1.8 or less; more preferably between about 2 and about 50 repeating units with a dispersity of about 1.5 or less. In a preferred embodiment, said polyethylene glycol fragment PEG fragment comprises, preferably consists of, a discrete number of repeating units m, preferably of 12 or 24 repeating _{units. In a preferred embodiment, said m (of said -(O-CH2-CH2)m-moiety) comprises,} preferably consists of, a discrete number of repeating units m, preferably of 12 or 24 repeating units. In a preferred embodiment, the PEG fragment comprise, preferably consist of, a discrete number of repeating units m of 2 to 100, preferably of a discrete number of repeating units m of 4 to 60. In a preferred embodiment, the PEG fragment comprise, preferably consist of, a discrete number of repeating units m of 4 to 60, preferably of a discrete number of repeating units m of 10 to 60. In a preferred embodiment, the PEG fragment comprise, preferably consist of, a discrete number of repeating units m of 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, _{P6797PC00 – 54 –} 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59 or 60. In a preferred embodiment, the PEG fragment comprise, preferably consist of, a discrete number of repeating units m of 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, or 60. In a preferred embodiment, the PEG fragment comprise, preferably consist of, a discrete number of repeating units m of 4. In a preferred embodiment, the PEG fragment comprise, preferably consist of, a discrete number of repeating units m of 12. In a preferred embodiment, the PEG fragment comprise, preferably consist of, a discrete number of repeating units m of 24. In a preferred embodiment, the PEG fragment comprise, preferably consist of, a discrete number of repeating units m of 36. In a preferred embodiment, the PEG fragment comprise, preferably consist of, a discrete number of contiguous repeating units m of 2 to 100, preferably of a discrete number of contiguous repeating units m of 4 to 60. In a preferred embodiment, the PEG fragment _{comprise, preferably consist of, a discrete number of contiguous repeating units m of 4 to 60,} preferably of a discrete number of contiguous repeating units m of 10 to 60. In a preferred embodiment, the PEG fragment comprise, preferably consist of, a discrete number of contiguous repeating units m of 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59 or 60. In a preferred embodiment, the PEG fragment comprise, preferably consist of, a discrete number of contiguous repeating units m of 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, or 60. In a preferred embodiment, the PEG fragment comprise, preferably consist of, a discrete number of contiguous repeating units m of 4. In a preferred embodiment, the PEG fragment comprise, preferably consist of, a discrete number of contiguous repeating units m of 12. In a preferred embodiment, the PEG fragment comprise, preferably consist of, a discrete number of contiguous repeating units m of 24. In a preferred embodiment, the PEG fragment comprise, preferably consist of, a discrete number of contiguous repeating units m of 36. In a preferred embodiment, said -(O-CH2-CH2)m-moiety of Formula I* or Formula I comprise, preferably consist of, a discrete number of repeating units m of 2 to 100, preferably of a discrete number of repeating units m of 4 to 60. In a preferred embodiment, said -(O-CH2- CH2)m-moiety comprise, preferably consist of, a discrete number of repeating units m of 4 to 60, preferably of a discrete number of repeating units m of 10 to 60. In a preferred embodiment, said -(O-CH2-CH2)m-moiety comprise, preferably consist of, a discrete number of repeating _{units m of 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27,} _{P6797PC00 – 55 –} 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59 or 60. In a preferred embodiment, said -(O-CH₂-CH₂)_m-moiety comprise, preferably consist of, a discrete number of repeating units m of 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, or 60. In a preferred embodiment, said -(O-CH₂-CH₂)_m-moiety comprise, preferably consist of, a discrete number of repeating units m of 4. In a preferred embodiment, said -(O-CH2-CH2)m-moiety comprise, preferably consist of, a discrete number of repeating units m of 12. In a preferred embodiment, said -(O-CH2-CH2)m-moiety comprise, preferably consist of, a discrete number of repeating units m of 24. In a preferred embodiment, said -(O-CH₂-CH₂)_m-moiety comprise, preferably consist of, a discrete number of repeating units m of 36. In a preferred embodiment, said -(O-CH₂-CH₂)_m-moiety of Formula I* or Formula I comprise, preferably consist of, a discrete number of contiguous repeating units m of 2 to 100, preferably of a discrete number of contiguous repeating units m of 4 to 60. In a preferred embodiment, said -(O-CH2-CH2)m-moiety comprise, preferably consist of, a discrete number of contiguous repeating units m of 4 to 60, preferably of a discrete number of contiguous repeating units m of 10 to 60. In a preferred embodiment, said -(O-CH2-CH2)m-moiety comprise, preferably consist of, a discrete number of contiguous repeating units m of 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59 or 60. In a preferred embodiment, said -(O-CH2-CH2)m-moiety comprise, preferably consist of, a discrete number of contiguous repeating units m of 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, _{52, 56, or 60. In a preferred embodiment said -(O-CH2-CH2)m-moiety comprise, preferably} consist of, a discrete number of contiguous repeating units m of 4. In a preferred embodiment, said -(O-CH₂-CH₂)_m-moiety comprise, preferably consist of, a discrete number of contiguous repeating units m of 12. In a preferred embodiment, said -(O-CH2-CH2)m-moiety comprise, preferably consist of, a discrete number of contiguous repeating units m of 24. In a preferred _{embodiment, said -(O-CH2-CH2)m-moiety comprise, preferably consist of, a discrete number of} contiguous repeating units m of 36. In preferred embodiments, the PEG fragment comprised in the inventive conjugates and compositions comprises, preferably consists of, a discrete number m of repeating –(O-CH2- CH₂)-units and is not defined in terms of an average chain length. Thus, the PEG fragment comprised in the inventive conjugates and compositions comprises, preferably consists of, a discrete number m of repeating –(O-CH₂-CH₂)-units and is not defined in terms of an average _{P6797PC00 – 56 –} chain length but has a specifically defined discrete molecular weight associated with the discrete number m of repeating –(O-CH₂-CH₂)-units. In a preferred embodiment, said PEG fragment comprises, preferably consists of, a discrete number m of repeating units –(O-CH2- CH₂)-units, wherein typically and preferably said discrete number (m) is a discrete number (m) of and between 25 to 100, further preferably of and between 25 to 60. In a preferred embodiment, said PEG fragment comprises, preferably consists of, a discrete number m of contiguous repeating units –(O-CH2-CH2)-units, wherein typically and preferably said discrete number (m) is a discrete number (m) of and between 25 to 100, further preferably of and between 25 to 60. The expressions “polyethylene glycol fragment comprising a discrete number (m) of _{repeating -(O-CH2-CH2)- units”, or “PEG fragment comprising a discrete number (m) of} _{repeating -(O-CH2-CH2)- units” shall refer to a fragment comprising, preferably consisting of,} _{a discrete number – typically herein referred to a discrete number m - of repeating -(O-CH2-} _{CH2)- units, wherein said discrete number (m) is a discrete, i.e. specific and single defined and} integer, number (m) of 25 to 100, preferably of 25 to 60. Thus, the expressions “polyethylene _{glycol fragment comprising a discrete number (m) of repeating -(O-CH2-CH2)- units”, or “PEG} _{fragment comprising a discrete number (m) of repeating -(O-CH2-CH2)- units” shall refer to a} _{fragment comprising, preferably consisting of, a discrete number m - of repeating -(O-CH2-} _{CH2)- units, wherein said discrete number (m) is a discrete, i.e. specific and single defined and} integer, number (m) of 25 to 100, preferably of 25 to 60, and thus said defined PEG fragments _{comprise, preferably consist of, a discrete number m of repeating –(O-CH2-CH2)- units and are} not defined in terms of an average chain length but they each have a specifically defined discrete molecular weight. When herein referring to a discrete number of 25 to 100, it shall refer to any integer of and between 25 to 100, i.e. any integer between 25 and 100 including the integer and discrete numbers mentioned as borders such as here 25 and 100. By way of further example, a _{PEG fragment comprising a discrete number (m) of repeating -(O-CH2-CH2)- units, wherein} said discrete number m is 36, refers to a PEG fragment comprising a chain of -(O-CH2-CH2)- _{units that contains exactly 36 -(O-CH2-CH2)- units. Such chain of exactly 36 -(O-CH2-CH2)-} _{units is abbreviated as PEG36. Such PEG fragment is in contrast to a “polymeric PEG fragment”,} a “polydisperse PEG fragment” or a “disperse PEG fragment”, which refers to a heteregeneous mixture of sizes and molecular weights as the result of a polymer reaction, typically in a Poisson distribution (J Herzberger et al.; Chem Rev, 2016, 116:2170-2243). The PEG fragments of the _{present invention comprising a discrete number (m) of repeating -(O-CH2-CH2)- units are not} _{P6797PC00 – 57 –} synthesized via a polymerization process. The PEG fragments of the present invention comprise _{a discrete number (m) of repeating -(O-CH2-CH2)- units and are single molecule fragments with} a discrete, i.e. defined and specified, chain length. Thus, the PEG fragments of the present _{invention comprising a discrete number (m) of repeating -(O-CH2-CH2)- units are single} molecule fragments with a discrete, i.e. defined and specified chain length. The PEG fragments of the present invention are not a mixture of molecular entities (such as those resulting from a random polymerization reaction). The discreteness of the inventive discrete PEG fragments distinguishes them from the polydisperse art. The PEG fragments of the present invention may comprise, preferably consist of, homogenous discrete PEG fragments or heterogeneous discrete PEG fragments, typically and preferably homogenous discrete PEG fragments. The term “homogenous discrete PEG fragments", as used herein, means a discrete PEG structure whose entire chemical backbone is made up of a continuous and contiguous and specific discrete number of only ethylene oxide units. In other words, no other functionality is present within said homogenous discrete PEG fragments. The termini of the respective reactive precursor molecules comprising homogeneous _{discrete PEG fragments, however, can and typically do have, for the sake of conjugation with} the PEI fragments and the targeting fragments, functional groups. The term “heterogeneous discrete PEG fragments", as used herein, means a discrete PEG structure wherein the basic _{ethylene oxide backbone comprising a discrete number of ethylene oxide units is broken up by} or substituted with other functional groups or units within its structure such as, for example, the inclusion of amide or ester bonds or other functional units. In preferred embodiments of the present invention, the PEG fragment is a homogenous discrete PEG fragment. In some preferred embodiments, the PEG fragment can be coupled to the LPEI fragment via a [3+2] cycloaddition between an azide and an alkene or alkyne to form a 1,2,3 triazole or a 4,5-dihydro-1H-[1,2,3]triazole, wherein the respective reactive precursor molecule comprising the PEG fragment further comprises the alkene or alkyne functional group. For example, in some preferred embodiments, the reactive precursor molecule comprising the PEG _{fragment comprises the repeating formula –[O-CH2-CH2]– and is substituted at a first end (i.e.,} terminus) with an alkene or alkyne group (e.g., via a linking moiety “X¹” as discussed herein) which can be coupled to the azide group of a corresponding respective reactive precursor molecule comprising the LPEI fragment. In some preferred embodiments, said alkene or alkyne group is an activated alkene or alkyne group capable of spontaneously reacting with an azide (e.g., without the addition of a catalyst such as a copper catalyst). For example, an activated _{P6797PC00 – 58 –} _{alkyne group can be incorporated into a 7- or 8-membered ring, resulting in a strained species} that reacts spontaneously with the azide group of the LPEI fragment. The PEG fragment comprised in the inventive conjugates and compositions comprises, _{preferably consists of, a discrete number m of repeating -O-CH2-CH2- units and is not defined} in terms of an average chain length, as it is the case for polymeric PEG fragments. In a preferred _{embodiment, said -(O-CH2-CH2)m- units comprise, preferably consist of, a discrete number of} _{repeating units m. In a preferred embodiment, said -(O-CH2-CH2)m- units comprise, preferably} consist of, a discrete number of contiguous repeating units m. In a preferred embodiment, the PEG fragment comprise, preferably consist of, a discrete number of repeating units m of 25 to 100, preferably of a discrete number of repeating units m of 25 to 60. In a preferred embodiment, the PEG fragment comprise, preferably consist of, a _{discrete number of repeating units m of 25 to 60, preferably of a discrete number of repeating} units m of 30 to 50. In a preferred embodiment, the PEG fragment comprise, preferably consist of, a discrete number of repeating units m of 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59 or 60. The synthesis of said PEG fragments comprising or consisting of discrete numbers repeating -(O- _{CH2-CH2)m- units and thus discrete PEGs are described in WO2004/073620 and} WO2013/033476. In a preferred embodiment, the PEG fragment comprise, preferably consist of, a discrete number of repeating units m of 28, 32, 36, 40, 44, 48, 52, 56, or 60. In a preferred embodiment, the PEG fragment comprise, preferably consist of, a discrete number of repeating units m of 28. In a preferred embodiment, the PEG fragment comprise, preferably consist of, a discrete number of repeating units m of 32. In a preferred embodiment, the PEG fragment comprise, preferably consist of, a discrete number of repeating units m of 36. In a preferred embodiment, the PEG fragment comprise, preferably consist of, a discrete number of repeating _{units m of 40. In a preferred embodiment, the PEG fragment comprise, preferably consist of, a} discrete number of repeating units m of 44. In a preferred embodiment, the PEG fragment comprise, preferably consist of, a discrete number of repeating units m of 48. In a preferred embodiment, the PEG fragment comprise, preferably consist of, a discrete number of contiguous repeating units m of 25 to 100, preferably of a discrete number of contiguous repeating units m of 25 to 60. In a preferred embodiment, the PEG fragment comprise, preferably consist of, a discrete number of contiguous repeating units m of 25 to 60, preferably of a discrete number of contiguous repeating units m of 30 to 50. In a preferred embodiment, the PEG fragment comprise, preferably consist of, a discrete number of _{P6797PC00 – 59 –} contiguous repeating units m of 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59 or 60. In a preferred embodiment, the PEG fragment comprise, preferably consist of, a discrete number of contiguous repeating units m of 28, 32, 36, 40, 44, 48, 52, 56, or 60. In a preferred embodiment, the PEG fragment comprise, preferably consist of, a discrete number of contiguous repeating units m of 28. In a preferred embodiment, the PEG fragment comprise, preferably consist of, a discrete number of contiguous repeating units m of 32. In a preferred embodiment, the PEG fragment comprise, preferably consist of, a discrete number of contiguous repeating units m of 36. In a preferred embodiment, the PEG fragment comprise, preferably consist of, a discrete number of contiguous repeating units m of 40. In a preferred embodiment, the PEG fragment comprise, preferably consist of, a discrete number of contiguous repeating units m of 44. In a preferred embodiment, the PEG fragment comprise, preferably consist of, a discrete number of contiguous repeating units m of 48. In a preferred embodiment, said -(O-CH2-CH2)m-moiety of Formula I* or Formula I consists of a discrete number of repeating units m of 25 to 100, preferably of a discrete number _{of repeating units m of 25 to 60. In a preferred embodiment, said -(O-CH2-CH2)m-moiety} consists of a discrete number of repeating units m of 25 to 60, preferably of a discrete number of repeating units m of 30 to 50. In a preferred embodiment, said -(O-CH₂-CH₂)_m-moiety consists of a discrete number of repeating units m of 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59 or 60. _{In a preferred embodiment, said -(O-CH2-CH2)m-moiety consists of a discrete number of} repeating units m of 28, 32, 36, 40, 44, 48, 52, 56, or 60. In a preferred embodiment, said -(O- CH2-CH2)m-moiety consists of a discrete number of repeating units m of 28. In a preferred embodiment, said -(O-CH₂-CH₂)_m-moiety consists of a discrete number of repeating units m of 32. In a preferred embodiment, said -(O-CH2-CH2)m-moiety consists of a discrete number of repeating units m of 36. In a preferred embodiment, said -(O-CH2-CH2)m-moiety consists of a discrete number of repeating units m of 40. In a preferred embodiment, said -(O-CH2-CH2)m- moiety consists of a discrete number of repeating units m of 44. In a preferred embodiment, said -(O-CH2-CH2)m-moiety consists of a discrete number of repeating units m of 48. In a preferred embodiment, said -(O-CH2-CH2)m-moiety of Formula I* or Formula I consists of a discrete number of contiguous repeating units m of 25 to 100, preferably of a _{discrete number of contiguous repeating units m of 25 to 60. In a preferred embodiment, said -} (O-CH₂-CH₂)_m-moiety consists of a discrete number of contiguous repeating units m of 25 to _{P6797PC00 – 60 –} 60, preferably of a discrete number of contiguous repeating units m of 30 to 50. In a preferred embodiment, said -(O-CH₂-CH₂)_m-moiety consists of a discrete number of contiguous repeating units m of 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59 or 60. In a preferred embodiment, said -(O- CH₂-CH₂)_m-moiety consists of a discrete number of contiguous repeating units m of 28, 32, 36, 40, 44, 48, 52, 56, or 60. In a preferred embodiment said -(O-CH2-CH2)m-moiety consists of a discrete number of contiguous repeating units m of 28. In a preferred embodiment, said -(O- CH₂-CH₂)_m-moiety consists of a discrete number of contiguous repeating units m of 32. In a preferred embodiment, said -(O-CH₂-CH₂)_m-moiety consists of a discrete number of contiguous repeating units m of 36. In a preferred embodiment, said -(O-CH2-CH2)m-moiety consists of a discrete number of contiguous repeating units m of 40. In a preferred embodiment, said -(O- CH2-CH2)m-moiety consists of a discrete number of contiguous repeating units m of 44. In a preferred embodiment, said -(O-CH₂-CH₂)_m-moiety consists of a discrete number of contiguous repeating units m of 48. I_{n another aspect, the present invention provides a composition comprising a first} polyplex, wherein said first polyplex comprise a first conjugate of the Formula I, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or enantiomer thereof, and a first _{nucleic acid, wherein said first nucleic acid is preferably non-covalently bound to said} conjugate: R² L wherein: i_{s a single bond or a double bond, preferably a double bond;} n is any integer between 1 and 1500, preferably any integer between 2 and 1500; m is a discrete number of repeating units m of 2 to 100, preferably of a discrete number of repeating units m of 4 to 60, and wherein preferably said discrete number m is a discrete _{number of contiguous repeating -(O-CH2-CH2)- units, and wherein said discrete number of} _{contiguous repeating -(O-CH2-CH2)- units) is any discrete number of 2 to 100, preferably of 4} to 60, most preferably 36; R¹ is an initiation residue, wherein preferably R¹ is -H or -CH3; _{P6797PC00 – 61 –} R² is independently -H or an organic residue, wherein at least 80%, preferably wherein _{at least 90%, of said R2 in said -(NR2-CH2-CH2)n– is H, further preferably said R2 is H;} Ring A is a 5 to 10-membered cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl, optionally substituted at any position with one or more R^A1; R^A1 is independently selected from C₁-C₆ alkyl, C₁-C₆ alkoxy, oxo, or halogen; or two R^A1, together with the atoms to which they are attached, can combine to form one or more fused C6-C10 aryl, C5-C6 heteroaryl, or C3-C6 cycloalkyl rings, wherein each fused aryl, heteroaryl, or cycloalkyl is optionally substituted with one or more R^A2; R^A2 is independently selected from C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen -SO₃H, or -OSO₃H; X¹ is a divalent covalent linking moiety; X² is a divalent covalent linking moiety; and L is a targeting fragment, wherein preferably said targeting fragment is capable of binding to a cell, and wherein further preferably said targeting fragment is capable of binding to a cell surface receptor, and wherein said first nucleic acid is an mRNA encoding a Cas protein, preferably wherein said Cas protein is Cas9. In a preferred embodiment, said R¹ is -H. In a preferred embodiment, said R¹ is -CH3. In another aspect, the present invention provides a composition comprising a first polyplex, wherein said first polyplex comprise a first conjugate of the Formula I, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or enantiomer thereof, and a first _{nucleic acid, wherein said first nucleic acid is preferably non-covalently bound to said} conjugate: R² L wherein: i_{s a single bond or a double bond, preferably a double bond;} n is any integer between 1 and 1500, preferably any integer between 2 and 1500; m is 36; R¹ is an initiation residue, wherein preferably R¹ is -H or -CH₃; _{P6797PC00 – 62 –} R² is independently -H or an organic residue, wherein at least 80%, preferably wherein _{at least 90%, of said R2 in said -(NR2-CH2-CH2)n– is H, further preferably said R2 is H;} Ring A is a 5 to 10-membered cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl, optionally substituted at any position with one or more R^A1; R^A1 is independently selected from C₁-C₆ alkyl, C₁-C₆ alkoxy, oxo, or halogen; or two R^A1, together with the atoms to which they are attached, can combine to form one or more fused C6-C10 aryl, C5-C6 heteroaryl, or C3-C6 cycloalkyl rings, wherein each fused aryl, heteroaryl, or cycloalkyl is optionally substituted with one or more R^A2; R^A2 is independently selected from C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen -SO₃H, or -OSO₃H; X¹ is a linking moiety of the formula –(Y¹)p–, wherein p is an integer between 1 and 20, and each occurrence of Y¹ is independently selected from a chemical bond, -CR¹¹R¹²-, -C(O)-, -O-, -S-, -NR¹³-, an amino acid residue, a divalent phenyl moiety, a divalent carbocycle moiety, a divalent heterocycle moiety, and a divalent heteroaryl moiety, wherein each divalent phenyl or heteroaryl is optionally substituted with one or more R¹³, and each divalent heterocycle is optionally substituted with one or more R¹⁴; wherein R¹¹, R¹² and R¹³ are independently, at each occurrence, H, -SO3H, -NH2, -CO2H, or C1-C6 alkyl, wherein each alkyl is optionally substituted with -CO2H or -NH2; and wherein R¹⁴ is independently, at each occurrence, H, C1- C₆ alkyl, or oxo, C₆-C₁₀ aryl, or 5 to 8-membered heteroaryl; X² is a linking moiety of the formula –(Y²)_q–, wherein q is an integer between 1 and 50, and each occurrence of Y² is independently selected from a chemical bond, -CR²¹R²²-, NR²³-, -O-, -S-, -C(O)-, an amino acid residue, a divalent phenyl moiety, a divalent carbocycle moiety a divalent heterocycle moiety, and a divalent heteroaryl moiety, wherein each divalent phenyl and divalent heteroaryl is optionally substituted with one or more R²³, and wherein each divalent heterocycle moiety is optionally substituted with one or more R²⁴; wherein R^21, R^22, and R²³ are each independently, at each occurrence, -H, -SO3H, -NH2, -CO2H, or C1-C6 alkyl, wherein each C1-C6 alkyl is optionally substituted with one or more -OH, oxo, -CO2H, -NH2, C6-C10 aryl, or 5 to 8-membered heteroaryl; and wherein R²⁴ is independently, at each occurrence, -H, -CO₂H, C₁-C₆ alkyl, or oxo; and L is a targeting fragment, wherein preferably said targeting fragment is capable of binding to a cell, and wherein further preferably said targeting fragment is capable of binding to a cell surface receptor, and _{P6797PC00 – 63 –} wherein said first nucleic acid is an mRNA encoding a Cas protein, preferably wherein said Cas protein is Cas9. In a preferred embodiment, said R¹ is -H. In a preferred embodiment, said R¹ is -CH3. In another aspect, the present invention provides a composition comprising a first polyplex, wherein said first polyplex comprise a first conjugate of the Formula I, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or enantiomer thereof, and a first _{nucleic acid, wherein said first nucleic acid is preferably non-covalently bound to said} conjugate: R² L wherein: i_{s a single bond or a double bond, preferably a double bond;} n is any integer between 1 and 1500, preferably any integer between 2 and 1500; m is 36; R¹ is an initiation residue, wherein preferably R¹ is -H or -CH3; R² is independently -H or an organic residue, wherein at least 80%, preferably wherein _{at least 90%, of said R2 in said -(NR2-CH2-CH2)n– is H, further preferably said R2 is H;} Ring A is a 5 to 10-membered cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl, optionally substituted at any position with one or more R^A1; R^A1 is independently selected from C₁-C₆ alkyl, C₁-C₆ alkoxy, oxo, or halogen; or two R^A1, together with the atoms to which they are attached, can combine to form one or more fused C6-C10 aryl, C5-C6 heteroaryl, or C3-C6 cycloalkyl rings, wherein each fused aryl, heteroaryl, or cycloalkyl is optionally substituted with one or more R^A2; R^A2 is independently selected from C₁-C₆ alkyl, C1-C6 alkoxy, halogen -SO3H, or -OSO3H; X¹ is a linking moiety of the formula –(Y¹)_p–, wherein p is an integer between 1 and 20, and each occurrence of Y¹ is independently selected from a chemical bond, -CR¹¹R¹²-, -C(O)-, -O-, -S-, -NR¹³-, an amino acid residue, a divalent phenyl moiety, a divalent carbocycle moiety, a divalent heterocycle moiety, and a divalent heteroaryl moiety, wherein each divalent phenyl or heteroaryl is optionally substituted with one or more R¹³, and each divalent heterocycle is optionally substituted with one or more R¹⁴; wherein R¹¹, R¹² and R¹³ are independently, at each _{P6797PC00 – 64 –} occurrence, H, -SO3H, -NH2, -CO2H, or C1-C6 alkyl, wherein each alkyl is optionally substituted with -CO₂H or -NH₂; and wherein R¹⁴ is independently, at each occurrence, H, C₁- C6 alkyl, or oxo, C6-C10 aryl, or 5 to 8-membered heteroaryl; X² is a linking moiety of the formula –(Y²)_q–, wherein q is an integer between 1 and 50, and each occurrence of Y² is independently selected from a chemical bond, -CR²¹R²²-, NR²³-, -O-, -S-, -C(O)-, an amino acid residue, a divalent phenyl moiety, a divalent carbocycle moiety a divalent heterocycle moiety, and a divalent heteroaryl moiety, wherein each divalent phenyl and divalent heteroaryl is optionally substituted with one or more R²³, and wherein each divalent heterocycle moiety is optionally substituted with one or more R²⁴; wherein R^21, R^22, and R²³ are each independently, at each occurrence, -H, -SO3H, -NH2, -CO2H, or C1-C6 alkyl, wherein each C₁-C₆ alkyl is optionally substituted with one or more -OH, oxo, -CO₂H, -NH₂, C6-C10 aryl, or 5 to 8-membered heteroaryl; and wherein R²⁴ is independently, at each occurrence, -H, -CO₂H, C₁-C₆ alkyl, or oxo; and L is a targeting fragment, wherein preferably said targeting fragment is capable of binding to a cell, and wherein further preferably said targeting fragment is capable of binding to a cell surface receptor wherein said cell surface receptor is EGFR, and wherein further preferably said targeting fragment is hEGF, and wherein said first nucleic acid is an mRNA encoding a Cas protein, preferably wherein said Cas protein is Cas9. In a preferred embodiment, said R¹ is -H. In a preferred embodiment, said R¹ is -CH3. In some embodiments, said first polyplex can further comprise a second nucleic acid, preferably wherein said second nucleic acid is a gRNA. In preferred embodiments, said first polyplex can further comprise a third nucleic acid, preferably wherein said third nucleic acid is a template DNA. In another aspect, the present invention provides a composition comprising a second polyplex, wherein said second polyplex comprise a second conjugate of the Formula I, or a _{pharmaceutically acceptable salt, solvate, hydrate, tautomer or enantiomer thereof, and a second} _{nucleic acid, wherein said second nucleic acid is preferably non-covalently bound to said} conjugate: R² L _{P6797PC00 – 65 –} Formula I wherein: i_{s a single bond or a double bond, preferably a double bond;} n is any integer between 1 and 1500, preferably any integer between 2 and 1500; m is a discrete number of repeating units m of 2 to 100, preferably of a discrete number of repeating units m of 4 to 60, and wherein preferably said discrete number m is a discrete _{number of contiguous repeating -(O-CH2-CH2)- units, and wherein said discrete number of} _{contiguous repeating -(O-CH2-CH2)- units) is any discrete number of 2 to 100, preferably of 4} to 60, most preferably 36; R¹ is an initiation residue, wherein preferably R¹ is -H or -CH3; R² is independently -H or an organic residue, wherein at least 80%, preferably wherein _{at least 90%, of said R2 in said -(NR2-CH2-CH2)n– is H, further preferably said R2 is H;} Ring A is a 5 to 10-membered cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl, optionally substituted at any position with one or more R^A1; R^A1 is independently selected from C₁-C₆ alkyl, C₁-C₆ alkoxy, oxo, or halogen; or two R^A1, together with the atoms to which they are attached, can combine to form one or more fused C6-C10 aryl, C5-C6 heteroaryl, or C3-C6 cycloalkyl rings, wherein each fused aryl, heteroaryl, or cycloalkyl is optionally substituted with one or more R^A2; R^A2 is independently selected from C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen -SO₃H, or -OSO₃H; X¹ is a divalent covalent linking moiety; X² is a divalent covalent linking moiety; and L is a targeting fragment, wherein preferably said targeting fragment is capable of binding to a cell, and wherein further preferably said targeting fragment is capable of binding to a cell surface receptor, and wherein said second nucleic acid is gRNA. In a preferred embodiment, said R¹ is -H. In a preferred embodiment, said R¹ is -CH3. In another aspect, the present invention provides a composition comprising a second polyplex, wherein said second polyplex comprise a second conjugate of the Formula I, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or enantiomer thereof, and a second _{nucleic acid, wherein said second nucleic acid is preferably non-covalently bound to said} conjugate: _{P6797PC00 – 66 –} R² L wherein: i_{s a single bond or a double bond, preferably a double bond;} n is any integer between 1 and 1500, preferably any integer between 2 and 1500; m is 36; R¹ is an initiation residue, wherein preferably R¹ is -H or -CH₃; R² is independently -H or an organic residue, wherein at least 80%, preferably wherein _{at least 90%, of said R2 in said -(NR2-CH2-CH2)n– is H, further preferably said R2 is H;} Ring A is a 5 to 10-membered cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl, optionally substituted at any position with one or more R^A1; R^A1 is independently selected from C₁-C₆ alkyl, C₁-C₆ alkoxy, oxo, or halogen; or two R^A1, together with the atoms to which they are attached, can combine to form one or more fused C6-C10 aryl, C₅-C₆ heteroaryl, or C₃-C₆ cycloalkyl rings, wherein each fused aryl, heteroaryl, or cycloalkyl is optionally substituted with one or more R^A2; R^A2 is independently selected from C1-C6 alkyl, C₁-C₆ alkoxy, halogen -SO₃H, or -OSO₃H; X¹ is a linking moiety of the formula –(Y¹)p–, wherein p is an integer between 1 and 20, and each occurrence of Y¹ is independently selected from a chemical bond, -CR¹¹R¹²-, -C(O)-, -O-, -S-, -NR¹³-, an amino acid residue, a divalent phenyl moiety, a divalent carbocycle moiety, a divalent heterocycle moiety, and a divalent heteroaryl moiety, wherein each divalent phenyl or heteroaryl is optionally substituted with one or more R¹³, and each divalent heterocycle is optionally substituted with one or more R¹⁴; wherein R¹¹, R¹² and R¹³ are independently, at each occurrence, H, -SO₃H, -NH₂, -CO₂H, or C₁-C₆ alkyl, wherein each alkyl is optionally substituted with -CO2H or -NH2; and wherein R¹⁴ is independently, at each occurrence, H, C1- C₆ alkyl, or oxo, C₆-C₁₀ aryl, or 5 to 8-membered heteroaryl; X² is a linking moiety of the formula –(Y²)q–, wherein q is an integer between 1 and 50, and each occurrence of Y² is independently selected from a chemical bond, -CR²¹R²²-, NR²³-, -O-, -S-, -C(O)-, an amino acid residue, a divalent phenyl moiety, a divalent carbocycle moiety a divalent heterocycle moiety, and a divalent heteroaryl moiety, wherein each divalent phenyl and divalent heteroaryl is optionally substituted with one or more R²³, and wherein each _{P6797PC00 – 67 –} divalent heterocycle moiety is optionally substituted with one or more R²⁴; wherein R^21, R^22, and R²³ are each independently, at each occurrence, -H, -SO₃H, -NH₂, -CO₂H, or C₁-C₆ alkyl, wherein each C1-C6 alkyl is optionally substituted with one or more -OH, oxo, -CO2H, -NH2, C₆-C₁₀ aryl, or 5 to 8-membered heteroaryl; and wherein R²⁴ is independently, at each occurrence, -H, -CO₂H, C₁-C₆ alkyl, or oxo; and L is a targeting fragment, wherein preferably said targeting fragment is capable of binding to a cell, and wherein further preferably said targeting fragment is capable of binding to a cell surface receptor, and wherein said second nucleic acid is gRNA. In a preferred embodiment, said R¹ is -H. In a preferred embodiment, said R¹ is -CH3. In another aspect, the present invention provides a composition comprising a second polyplex, wherein said second polyplex comprise a second conjugate of the Formula I, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or enantiomer thereof, and a second _{nucleic acid, wherein said second nucleic acid is preferably non-covalently bound to said} conjugate: R² L wherein: i_{s a single bond or a double bond, preferably a double bond;} n is any integer between 1 and 1500, preferably any integer between 2 and 1500; m is 36; R¹ is an initiation residue, wherein preferably R¹ is -H or -CH3; R² is independently -H or an organic residue, wherein at least 80%, preferably wherein _{at least 90%, of said R2 in said -(NR2-CH2-CH2)n– is H, further preferably said R2 is H;} Ring A is a 5 to 10-membered cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl, optionally substituted at any position with one or more R^A1; R^A1 is independently selected from C₁-C₆ alkyl, C₁-C₆ alkoxy, oxo, or halogen; or two R^A1, together with the atoms to which they are attached, can combine to form one or more fused C6-C10 aryl, C₅-C₆ heteroaryl, or C₃-C₆ cycloalkyl rings, wherein each fused aryl, heteroaryl, or cycloalkyl _{P6797PC00 – 68 –} is optionally substituted with one or more R^A2; R^A2 is independently selected from C1-C6 alkyl, C₁-C₆ alkoxy, halogen -SO₃H, or -OSO₃H; X¹ is a linking moiety of the formula –(Y¹)p–, wherein p is an integer between 1 and 20, and each occurrence of Y¹ is independently selected from a chemical bond, -CR¹¹R¹²-, -C(O)-, -O-, -S-, -NR¹³-, an amino acid residue, a divalent phenyl moiety, a divalent carbocycle moiety, a divalent heterocycle moiety, and a divalent heteroaryl moiety, wherein each divalent phenyl or heteroaryl is optionally substituted with one or more R¹³, and each divalent heterocycle is optionally substituted with one or more R¹⁴; wherein R¹¹, R¹² and R¹³ are independently, at each occurrence, H, -SO₃H, -NH₂, -CO₂H, or C₁-C₆ alkyl, wherein each alkyl is optionally substituted with -CO2H or -NH2; and wherein R¹⁴ is independently, at each occurrence, H, C1- C₆ alkyl, or oxo, C₆-C₁₀ aryl, or 5 to 8-membered heteroaryl; X² is a linking moiety of the formula –(Y²)q–, wherein q is an integer between 1 and 50, and each occurrence of Y² is independently selected from a chemical bond, -CR²¹R²²-, NR²³-, -O-, -S-, -C(O)-, an amino acid residue, a divalent phenyl moiety, a divalent carbocycle moiety _{a divalent heterocycle moiety, and a divalent heteroaryl moiety, wherein each divalent phenyl} and divalent heteroaryl is optionally substituted with one or more R²³, and wherein each divalent heterocycle moiety is optionally substituted with one or more R²⁴; wherein R^21, R^22, and R²³ are each independently, at each occurrence, -H, -SO₃H, -NH₂, -CO₂H, or C₁-C₆ alkyl, wherein each C₁-C₆ alkyl is optionally substituted with one or more -OH, oxo, -CO₂H, -NH₂, C6-C10 aryl, or 5 to 8-membered heteroaryl; and wherein R²⁴ is independently, at each _{occurrence, -H, -CO2H, C1-C6 alkyl, or oxo; and} L is a targeting fragment, wherein preferably said targeting fragment is capable of binding to a cell, and wherein further preferably said targeting fragment is capable of binding _{to a cell surface receptor wherein said cell surface receptor is EGFR, and wherein further} preferably said targeting fragment is hEGF, and wherein said second nucleic acid is a gRNA. In a preferred embodiment, said R¹ is -H. In a preferred embodiment, said R¹ is -CH3. W_{hen two polyplexes are present in said composition as described herein, either said} first or said second polyplex can further comprise a third nucleic acid, preferably wherein said third nucleic acid is a template DNA. Thus, in some embodiments, said composition comprises a first polyplex and a second polyplex, wherein said first polyplex comprises a first nucleic acid and a third nucleic acid, and wherein said second polyplex comprises a second nucleic acid. In some embodiments, said composition comprises a first polyplex and a second polyplex, _{P6797PC00 – 69 –} wherein said first polyplex comprises a first nucleic acid, and wherein said second polyplex comprises a second nucleic acid and a third nucleic acid. Most preferably wherein said first nucleic acid is an mRNA encoding a Cas protein, preferably Cas9; said second nucleic acid is a gRNA; and said third nucleic acid is a template DNA. In another aspect, the present invention provides a composition comprising a third polyplex, wherein said third polyplex comprise a third conjugate of the Formula I, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or enantiomer thereof, and a third _{nucleic acid, wherein said third nucleic acid is preferably non-covalently bound to said} conjugate: R² L wherein: i_{s a single bond or a double bond, preferably a double bond;} n is any integer between 1 and 1500, preferably any integer between 2 and 1500; m is a discrete number of repeating units m of 2 to 100, preferably of a discrete number of repeating units m of 4 to 60, and wherein preferably said discrete number m is a discrete _{number of contiguous repeating -(O-CH2-CH2)- units, and wherein said discrete number of} _{contiguous repeating -(O-CH2-CH2)- units) is any discrete number of 2 to 100, preferably of 4} to 60, most preferably 36; R¹ is an initiation residue, wherein preferably R¹ is -H or -CH₃; R² is independently -H or an organic residue, wherein at least 80%, preferably wherein _{at least 90%, of said R2 in said -(NR2-CH2-CH2)n– is H, further preferably said R2 is H;} Ring A is a 5 to 10-membered cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl, optionally substituted at any position with one or more R^A1; R^A1 is independently selected from C₁-C₆ alkyl, C₁-C₆ alkoxy, oxo, or halogen; or two R^A1, together with the atoms to which they are attached, can combine to form one or more fused C6-C10 aryl, C₅-C₆ heteroaryl, or C₃-C₆ cycloalkyl rings, wherein each fused aryl, heteroaryl, or cycloalkyl is optionally substituted with one or more R^A2; R^A2 is independently selected from C1-C6 alkyl, C₁-C₆ alkoxy, halogen -SO₃H, or -OSO₃H; X¹ is a divalent covalent linking moiety; _{P6797PC00 – 70 –} X² is a divalent covalent linking moiety; and L is a targeting fragment, wherein preferably said targeting fragment is capable of binding to a cell, and wherein further preferably said targeting fragment is capable of binding to a cell surface receptor, and wherein said third nucleic acid is template DNA. In a preferred embodiment, said R¹ is -H. In a preferred embodiment, said R¹ is -CH3. In another aspect, the present invention provides a composition comprising a third polyplex, wherein said third polyplex comprise a third conjugate of the Formula I, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or enantiomer thereof, and a third _{nucleic acid, wherein said third nucleic acid is preferably non-covalently bound to said} conjugate: R² L wherein: i_{s a single bond or a double bond, preferably a double bond;} n is any integer between 1 and 1500, preferably any integer between 2 and 1500; m is 36; R¹ is an initiation residue, wherein preferably R¹ is -H or -CH₃; R² is independently -H or an organic residue, wherein at least 80%, preferably wherein _{at least 90%, of said R2 in said -(NR2-CH2-CH2)n– is H, further preferably said R2 is H;} Ring A is a 5 to 10-membered cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl, optionally substituted at any position with one or more R^A1; R^A1 is independently selected from C₁-C₆ alkyl, C₁-C₆ alkoxy, oxo, or halogen; or two R^A1, together with the atoms to which they are attached, can combine to form one or more fused C6-C10 aryl, C₅-C₆ heteroaryl, or C₃-C₆ cycloalkyl rings, wherein each fused aryl, heteroaryl, or cycloalkyl is optionally substituted with one or more R^A2; R^A2 is independently selected from C1-C6 alkyl, C₁-C₆ alkoxy, halogen -SO₃H, or -OSO₃H; X¹ is a linking moiety of the formula –(Y¹)p–, wherein p is an integer between 1 and 20, and each occurrence of Y¹ is independently selected from a chemical bond, -CR¹¹R¹²-, -C(O)-, -O-, -S-, -NR¹³-, an amino acid residue, a divalent phenyl moiety, a divalent carbocycle moiety, _{P6797PC00 – 71 –} a divalent heterocycle moiety, and a divalent heteroaryl moiety, wherein each divalent phenyl or heteroaryl is optionally substituted with one or more R¹³, and each divalent heterocycle is optionally substituted with one or more R¹⁴; wherein R¹¹, R¹² and R¹³ are independently, at each occurrence, H, -SO₃H, -NH₂, -CO₂H, or C₁-C₆ alkyl, wherein each alkyl is optionally substituted with -CO₂H or -NH₂; and wherein R¹⁴ is independently, at each occurrence, H, C₁- C6 alkyl, or oxo, C6-C10 aryl, or 5 to 8-membered heteroaryl; X² is a linking moiety of the formula –(Y²)q–, wherein q is an integer between 1 and 50, and each occurrence of Y² is independently selected from a chemical bond, -CR²¹R²²-, NR²³-, -O-, -S-, -C(O)-, an amino acid residue, a divalent phenyl moiety, a divalent carbocycle moiety a divalent heterocycle moiety, and a divalent heteroaryl moiety, wherein each divalent phenyl and divalent heteroaryl is optionally substituted with one or more R²³, and wherein each divalent heterocycle moiety is optionally substituted with one or more R²⁴; wherein R^21, R^22, and R²³ are each independently, at each occurrence, -H, -SO₃H, -NH₂, -CO₂H, or C₁-C₆ alkyl, _{wherein each C1-C6 alkyl is optionally substituted with one or more -OH, oxo, -CO2H, -NH2,} C₆-C₁₀ aryl, or 5 to 8-membered heteroaryl; and wherein R²⁴ is independently, at each occurrence, -H, -CO2H, C1-C6 alkyl, or oxo; and L is a targeting fragment, wherein preferably said targeting fragment is capable of binding to a cell, and wherein further preferably said targeting fragment is capable of binding to a cell surface receptor, and wherein said third nucleic acid is template DNA. In a preferred embodiment, said R¹ is -H. In a preferred embodiment, said R¹ is -CH3. In another aspect, the present invention provides a composition comprising a third polyplex, wherein said third polyplex comprise a third conjugate of the Formula I, or a _{pharmaceutically acceptable salt, solvate, hydrate, tautomer or enantiomer thereof, and a third} _{nucleic acid, wherein said third nucleic acid is preferably non-covalently bound to said} conjugate: R² L wherein: i_{s a single bond or a double bond, preferably a double bond;} _{P6797PC00 – 72 –} n is any integer between 1 and 1500, preferably any integer between 2 and 1500; m is 36; R¹ is an initiation residue, wherein preferably R¹ is -H or -CH3; R² is independently -H or an organic residue, wherein at least 80%, preferably wherein _{at least 90%, of said R2 in said -(NR2-CH2-CH2)n– is H, further preferably said R2 is H;} Ring A is a 5 to 10-membered cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl, optionally substituted at any position with one or more R^A1; R^A1 is independently selected from C₁-C₆ alkyl, C₁-C₆ alkoxy, oxo, or halogen; or two R^A1, together with the atoms to which they are attached, can combine to form one or more fused C₆-C₁₀ aryl, C5-C6 heteroaryl, or C3-C6 cycloalkyl rings, wherein each fused aryl, heteroaryl, or cycloalkyl is optionally substituted with one or more R^A2; R^A2 is independently selected from C₁-C₆ alkyl, C1-C6 alkoxy, halogen -SO3H, or -OSO3H; X¹ is a linking moiety of the formula –(Y¹)_p–, wherein p is an integer between 1 and 20, and each occurrence of Y¹ is independently selected from a chemical bond, -CR¹¹R¹²-, -C(O)-, -O-, -S-, -NR¹³-, an amino acid residue, a divalent phenyl moiety, a divalent carbocycle moiety, a divalent heterocycle moiety, and a divalent heteroaryl moiety, wherein each divalent phenyl or heteroaryl is optionally substituted with one or more R¹³, and each divalent heterocycle is optionally substituted with one or more R¹⁴; wherein R¹¹, R¹² and R¹³ are independently, at each occurrence, H, -SO₃H, -NH₂, -CO₂H, or C₁-C₆ alkyl, wherein each alkyl is optionally substituted with -CO2H or -NH2; and wherein R¹⁴ is independently, at each occurrence, H, C1- C6 alkyl, or oxo, C6-C10 aryl, or 5 to 8-membered heteroaryl; X² is a linking moiety of the formula –(Y²)_q–, wherein q is an integer between 1 and 50, and each occurrence of Y² is independently selected from a chemical bond, -CR²¹R²²-, NR²³-, -O-, -S-, -C(O)-, an amino acid residue, a divalent phenyl moiety, a divalent carbocycle moiety a divalent heterocycle moiety, and a divalent heteroaryl moiety, wherein each divalent phenyl and divalent heteroaryl is optionally substituted with one or more R²³, and wherein each divalent heterocycle moiety is optionally substituted with one or more R²⁴; wherein R^21, R^22, and R²³ are each independently, at each occurrence, -H, -SO₃H, -NH₂, -CO₂H, or C₁-C₆ alkyl, wherein each C1-C6 alkyl is optionally substituted with one or more -OH, oxo, -CO2H, -NH2, C6-C10 aryl, or 5 to 8-membered heteroaryl; and wherein R²⁴ is independently, at each occurrence, -H, -CO₂H, C₁-C₆ alkyl, or oxo; and L is a targeting fragment, wherein preferably said targeting fragment is capable of binding to a cell, and wherein further preferably said targeting fragment is capable of binding _{P6797PC00 – 73 –} to a cell surface receptor wherein said cell surface receptor is EGFR, and wherein further preferably said targeting fragment is hEGF, and wherein said third nucleic acid is template DNA. In a preferred embodiment, said R¹ is -H. In a preferred embodiment, said R¹ is -CH₃. I_{n some preferred embodiments, the conjugates of the present invention comprise an} _{LPEI fragment present as a disperse polymeric moiety, wherein n is between about 280 and} about 700 with a dispersity of about 3 or less, preferably between about 350 and about 630 with _{a dispersity of about 2 or less, and more preferably between about 400 and 580 with a dispersity} about 1.2 or less, and wherein said conjugates of the present invention further comprise an PEG fragment present (i) as a disperse polymeric moiety, wherein m is between about 2 and about 80 and a dispersity of about 2 or less, preferably between about 2 and about 70 with a dispersity of about 1.8 or less; more preferably between about 2 and about 50 repeating units with a _{dispersity of about 1.5, or (ii) as a discrete number of repeating units m, wherein preferably} discrete number of repeating units m are 12 or 24 repeating units. In some embodiments, the conjugates of the present invention comprise an LPEI fragment present as a disperse polymeric moiety of about 17 and 25 KDa, with a dispersity of _{about 1.2 or less and a PEG fragment comprising, preferably consisting of, 12 repeating units.} _{In some preferred embodiments, the conjugates of the present invention can comprise an LPEI} _{fragment present as a disperse polymeric moiety with a molecular weight of between about 17} _{and 25 KDa, with a dispersity of about 1.2 or less and a PEG fragment, preferably consisting} of, 24 repeating units. Targeting Fragment T_{he inventive conjugates comprise a targeting fragment which allows to direct the} _{inventive conjugate and the inventive polyplex to a particular target cell type, collection of cells,} _{organ or tissue. Typically and preferably, the targeting fragment is capable of binding to a target} _{cell, preferably to a cell receptor or cell surface receptor thereof.} As used herein, the term “cell surface receptor”, as used herein refers to a protein, _{glycoprotein or lipoprotein which is present at the surface of the cell, and which is typically and} _{preferably a distinctive marker for the recognition of a cell. Typically and preferably, said cell} _{surface receptor is able to bind to a ligand which include hormones, neurotransmitters,} cytokines, growth factors, cell adhesion molecules, or nutrients, in the form of peptides, small _{P6797PC00 – 74 –} _{molecules, saccharides and oligosaccharides, lipids, amino acids, and such other binding} _{moieties such as antibodies, aptamers, affibodies, antibody fragments and the like.} The inventive conjugate and polyplex comprising the targeting fragment is aiming to mimic such ligand-receptor interaction. Thus, in a preferred embodiment, said targeting fragment is capable of binding to a cell surface receptor. In a preferred embodiment, said cell _{surface receptor is selected from a growth factor receptor, an extracellular matrix protein, a} peripheral membrane protein, a transmembrane protein, preferably transmembrane protein of type II, a cytokine receptor, a hormone receptor, a glycosylphosphatidylinositol (GPI) anchored membrane protein, a carbohydrate-binding integral membrane protein, an asialoglycoprotein _{receptor (ASGPr), a lectin, an ion channel, a G-protein coupled receptor, and an enzyme-linked} receptor such as a tyrosine kinase-coupled receptor. In a preferred embodiment, said targeting fragment is capable of binding to a cell surface receptor. In a preferred embodiment, said cell surface receptor is selected from a growth factor receptor, an extracellular matrix protein, a peripheral membrane protein, a transmembrane protein, preferably transmembrane protein of type II, a cytokine receptor, a hormone receptor, a glycosylphosphatidylinositol (GPI) anchored membrane protein, a carbohydrate-binding integral membrane protein a lectin, an ion channel, a G-protein coupled receptor, and an enzyme-linked receptor such as a tyrosine kinase-coupled receptor. In a preferred embodiment, said cell surface receptor is a growth factor receptor. In a preferred embodiment, said cell surface receptor is an extracellular matrix protein. In a preferred embodiment, said cell surface receptor is a cytokine receptor. In a preferred embodiment, said cell surface receptor is a _{hormone receptor. In a preferred embodiment, said cell surface receptor is a} glycosylphosphatidylinositol (GPI) anchored membrane protein. In a preferred embodiment, said cell surface receptor is a carbohydrate-binding integral membrane protein. In a preferred embodiment, said cell surface receptor is a lectin. In a preferred embodiment, said cell surface receptor is an ion channel. In a preferred embodiment, said cell surface receptor is an enzyme- linked receptor, wherein preferably said enzyme-linked receptor is a tyrosine kinase-coupled _{receptor. In a preferred embodiment, said cell surface receptor is a peripheral membrane} protein. In a preferred embodiment, said cell surface receptor is a transmembrane protein. In a preferred embodiment, said cell surface receptor is a transmembrane protein of type II. In a preferred embodiment, said cell surface receptor is selected from an epidermal _{growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), prostate} _{specific membrane antigen (PSMA), an insulin-like growth factor 1 receptor (IGF1R), a} _{P6797PC00 – 75 –} vascular endothelial growth factor receptor (VEGFR), a platelet-derived growth factor _{receptor (PDGFR) and a fibroblast growth factor receptor (FGFR). In a preferred embodiment,} said cell surface receptor is an epidermal growth factor receptor (EGFR). In a preferred _{embodiment, said cell surface receptor is a human epidermal growth factor receptor 2 (HER2).} _{In a preferred embodiment, said cell surface receptor is a prostate specific membrane antigen} (PSMA). In a preferred embodiment, said cell surface receptor is an insulin-like growth factor 1 receptor (IGF1R). In a preferred embodiment, said cell surface receptor is a vascular endothelial growth factor receptor (VEGFR). In a preferred embodiment, said cell surface _{receptor is a platelet-derived growth factor receptor (PDGFR). In a preferred embodiment, said} cell surface receptor is a fibroblast growth factor receptor (FGFR). The targeting fragment in accordance with the present invention aims to locate and to _{deliver, in particular to selectively deliver, the inventive polyplexes and payloads such as the} _{nucleic acids to the desired target, in particular to the desired target cell. In addition, the} inventive conjugate comprising said targeting fragment not only allows to selectively deliver _{the conjugate and polyplex to a target such as a target cell, but, in addition, allows to enable} _{internalization and to facilitate selective cellular uptake of the polyanion payload e.g., nucleic} acid payload, by the target, in particular by the target cell. Thus, the targeting fragment in _{accordance with the present invention represents a portion of the inventive conjugate and} _{polyplex that is capable of specific binding to a selected target, preferably to a selected target} cell, further preferably to a cell receptor. In a preferred embodiment, said targeting fragment is capable of binding to a target cell. In a preferred embodiment, said targeting fragment is capable of binding to a selected target cell type. In a preferred embodiment, said targeting fragment is capable of binding to a target _{cell receptor. In a preferred embodiment, said targeting fragment is capable of binding to a} target cell surface receptor. In a preferred embodiment, said targeting fragment functions to bind to a target cell. In a preferred embodiment, said targeting fragment functions to bind to a selected target cell type. In a preferred embodiment, said targeting fragment functions to bind to a target cell receptor, _{In a preferred embodiment, said targeting fragment functions to bind to a target cell surface} receptor. In a preferred embodiment, said targeting fragment is capable of specifically binding to a _{target cell. In a preferred embodiment, said targeting fragment is capable of specifically binding} to a selected target cell type. In a preferred embodiment, said targeting fragment is capable of _{P6797PC00 – 76 –} _{specifically binding to a target cell receptor. In a preferred embodiment, said targeting fragment} is capable of specifically binding to a target cell surface receptor. In one embodiment, said specifically binding to a target cell, to a target cell or to a target _{cell surface receptor, means that the targeting fragment and the inventive conjugate and/or} _{inventive polyplex, respectively, binds to said target cell, said target cell receptor, said target} _{cell surface receptor, at least twice, preferably at least three times, further preferably at least} four times, again further preferably at least five times as strong as it binds to other non-targeted _{cells, cell receptors, cell surface receptors, typically and preferably measured by the} _{dissociation constant (KD). Preferably, a targeting fragment binds to the selected cell surface} receptor with a KD of less than 10^-5 M, preferably less than 10^-6 M, more preferably less than 10^-7 M and even more preferably less than 10^-8 M. In one embodiment, said specifically binding to a target cell, to a target cell receptor or to a target cell surface receptor means that the targeting fragment and the inventive conjugate and/or inventive polyplex, respectively, binds to said target cell, said target cell receptor or said target cell surface receptor at least twice, preferably at least three times, further preferably at least five times, again further preferably at least ten times, further preferably at least hundred times as strong as the corresponding conjugate and/or polyplex that is identical to the inventive conjugate and/or the inventive polyplex but comprises instead of the targeting fragment a non- specific fragment such as an hydroxyl group or a -OMe moiety, preferably the -OMe moiety. The binding to the target cell, to the target cell receptor or to the target cell surface receptor is typically and preferably measured by the dissociation constant (KD). Preferably, a targeting fragment binds to the selected target cell surface receptor with a KD of less than 10^-5 M, _{preferably less than 10-6 M, more preferably less than 10-7 M and even more preferably less} _{than 10-8 M. In a preferred embodiment, said binding or said specific binding, and thus the level} _{of binding of the inventive conjugate and inventive polyplex, respectively, can be determined} by binding assays or displacement assays or by FRET or other measures demonstrating interaction between the targeting fragment and the cell receptor, preferably the cell surface receptor. The term “binding”, as used herein with reference to the binding of the targeting fragment _{to a cell, a cell receptor or a cell surface receptor refers preferably to interactions via non-} covalent binding, such as electrostatic interactions, van der Waals interaction, hydrogen bonds, hydrophobic interactions, ionic bonds, charge interactions, afﬁnity interactions, and/or dipole- dipole interactions. _{P6797PC00 – 77 –} In another embodiment, said specifically binding to a target cell, to a target cell receptor or to a target cell surface receptor results in a biological effect which is caused by said specific _{binding of the targeting fragment and inventive conjugate and/or the inventive polyplex,} _{respectively, and/or is caused by the delivered inventive conjugate and/or polyplex and} _{polyanion payload, e.g., nucleic acid payload, which biological effect is at least 2-fold,} preferably at least 3-fold, further preferably at least 5-fold and again further preferably at least 10-fold, and again further preferably at least 25-fold, at least 50-fold or at least 100-fold greater, as compared to said biological effect of a non-targeted cell, a non-targeted cell receptor or a non-targeted cell surface receptor. In another embodiment, said specifically binding to a target cell, to a target cell receptor, or to a target cell surface receptor results in a biological effect which is caused by said specific binding of the targeting fragment and inventive conjugate and/or the inventive polyplex, respectively, and/or is caused by the delivered inventive conjugate and/or polyplex and polyanion payload, e.g., nucleic acid payload, which biological effect is at least 2-fold, preferably at least 3-fold, further preferably at least 5-fold and again further preferably at least 10-fold, and again further preferably at least 25-fold, at least 50-fold or at least 100-fold greater, as compared to said biological effect caused by the corresponding conjugate and/or polyplex that is identical to the inventive conjugate and/or the inventive polyplex but comprises instead of the targeting fragment a non-specific fragment such as an hydroxyl group or a -OMe moiety, preferably the -OMe moiety. T_{he binding and specific binding can be determined as well by measures of activation of} protein signalling and therefore can be measured by protein phosphorylation or protein _{expression, mRNA expression in cells or tissues (using western blot analysis, real time PCR,} RNAseq IHC etc). The level of delivery of an inventive polyplex to a particular tissue may be _{measured by comparing the efficacy of the CRISPR/Cas9 gene editing components in a cell} with overexpression vs a cell with normal and low expression by means of western blot analysis or luminescence/fluorescent assay, flow cytometry assays or measuring the effect of _{CRISPR/Cas9 gene editing by measures of such as ELISA, ECLIA. One can compare the} amount of gene editing of a protein in cells/tissues with overexpression of the target receptor as compared to normal cells/tissues or cells/tissues with low expression by means of western blot analysis or luminescence/fluorescent assay, flow cytometry assays or measuring the extent _{of gene editing by measures of such as ELISA, ECLIA. One can measure the efficacy of the} CRISPR/Cas9 gene editing components by comparing the amount of protein modified in a _{P6797PC00 – 78 –} tissue to the weight of said tissue, or comparing the amount of protein modified in a tissue to the amount of total protein in said tissue. lt will be understood that the delivery of an inventive polyplex to a target cell or target tissue need not be determined in a subject being treated, it may be determined in a surrogate such as an animal model or a cellular model. T_{hus, in a preferred embodiment, said biological effect is the total amount of modified} protein compared to unmodified protein. In one embodiment, said target cells include, but are not limited to, hepatocytes, epithelial cells, hematopoietic cells, epithelial cells, endothelial cells, lung cells, bone cells, stem cells, mesenchymal cells, neural cells, cardiac cells, adipocytes, vascular smooth muscle cells. Thus, in one embodiment, the target cell is a cell in the liver. In one embodiment, the target cell is an epithelial cell. In one embodiment, the target cell is a hepatocyte. In one embodiment, the target cell is a hematopoietic cell. In one embodiment, the target cell is a muscle cell. In one _{embodiment, the target cell is an endothelial cell. In one embodiment the target cell is a tumor} cell or a cell in the tumor microenvironment. In one embodiment, the target cell is a blood cell. In one embodiment, the target cell is a cell in the lymph nodes. In one embodiment, the target cell is a cell in the lung. In one embodiment, the target cell is a cell in the skin. In one embodiment, the target cell is a spleen cell. In one embodiment, the target cell is an antigen presenting cell such as a professional antigen presenting cell in the spleen. In one embodiment, the target cell is a dendritic cell in the spleen. In one embodiment, the target cell is a T cell. In one embodiment, the target cell is a B cell. In one embodiment, the target cell is a NK cell. In one embodiment, the target cell is a monocyte. In some embodiments, said targeting fragment selectively or preferentially interacts with a particular cell type. The targeting fragment not only serves to selectively target the conjugates and polyplexes of present invention to a certain cell, but further typically facilitates selective uptake of the conjugates and corresponding polyplexes of the present invention within _{a certain cell type. In some embodiments, said targeting fragment selectively or preferentially} interacts with a particular cell surface receptor. When the targeting fragment of a conjugate and/or polyplex selectively or preferentially interacts with a cell surface receptor, the conjugate _{and/or polyplex can be selectively or preferentially taken up into the cell that comprises said} cell surface receptor. I_{n a preferred embodiment, said targeting fragment is a peptide, a protein, a small} molecule ligand, a saccharide, an oligosaccharide, a lipid, an amino acid, wherein said peptide, said protein, said small molecule ligand, said saccharide, said oligosaccharide, said lipid, said _{P6797PC00 – 79 –} _{amino acid is selected from a hormone, a neurotransmitter, a cytokine, a growth factor, a cell} _{adhesion molecule, or a nutrient, and wherein said targeting fragment is an antibody, an} _{antibody fragment, an aptamer or an affibody.} The term “small molecule ligand” as used herein, and in particular with reference to the inventive targeting fragment relates to a chemical moiety that has a molecular weight of at least 75 g/mol, preferably of at least 100 g/mol, and further preferably of at least 200 g/mol and has, preferably, a molecular weight of less than about 2000 g/mol. In some embodiments, the small _{molecule has a molecular weight of less than about 1500 g/mol, more preferably less than about} 1000 g/mol. In a further preferred embodiment, the small molecule has a molecular weight of less than about 800 g/mol, again more preferably less than about 500 g/mol. The term “small _{molecule ligand” as used herein, and in particular with reference to the inventive targeting} fragment shall further preferably relates to such ligand capable of binding, preferably _{specifically binding, to a target cell, to a target cell receptor, or preferably to a target cell surface} receptor. In a preferred embodiment, said small molecule ligand has a molecular weight of at least 75 g/mol, preferably of at least 100 g/mol, and further preferably of at least 200 g/mol and has, preferably, a molecular weight of less than about 2000 g/mol, preferably of less than about 1500 g/mol. In a preferred embodiment, said small molecule ligand has a molecular weight of at least 75 g/mol, preferably of at least 100 g/mol, and further preferably of at least 200 g/mol and has, preferably, a molecular weight of less than about 2000 g/mol, preferably of less than about 1500 g/mol, and wherein said small molecule ligand is capable of binding, preferably specifically binding, to a target cell surface receptor. In some embodiments, the targeting fragment is a native, natural or modified ligand or a paralog thereof, or a non-native ligand such as an antibody, a single-chain variable fragment _{(scFv), or an antibody mimetic such as an affibody. In a preferred embodiment, the targeting} fragment is a native, natural or modified cell surface antigen ligand or a paralog thereof, or a non-native cell surface antigen ligand such as an antibody, a single-chain variable fragment _{(scFv), or an antibody mimetic such as an affibody. In a preferred embodiment, the targeting} fragment is a native, natural or modified cell surface receptor ligand or a paralog thereof, or a non-native cell surface receptor ligand such as an antibody, a single-chain variable fragment _{(scFv), or an antibody mimetic such as an affibody. In a preferred embodiment, the targeting} fragment is a small molecule ligand, a peptide, a protein, an aptamer, a native, natural or modified ligand and/or a paralog thereof. In a preferred embodiment, the targeting fragment is a small molecule ligand, a peptide, a protein, an aptamer, a native, natural or modified cell _{P6797PC00 – 80 –} surface antigen ligand and/or a paralog thereof, wherein said small molecule ligand has a molecular weight of at least 75 g/mol, preferably of at least 100 g/mol, and further preferably of at least 200 g/mol and has, preferably, a molecular weight of less than about 2000 g/mol, _{preferably of less than about 1500 g/mol. In a preferred embodiment, the targeting fragment is} a small molecule ligand, a peptide, a protein, an aptamer, a native, natural or modified cell surface receptor ligand and/or a paralog thereof, wherein said small molecule ligand has a molecular weight of at least 75 g/mol, preferably of at least 100 g/mol, and further preferably of at least 200 g/mol and has, preferably, a molecular weight of less than about 2000 g/mol, _{preferably of less than about 1500 g/mol. In a preferred embodiment, the targeting fragment is} a small molecule ligand, a peptide, a protein, an aptamer, a native, natural or modified ligand and/or a paralog thereof, an antibody, a single-chain variable fragment (scFv), or an antibody mimetic such as an affibody. In a preferred embodiment, the targeting fragment is a small molecule ligand, a peptide, a protein, an aptamer, a native, natural or modified cell surface receptor ligand and/or a paralog thereof. In a preferred embodiment, the targeting fragment is a small molecule ligand, a peptide, a protein, an aptamer, a native, natural or modified ligand and/or a paralog thereof, and wherein said small molecule ligand, said peptide, said protein, said aptamer, said native, natural or modified ligand and/or said paralog thereof is capable of binding, preferably selectively binding, to a cell surface receptor. In a preferred embodiment, said targeting fragment is a small _{molecule ligand. In a preferred embodiment, said targeting fragment is a small molecule ligand,} wherein said small molecule ligand is capable of binding, preferably selectively binding, to a _{cell surface receptor. In a preferred embodiment, said targeting fragment is a peptide. In a} preferred embodiment, said targeting fragment is a peptide, wherein said peptide is capable of binding, preferably selectively binding, to a cell surface receptor. In a preferred embodiment, _{said targeting fragment is a protein. In a preferred embodiment, said targeting fragment is a} protein, wherein said protein is capable of binding, preferably selectively binding, to a cell _{surface receptor. In a preferred embodiment, said targeting fragment is an aptamer. In a} preferred embodiment, said targeting fragment is an aptamer, wherein said aptamer is capable of binding, preferably selectively binding, to a cell surface receptor. In a preferred embodiment, said targeting fragment is a native, natural or modified ligand and/or a paralog thereof, _{preferably a native, natural or modified cell surface receptor ligand and/or a paralog thereof. In} a preferred embodiment, said targeting fragment is a native, natural or modified ligand and/or _{a paralog thereof, wherein said native, natural or modified ligand and/or said paralog thereof is} _{P6797PC00 – 81 –} capable of binding, preferably selectively binding, to a cell surface receptor. In a preferred embodiment, said targeting fragment is an antibody, a single-chain variable fragment (scFv), _{or an antibody mimetic such as an affibody. In a preferred embodiment, said targeting fragment} is an antibody, a single-chain variable fragment (scFv), or an antibody mimetic such as an affibody, wherein said antibody, a single-chain variable fragment (scFv), or an antibody mimetic such as an affibody is capable of binding, preferably selectively binding, to a cell surface receptor. In a preferred embodiment, the targeting fragment is a small molecule ligand, a peptide, _{a protein, an aptamer, an antibody, an antibody fragment, preferably a single-chain variable} fragment (scFv), an antibody mimetic, preferably selected from an affibody, nanobody, diabody, designed ankyrin repeat protein (DARPin), a growth factor or a functional fragment thereof, preferably hEGF), a hormone or a functional fragment thereof, preferably insulin, a cytokine or a functional fragment thereof, an integrin, an interleukin or a functional fragment _{thereof, an enzyme, a nucleic acid, a fatty acid, a carbohydrate, mono-, oligo- or} polysaccharides, a peptidoglycan, a glycopeptide, asialoorosomucoid, mannose-6-phospate, mannose, Sialyl-Lewis^x, N-acetyllactosamine, galactose, lysosomotropic agents, and/or a nucleus localizing agents, preferably T-antigen, a tumor low pH insertion peptide (PHLIP), a p32 targeting peptide, preferably LyP-1 tumor homing peptide, insulin-like growth factor 1, vascular endothelial growth factor, platelet-derived growth factor, and/or a fibroblast growth factor. In some embodiments the targeting fragment is a non-native ligand such as an antibody or an antibody fragment (e.g., a single-chain variable fragment (scFv), an antibody mimetic such as an affibody, nanobody, diabody, designed ankyrin repeat protein (DARPin), or other antibody variant). In some embodiment, the targeting fragment is a growth factor or a fragment, _{preferably a functional fragment, thereof (e.g., hEGF); a hormone or a fragment preferably a} _{functional fragment, thereof (e.g., insulin), asialoorosomucoid, mannose-6-phospate, mannose,} Sialyl-Lewis^x, N-acetyllactosamine, galactose, lysosomotropic agents, and/or a nucleus localizing agents (e.g., T-antigen), a tumor low pH insertion peptide (PHLIP), a p32 targeting peptide such as LyP-1 tumor homing peptide, insulin-like growth factor 1, vascular endothelial growth factor, platelet-derived growth factor, and/or a fibroblast growth factor. Further non- limiting examples of targeting fragments include an enzyme, a nucleic acid, a fatty acid, a _{carbohydrate, mono-, oligo- or polysaccharides, a peptidoglycan, a glycopeptide.} _{In a preferred embodiment, said targeting fragment is a small molecule ligand, a peptide,} _{P6797PC00 – 82 –} a protein, an aptamer, an antibody, an antibody fragment, preferably a Fab, Fab', F(ab')2 or a scFv fragment, an antibody mimetic, preferably selected from an affibody, nanobody, diabody, designed ankyrin repeat protein (DARPin), a growth factor or a functional fragment thereof, preferably hEGF, a hormone or a functional fragment thereof, preferably insulin, a cytokine or a functional fragment thereof, an interleukin or a functional fragment thereof, an enzyme, a _{nucleic acid, a fatty acid, a carbohydrate, mono-, oligo- or polysaccharides, a peptidoglycan, a} glycopeptide, asialoorosomucoid, mannose-6-phospate, mannose, Sialyl-Lewis^x, N- acetyllactosamine, galactose, lysosomotropic agents, and/or a nucleus localizing agents, preferably T-antigen, a tumor low pH insertion peptide (PHLIP), a p32 targeting peptide, preferably LyP-1 tumor homing peptide, insulin-like growth factor 1, vascular endothelial growth factor, platelet-derived growth factor, and/or a fibroblast growth factor. In some embodiments, said targeting fragment L is selected from hEGF; an anti-HER2 _{peptide, preferably an anti-HER2 antibody or affibody; DUPA; a folate receptor-targeting} _{fragment, folic acid; a somatostatin receptor-targeting fragment, preferably somatostatin and/or} octreotide; an integrin-targeting fragment, preferably an arginine-glycine-aspartic acid (RGD)- containing fragment; a low pH insertion peptide; an asialoglycoprotein receptor-targeting fragment, preferably asialoorosomucoid; an insulin-receptor targeting fragment, preferably insulin; a mannose-6-phosphate receptor targeting fragment, preferably mannose-6-phosphate; a mannose-receptor targeting fragment, preferably mannose; a Sialyl Lewis^x antigen targeting fragments, preferably E-selectin; a sigma-2 receptor agonist, preferably N,N- dimethyltryptamine (DMT), sphingolipid-derived amine, and/or steroid, more preferably progesterone; a p32-targeting ligand, preferably anti-p32 antibody or p32-binding LyP-1 tumor- homing peptide; a Trop-2 targeting fragment, preferably an anti-Trop-2 antibody and/or antibody fragment; insulin-like growth factor 1; vascular endothelial growth factor; platelet- derived growth factor; and fibroblast growth factor. In some embodiments, said targeting fragment L is selected from a targeting fragment derived from hEGF; an anti-HER2 peptide, preferably an anti-HER2 antibody or affibody; DUPA; folic acid; a somatostatin receptor-targeting fragment, preferably somatostatin and/or octreotide; an integrin-targeting fragment, preferably an arginine-glycine-aspartic acid (RGD)- containing fragment; a low pH insertion peptide; asialoglycoprotein receptor-targeting fragment, , preferably asialoorosomucoid; an insulin-receptor targeting fragment, preferably insulin; a mannose-6-phosphate receptor targeting fragment, preferably mannose-6-phosphate; a mannose-receptor targeting fragment, preferably mannose; a Sialyl Lewis^x antigen targeting _{P6797PC00 – 83 –} fragments, preferably E-selectin; a sigma-2 receptor agonist, preferably N,N- dimethyltryptamine (DMT), sphingolipid-derived amine, and/or steroid, more preferably progesterone; a p32-targeting ligand, preferably anti-p32 antibody or p32-binding LyP-1 tumor- _{homing peptide; a Trop-2 targeting fragment, preferably an anti-Trop-2 antibody and/or} antibody fragment; insulin-like growth factor 1; vascular endothelial growth factor; platelet- derived growth factor; and fibroblast growth factor. In a preferred embodiment, said targeting fragment is selected from an EGFR targeting fragment; a PSMA targeting fragment; an anti-HER2 peptide, preferably an anti-HER2 antibody or affibody; folic acid; a somatostatin receptor-targeting fragment, preferably somatostatin and/or octreotide; an integrin-targeting fragment, preferably an arginine-glycine- aspartic acid (RGD)-containing fragment; a low pH insertion peptide; asialoglycoprotein receptor-targeting fragment, preferably asialoorosomucoid; an insulin-receptor targeting fragment, preferably insulin; a mannose-6-phosphate receptor targeting fragment, preferably mannose-6-phosphate; a mannose-receptor targeting fragment, preferably mannose; a Sialyl Lewis^x antigen targeting fragments, preferably E-selectin; a sigma-2 receptor agonist, preferably N,N-dimethyltryptamine (DMT), sphingolipid-derived amine, and/or steroid, more preferably progesterone; a p32-targeting ligand, preferably anti-p32 antibody or p32-binding _{LyP-1 tumor-homing peptide; a Trop-2 targeting fragment, preferably an anti-Trop-2 antibody} and/or antibody fragment; insulin-like growth factor 1; vascular endothelial growth factor; platelet-derived growth factor; and fibroblast growth factor. In a preferred embodiment, the targeting fragment is an epidermal growth factor such as human epidermal growth factor (hEGF), wherein typically and preferably said coupling to the rest of said conjugate is effected via an amino group of said hEGF. The hEGF can be _{selectively taken up by cells that have increased expression (e.g., overexpression) of human} epidermal growth factor receptor (EGFR). In a preferred embodiment, said targeting fragment is capable of binding to epidermal growth factor receptor (EGFR), which is also named herein as EGFR targeting fragment. EGFR is a transmembrane glycoprotein that is a member of the protein kinase superfamily and a receptor for members of the epidermal growth factor family. EGFR is a cell surface protein that binds to epidermal growth factor, thus inducing receptor dimerization and tyrosine autophosphorylation leading to cell proliferation. In a preferred embodiment, said _{EGFR targeting fragment is capable of binding to epitopes on the extracellular domain of} EGFR. _{P6797PC00 – 84 –} In a preferred embodiment, said targeting fragment is capable of binding to a cell EGFR expressing. In a preferred embodiment, said targeting fragment is capable of binding to a cell overexpressing EGFR. In one embodiment, said cell overexpressing EGFR means that the level of EGFR expressed in said cell of a certain tissue is elevated in comparison to the level of EGFR as measured in a normal healthy cell of the same type of tissue under analogous conditions. In one embodiment, said cell overexpressing EGFR refers to an increase in the level of EGFR in a cell relative to the level in the same cell or closely related non-malignant cell under normal physiological conditions. In one embodiment, said cell overexpressing EGFR relates to expression of EGFR that is at least 10-fold, further preferably at least 20-fold, as compared to _{the expression of EGFR in a normal cell or in a normal tissue.} In a preferred embodiment, said targeting fragment is capable of binding to a cell expressing or overexpressing EGFR. For example, EGFR is overexpressed in neoplastic tissue and cancer types, such as glioma and carcinoma or cancer of epithelial origin, including of head and neck, thyroid, breast, ovarian, colon, gastric colorectal, stomach small intestine, cervix, bladder, lung, nasopharyngeal and esophageal tissue, such as squamous cells (e.g., Gan et al., J Cell Mol Med.2009 Sep; 13(9b): 3993–4001; Aratani et al., Anticancer Research June 2017, _{37 (6) 3129-3135), in particular in glioma, non-small-cell-lung-carcinoma, breast cancer,} _{glioblastoma, squamous cell carcinoma, e.g. head and neck squamous cell carcinoma, small} intestinal, colorectal cancer, adenocarcinoma, ovary cancer, bladder cancer or prostate cancer, and metastases thereof. EGFR expression and overexpression are detected preferably using a monoclonal antibody targeting EGFR, e.g. by immunohistochemical methods (as e.g. described in Kriegs et al., Nature, 2019, 9:13564; Prenzel et al., Endocr Relat Cancer 8, 11-31, 2001). A cut-off of 5% or more EGFR positive cells can be used to define EGFR expression in different types of _{tissues or cells. Thus, cells or tissue with <5% positive cells can be considered to be negative.} In a preferred embodiment, said targeting fragment is capable of specifically binding to EGFR. Typically, specific binding refers to a binding affinity or dissociation constant KD of the targeting fragment in the range of between about 1 x 10^-3 M and about 1 x 10^-12 M. In preferred embodiment, said targeting fragment is capable of specifically binding to EGFR, wherein typically and preferably said affinity or specific binding is measured by the dissociation constant (K_D) and said affinity or specific binding refers to a K_D of less than 10^-3 M, preferably of less than 10^-4 M, further preferably of less than 10^-5 M, further preferably of less than 10^-6 M, more preferably of less than 10^-7 M and even more preferably of less than 10^-8 M, and again _{P6797PC00 – 85 –} further preferably of less than 10^-9 M. In a preferred embodiment, said targeting fragment is capable of specifically binding to EGFR, wherein typically and preferably said affinity or _{specific binding is measured by the dissociation constant (KD) and said specific binding refers} to a K_D of less than 10^-3 M, of less than 10^-4 M, of less than 10^-5 M, of less than 10^-6 M, of less than 10^-7 M, of less than 10^-8 M, and of less than 10^-9 M. To detect binding or the complex or measure affinity, molecules can be analyzed using a competition binding assay, typically and preferably such as Biacore 3000 instrument (Biacore Inc., Piscataway NJ; as described, for example, in Wei-Ting Kuo et al., PLoS One.2015, 10(2): e0116610 or in US2017224620A1). Preferably, binding results in formation of a complex between the EGFR targeting fragment and EGFR, wherein the binding or complex can be detected. I_{n a preferred embodiment, said targeting fragment is an EGFR antibody, an EGFR} affibody, an EGFR aptamer, an EGFR targeting peptide or an EGFR targeting tyrosine kinase inhibitor. In a preferred embodiment, said EGFR targeting fragment is an EGFR antibody, an EGFR affibody, an EGFR aptamer, an EGFR targeting peptide or an EGFR targeting tyrosine kinase inhibitor. In a preferred embodiment, said targeting fragment is an EGFR targeting peptide. An EGFR targeting peptide refers, typically and preferably, to peptide ligands of EGFR. Such peptide ligands are known to the skilled person and have been described, for example in _{US2017224620A1 and by Gent et al., 2018, Pharmaceutics 2018, 10, 2 (the disclosures of} _{which are incorporated herein by reference in its entirety). EGFR targeting peptides have low} immunogenic potential and show good penetration into solid tumor tissues. In a preferred embodiment, said EGFR targeting peptide has a molecular weight of about 1000 g/mol to about 2000 g/mol, preferably of about 1100 g/mol to about 1900g/mol, further preferably of about 1200 g/mol to about 1800 g/mol, and again more preferably of about 1300 g/mol to about 1700 g/mol. I_{n a preferred embodiment, the EGFR targeting peptide comprises, or preferably} _{consists of, the sequence YHWYGYTPQNVI (GE11) (SEQ ID NO:1). In a preferred} embodiment, said targeting fragment comprises, or preferably consists of, the sequence YHWYGYTPQNVI (GE11) (SEQ ID NO:1). GE-11 has excellent afﬁnity towards EGFR and shows also binding specificity for EGFR (kd = 22 nM) (Ruoslahtiet al., Adv. Mater.2012, 24, 3747–3756; Li et al., J. Res. Commun. 2005, 19, 1978–1985). GE11 moves from EGFR after the addition of the physiologic ligand EGF, demonstrating both its selective binding to EGFR _{and its receptor afﬁnity. GE11 has been reported to have a high potential to accelerate} _{P6797PC00 – 86 –} _{nanoparticle endocytosis due to an alternative EGFR-dependent actin-driven pathway.} (Mickeler et al., Nano Lett.2012, 12, 3417–3423; Song et al., FASEB J.2009, 23, 1396–1404) _{It has been showed that the EGFR level on the surface of cancer cells remains constant after} treatment with GE11 polyplexes, indicating an EGFR recycling process with a prolonged receptivity of the cells for circulating GE11 polyplexes. In a preferred embodiment, said EGFR targeting fragment comprises, or preferably _{consists of, GE11 (SEQ ID NO:1), in particular, in use for treating solid tumors characterized} by EGFR-overexpressing cells. The inventive conjugate and polyplexes comprising, or _{preferably consisting, GE11 as the targeting fragment are believed to be stable polyplexes} _{ensuring that the polyanion, e.g., nucleic acid payload is not released before the polyplex has} _{reached its target cell.} In a preferred embodiment, said targeting fragment is an EGFR antibody. An EGFR antibody refers to an antibody that binds to EGFR. In a preferred embodiment, said EGFR antibody is a human. In a preferred embodiment, said EGFR antibody is a humanized EGFR antibody. In a preferred embodiment, said EGFR antibody is a monoclonal human. In a preferred embodiment, said EGFR antibody is a humanized EGFR antibody. In a preferred embodiment, said EGFR antibody is a monoclonal fully human EGFR antibody. In another preferred embodiment, the EGFR antibody is a scFv or Fab fragment. EGFR antibodies are known to the skilled person and have been described for example in WO2008/105773 and in WO2017/185662 (the disclosure of which is incorporated herein by reference in its entirety) and include Bevacizumab, Panitumumab, Cetuximab, Tomuzotuximab, Futuximab, Zatuximab, Modotuximab, Imgatuzumab, Zalutumumab, Matuzumab, Necitumumab, Nimotuzumab, CEVIAvax EGF, clones EGFR, L8A4, E6.2, TH190DS, Pep2, Pep3, LR-DM1, P1X, YC088, ratML66, FM329, TGM10-1, F4, 2F8, 15H8, TAB-301MZ-S(P), mAb528, 2224, E7.6.3, C225, CBL155, MR1, MR1, L211C, N5-4, TH83DS, L2-12B, 15H8, 12Do3, 7A7, 42C11 (MOB-1078z), PABL-080, HPAB-2204LY- S(P), VHH205, ABT-806, , Tab-271MZ, Hu225, LA22, Fab fragment DL11, Fab fragment DX 1-6, VHH104, OA-cb6, 07D06, Fab fragment HPAB-0419-FY-F(E), Fab fragment TAB- 285MZ-F(E), Fab fragment TAB-293MZ-F(E), Fab fragment HPAB-0136-YJ-F(E), FGF-R2, EG-19-11, Fab fragment pSEX81-63, DX 1-4, scFv fragment DX 1-6, EG-26-11, EG-26-11, DX1-4, TAB-326MZ, scFv fragment 528, scFv fragment LA1, scFv fragment 07D06, single domain antibody VHH139, scFv fragment EG-19-11, single domain Antibody VHH134, single domain Antibody 9G8, ABT-414, AMG-595, and IMGN-289. One of ordinary skill in the art _{P6797PC00 – 87 –} will appreciate that any antibody that recognizes and/or speciﬁcally binds to EGFR may be used in accordance with the present invention. In a preferred embodiment, said targeting fragment is an EGFR inhibitor. An EGFR inhibitor refers to targeting fragment that block cell-surface localization and signaling of the EGFR, such as oligosaccharyltransferase inhibitors like nerve growth inhibitor-1; or EGFR kinase inhibitors, such as afatinib, erlotinib, osimertinib and gefitinib. EGFR inhibitors are known to the skilled person and have been described for example in WO2018078076 and in US2017224620A1 (the disclosure of which is incorporated herein by reference in its entirety). In a preferred embodiment, said targeting fragment is an EGFR aptamer. Preferred EGFR targeting aptamers include, but are not limited to those disclosed in Na Li et al. (PLoS One. 2011; 6(6): e20299), Deng-LiangWang et al. (Biochemical and Biophysical Res Com, 453(4), 2014, pp 681-685), Min Woo Kim et al. (Theranostics 2019; 9(3):837-852), Akihiro Eguchi et al. (JACS Au 2021, 1, 5, 578-585) or Yingpan Song et al. (RSC Adv., 2020, 10, 28355–28364), the disclosures of which are incorporated herein by reference in its entirety. T_{he term EGFR aptamer includes also EGFR aptamer derivatives and/or functional} fragments of EGFR aptamer. In some embodiments, in the EGFR aptamer derivatives fewer than 30, 25, 20, 15, 10, 5, 4, 3, 2, or 1 nucleic acid is substituted relative to the corresponding EGFR aptamer. In some embodiments, the sequences of the EGFR aptamer derivatives are at least 80%, preferably 85%, more preferably 90%, again more preferably 95%, most preferably 99% identical with the corresponding EGFR aptamer. In a preferred embodiment, said targeting fragment is an EGFR affibody. Preferred EGFR affibodies include, but are not limited to ZEGFR:1907, ZEGFR:2377 or ZEGFR:03115 (available from Affibody Medical AB) or the dimeric form of these affibodies. In a preferred embodiment said EGFR affibody has the sequence of SEQ ID NO:2. In a preferred embodiment, said targeting fragment is the EGFR ligand epidermal growth factor (EGF). Thus, in a preferred said targeting fragment is epidermal growth factor (EGF). In a preferred embodiment, said targeting fragment is human EGF (hEGF), mouse EGF (mEGF), rat EGF, or guinea pig EGF. In a very preferred embodiment, said targeting fragment is human EGF (hEGF). In a very preferred embodiment, said targeting fragment comprises, preferably consists of, the sequence of SEQ ID NO:3. In some embodiments, EGF is modified, e.g., by deleting or exchanging one or more amino acids or truncation of EGF. Modified and/or truncated EGF molecules are for example disclosed in WO2019023295A1. EGF has many residues conserved across rat, mouse, guinea _{P6797PC00 – 88 –} pig and human species (Savage et al., J. Biol. Chem.., 247: 7612-7621, 1973; Carpenter and Cohen, Ann. Rev. Biochem., 48: 193-316, 1979; Simpson et al., Eur J Biochem, 153:629-37, 1985). In particular, six cysteine residues at positions 6, 14, 20, 31, 33, and 42 are conserved as they form three disulfide bridges to provide conserved tertiary protein structure. Also conserved across all four species are residues as positions 7, 9, 11, 12, 13, 15, 18, 21, 24, 29, 32, 34, 36, 37, 39, 41, 46, and 47. Many of these residues may be expected to facilitate or provide key binding interactions with the corresponding EGFR. It has been described that both the full length human EGF (53 residues) and a truncated form (48 residues), which results from trypsin cleavage, retain strong binding affinity and activation of the EGFR (Calnan et al., 47(5):622-7, 2000; Gregory, Regul Pept, 22:217-26, 1988). Mutagenesis studies have been reported for various residues to correlate the effect of replacement of specific residues on binding of EGF to the EGFR or activation of the EGFR (Campion et al., Biochemistry, 29, 9988-9993, 1990; Engler et al., J. Biol. Chem., 267:2274-2281, 1992; Tadaki and Niyogi. J. Biol. Chem., 268: 10114-10119, 1993). An x-ray crystal structure of EGF bound to EGFR has been solved which shows key binding interactions and also identifies residues not directly involved in binding (Ogiso et al., Cell, Vol.110, 775-787, 2002). I_{n a preferred embodiment, said targeting fragment is capable of binding to prostate} _{specific membrane antigen (PSMA), which is also named herein as PSMA targeting fragment.} PSMA is a multifunctional transmembrane protein that functions as a glutamate carboxypeptidase and also demonstrates rapid, ligand-induced internalization and recycling (Liu H, et al., 1998, Cancer Res 58:4055–4060). PSMA is mainly expressed in four tissues of the body, including prostate epithelium, the proximal tubules of the kidney, the jejunal brush border of the small intestine and ganglia of the nervous system (Mhawech-Fauceglia et al., Histopathology 2007, 50:472–483). In a preferred embodiment, said targeting fragment is capable of binding to epitopes on the extracellular domain of PSMA. I_{n a preferred embodiment, said targeting fragment, preferably said PSMA targeting} fragment, is capable of binding to a cell expressing PSMA. In a preferred embodiment, said targeting fragment, preferably said PSMA targeting fragment, is capable of binding to a cell overexpressing PSMA. For example, PSMA is overexpressed in neoplastic tissue and in malignant prostate, especially in prostatic adenocarcinoma relative to normal tissue, and the level of PSMA expression is further up-regulated as the disease progresses into metastatic phases (Silver et al., 1997, Clin. Cancer Res., 3:81). PSMA is expressed and overexpressed also in other tumor types (Mhawech-Fauceglia et al., Histopathology 2007, 50:472–483; Israeli RS _{P6797PC00 – 89 –} _{et al, Cancer Res 1994, 54:1807-1811; Chang SS et al, Cancer Res 1999, 59:3192-198).} In one embodiment, said overexpressing PSMA means that the level of PSMA expressed in said cell of a certain tissue is elevated in comparison to the level of PSMA as measured in a normal healthy cell of the same type of tissue under analogous conditions. In one embodiment, said overexpressing PSMA refers to an increase in the level of PSMA in a cell relative to the level in the same cell or closely related non-malignant cell under normal physiological conditions. In one embodiment, said cell overexpressing PSMA relates to _{expression of PSMA that is at least 10-fold higher as compared to a normal cell or a normal} _{tissue. In one embodiment, said cell overexpressing PSMA relates to expression of PSMA with} a cut-off of 5% or more PSMA positive cells, as e.g. described in Mhawech-Fauceglia et al., 2007, which can be used to define PSMA expression in different types of tissues or cells. Thus, cells or tissue with < 5% positive cells was considered to be negative, or where the PSMA expression is categorized according to its intensity and scored as 0 (no expression), 1 (low expression), 2 (medium expression), and 3 (high expression), as described in Hupe et al., 2018 2018 (Hupe MC et al, Frontiers in Oncology 2018, 8 (623): 1-7). In a preferred embodiment, said targeting fragment is capable of binding to a cell expressing or overexpressing PSMA. Cells expressing PSMA typically include tumor cells, such as prostate, bladder, pancreas, lung, kidney, colon tumor cells, melanomas, and sarcomas. In a preferred embodiment said targeting fragment is capable of binding to a cell expressing or overexpressing PSMA, wherein said cell is a tumor cell, preferably selected from a prostate, a bladder, a pancreas, a lung, a kidney and a colon tumor cell, a melanoma, and a sarcoma. In a preferred embodiment said targeting fragment is capable of binding to a cell expressing or overexpressing PSMA, wherein said cell is a tumor cell, wherein said tumor cell is a prostate tumor cell. I_{n a preferred embodiment, said targeting fragment is capable of specifically binding to} PSMA, wherein typically and preferably said affinity or specific binding is measured by the dissociation constant (KD) and said affinity or specific binding refers to a KD of less than 10^-3 _{M, preferably of less than 10-4 M, further preferably of less than 10-5 M, further preferably of} less than 10^-6 M, more preferably of less than 10^-7 M and even more preferably of less than 10- ⁸ M, and again further preferably of less than 10^-9 M, and again further preferably of less than 10^-10 M. In a preferred embodiment, said targeting fragment is capable of specifically binding to PSMA, wherein typically and preferably said affinity or specific binding is measured by the dissociation constant (K_D) and said affinity or specific binding refers to a K_D of less than 10^-3 _{P6797PC00 – 90 –} M, of less than 10^-4 M, of less than 10^-5 M, of less than 10^-6 M, of less than 10^-7 M, of less than _{10-8 M, and of less than 10-9 M. Preferably, binding results in formation of a complex between} the targeting fragment and PSMA, wherein the binding or complex can be detected, typically _{and preferably using a Biacore 3000 instrument (Biacore Inc., Piscataway NJ) or or cell based} binding assays or Flow Induced Dispersion Analysis (FIDA), typically and preferably as described in Kularatne et al, Mol Pharm.2009 ; 6(3): 790–800. In a preferred embodiment, said targeting fragment is a PSMA antibody, a PSMA aptamer or a small-molecule PSMA targeting fragment. In a preferred embodiment, said PSMA targeting fragment is a PSMA antibody, a PSMA aptamer or a small-molecule PSMA targeting fragment. The term “small molecule PSMA targeting fragment” as used herein relates to a chemical moiety that has a molecular weight of less than about 2000 g/mol, and that is typically and preferably capable of binding to PSMA. In some embodiments, the small molecule PSMA targeting fragment has a molecular weight of less than about 1800 g/mol. In some embodiments, _{the small molecule PSMA targeting fragment has a molecular weight of less than about 1500} g/mol, more preferably less than about 1000 g/mol. In a further preferred embodiment, the small molecule has a molecular weight of less than about 800 g/mol, again more preferably less than about 500 g/mol. In some embodiments, said PSMA targeting fragment is a PSMA antibody that is an antibody capable of binding to PSMA. In some embodiments, said antibody is a monoclonal antibody, a polyclonal antibody, and/or an antibody fragment, preferably a functional fragment _{thereof, a chimeric antibody, a recombinant antibody, and/or a bi- or multispecific antibody.} Such PSMA antibodies include, but are not limited to, scFv antibodies A5, G0, G1, G2, and G4 and mAbs 3/E7, 3/F11, 3/A12, K7, K12, and D20 (Elsasser-Beile et al., 2006, Prostate, 66:1359); mAbs E99, J591, J533, and J415 (Liu et al., 1997, Cancer Res., 57:3629; Liu et al., 1998, Cancer Res., 58:4055; Fracasso et al., 2002, Prostate, 53:9; McDevitt et al., 2000, Cancer _{Res., 60:6095; McDevitt et al., 2001, Science, 294:1537; Smith-Jones et al., 2000, Cancer Res.,} 60:5237; Vallabhajosula et al., 2004, Prostate, 58:145; Bander et al., 2003, J. Urol., 170:1717; Patri et al., 2004, Bioconj. Chem., 15:1174; and U.S. Patent 7,163,680); mAb 7E11-C5.3 (Horoszewicz et al., 1987, Anticancer Res., 7:927); antibody 7E11 (Horoszewicz et al., 1987, Anticancer Res., 7:927; and U.S. Patent 5,162,504); and antibodies described in Chang et al., 1999, Cancer Res., 59:3192; Murphy et al., 1998, J. Urol., 160:2396; Grauer et al., 1998, Cancer Res., 58:4787; and Wang et al., 2001, Int. J. Cancer, 92:871. One of ordinary skill in the art will appreciate that any antibody that recognizes and/or speciﬁcally binds to PSMA may be used in _{P6797PC00 – 91 –} accordance with the present invention. All foregoing documents and disclosures are incorporated herein by reference in their entirety. In some embodiments, said targeting fragment capable of binding to PSMA is an aptamer. PSMA targeting aptamers include, but are not limited to, the A10 aptamer or A9 aptamer (Lupold et al., 2002, Cancer Res., 62:4029; and Chu et al., 2006, Nuc. Acid Res., 34: e73), derivatives thereof, and/or functional fragments thereof. In some embodiments, in the aptamer derivatives fewer than 30, 25, 20, 15, 10, 5, 4, 3, 2, or 1 nucleic acid is substituted relative to the aptamer. In some embodiments, the sequences of the aptamer derivatives are at least 80%, preferably 85%, more preferably 90%, again more preferably 95%, most preferably 99% identical. In a preferred embodiment, said targeting fragment is a small molecule PSMA targeting fragment. In a preferred embodiment, said PSMA targeting fragment is a small molecule PSMA targeting fragment, preferably a small molecule PSMA targeting peptidase inhibitor. In a preferred embodiment, said small molecule PSMA peptidase inhibitors include 2-PMPA, GPI5232, VA-033, phenylalkylphosphonamidates (Jackson et al., 2001, Curr. Med. Chem., 8:949; Bennett et al., 1998, J. Am. Chem. Soc., 120:12139; Jackson et al., 2001, J Med. Chem., _{44:4170; Tsukamoto et al., 2002, Bioorg. Med. Chem. Lett., 12 :2189; Tang et al., 2003,} Biochem. Biophys. Res. Commun., 307: 8; Oliver et al., 2003, Bioorg. Med. Chem., 11:4455; and Maung et al., 2004, Bioorg. Med. Chem., 12:4969), and/or analogs and derivatives thereof. All of the foregoing documents (scientific and other publications, patents and patent applications) are incorporated herein by reference in their entirety. In some embodiments, said small molecule PSMA targeting fragment is a protein, a peptide, an amino acid or a derivative thereof. In a preferred embodiment, said small molecule PSMA targeting fragment includes thiol and indole thiol derivatives, such as 2-MPPA and 3-(2-mercaptoethyl)-1H-indole-2- carboxylic acid derivatives (Majer et al., 2003, J Med. Chem., 4611989; and U.S. Patent Publication 2005/0080128). In some embodiments, said small molecule PSMA targeting fragments comprise hydroxamate derivatives (Stoermer et al., 2003, Bioorg. Med. Chem. Lett., 1312097). In a preferred embodiment, said small molecule PSMA peptidase inhibitors include androgen receptor targeting agents (ARTAs), such as those described in U.S. Patents 7,026,500; 7,022,870; 6,998,500; 6,995,284; 6,838,484; 6,569,896; 6,492,554; and in U.S. Patent Publications 2006/0287547; 2006/0276540; 2006/0258628; 2006/0241180; 2006/0183931; 2006/0035966; 2006/0009529; 2006/0004042; 2005/0033074; 2004/0260108; 2004/0260092; 2004/0167103; 2004/0147550; 2004/0147489; 2004/0087810; 2004/0067979; 2004/0052727; _{P6797PC00 – 92 –} 2004/0029913; 2004/0014975; 2003/0232792; 2003/0232013; 2003/0225040; 2003/0162761; 2004/0087810; 2003/0022868; 2002/0173495; 2002/0099096; 2002/0099036. In some embodiments, said small molecule PSMA targeting fragments include polyamines, such as putrescine, spermine, and spermidine (U.S. Patent Publications 2005/0233948 and _{2003/0035804). All foregoing documents and disclosures are incorporated herein by reference} in their entirety. In a preferred embodiment, said small molecule PSMA peptidase inhibitors include _{PBDA- and urea-based inhibitors, such as ZJ 43, ZJ , ZJ 17, ZJ 38 (Nan et al., 2000, J. Med.} Chem., 43:772; and Kozikowski et al., 2004, J. Med. Chem., 47 , 7, 1729-1738), and/or and analogs and derivatives thereof. Other agents which bind PSMA can also be used as PSMA targeting fragment including, for example those found in Clin. Cancer Res., 200814:3036-43, or PSMA targeting fragments prepared by sequentially adding components to a preformed urea, such as the lysine-urea-glutamate compounds described in Banerjee et al. (J. Med. Chem. vol. 51, pp. 4504-4517, 2008). In a preferred embodiment, said one or more targeting fragments capable of binding to prostate specific membrane antigen (PSMA) are small-molecule PSMA targeting fragments, more preferably small urea-based inhibitors. In preferred embodiments, said small molecule PSMA targeting fragments are urea- based inhibitors (herein also called urea-based peptidase inhibitors), more preferably small urea-based inhibitors, such as disclosed in Kularatne et al., Mol Pharmaceutics 2009, 6, 780; Kularatne et al., Mol. Pharmaceutics 2009, 6, 790; Kopka et al., J Nucl Med 2017, 58:17S-26S, Kozikowski et al., J Med Chem. 2001, 44:298–301, Kozikowski et al., J Med Chem. 2004, 47:1729-1738, WO2017/044936, WO2011/084518, WO2011/084521, WO2011/084513, WO2012/166923, WO2008/105773, WO2008/121949, WO2012/135592, WO2010/005740, WO2015/168379, WO03/045436, WO03/045436, WO2016/183447, US2015/258102, WO2011/084513, WO 2017/089942, US2010/278927, WO2012/016188, WO2008/124634, WO2009/131435, US 2007/225213, WO2017/086467, WO2009/026177, WO2012005572, WO2014/072357, and WO2011/108930. All foregoing documents and disclosures are incorporated herein by reference in their entirety. In a preferred embodiment, said targeting fragment is a dipeptide urea based PSMA peptidase inhibitor, preferably a small molecule dipeptide urea-based PSMA peptidase inhibitor. In a preferred embodiment, said PSMA targeting fragment is a dipeptide urea based PSMA peptidase inhibitor, preferably a small molecule dipeptide urea-based PSMA peptidase inhibitor. _{P6797PC00 – 93 –} The term “urea based PSMA peptidase inhibitor” relate to a PSMA peptidase inhibitor comprising an urea group. The term “dipeptide urea based PSMA peptidase inhibitor” relate to PSMA peptidase inhibitor comprising an urea group and two peptides or amino acids each independently attached to the -NH₂ groups of the urea group, while the term “small molecule dipeptide urea-based PSMA peptidase inhibitor” further refers that the dipeptide urea based PSMA peptidase inhibitor has a molecular weight of less than about 2000 g/mol, and that is typically and preferably capable of binding to PSMA. In some embodiments, the small molecule dipeptide urea-based PSMA peptidase inhibitor has a molecular weight of less than about 1800 g/mol, less than about 1500 g/mol, preferably less than about 1000 g/mol. In a further preferred embodiment, the small molecule dipeptide urea-based PSMA peptidase inhibitor has a molecular weight of less than about 800 g/mol, again more preferably less than about 500 g/mol. PSMA peptidase inhibitors are able to reduce the activity of the PSMA _{transmembrane zinc(II) metalloenzyme that catalyzes the cleavage of terminal glutamates.} More preferably, said small molecule urea-based PSMA peptidase inhibitor has a molecular weight of less than about 500 g/mol. Again more preferably, said small molecule urea-based PSMA peptidase inhibitor is a Glutamate-urea based PSMA peptidase inhibitor, preferably such as mentioned in Kopka et al., J Nuc Med, 58(9), suppl.2, 2017; Wirtz et al., EJNMMI Research (2018) 8:84 and references cited therein, all incorporated herein by reference in their entirety. In a preferred embodiment, said targeting fragment, preferably said urea based PSMA peptidase inhibitor is a glutamate-urea moiety of formula 1, preferably of formula 1*: CO₂H CO₂H racemates thereof; wherein R is preferably substituted or unsubstituted alkyl, substituted or unsubstituted _{aryl, and any combination thereof; more preferably R is C1-6-alkyl, preferably C2-C4-alkyl,} substituted one or more times, preferably one time with OH, SH, NH2, or COOH, wherein one of said NH₂, OH or SH or COOH group serve as the point of covalent attachment to the X² linking moiety and the PEG fragment respectively, wherein the alkyl group is optionally be interrupted by N(H), S or O. In another preferred embodiment, R is C_1-6-alkyl, preferably C₂- C4-alkyl, substituted one time with OH, SH, NH2, or COOH, wherein said NH2, OH, or SH or COOH group serve as the point of covalent attachment to the X² linking moiety and the PEG _{P6797PC00 – 94 –} fragment respectively. In a very preferred embodiment, R is C2-alkyl substituted one time with COOH, wherein said COOH group serve as the point of covalent attachment to the X² linking moiety and the PEG fragment respectively. In a preferred embodiment, said targeting fragment is a glutamate-urea moiety of formula 1: CO₂H 1, C4 -alkyl, substituted one or more times, preferably one time with OH, SH, NH2, or COOH, wherein one of said NH2, OH or SH or COOH group serve as the point for covalent attachment to the X² linking moiety and the PEG fragment _{respectively, and wherein the alkyl group is optionally be interrupted by N(H), S or O. In} another preferred embodiment, R is C_1-6-alkyl, preferably C₂-C₄-alkyl, substituted one time with OH, SH, NH2, or COOH, wherein said NH2, OH, or SH or COOH group serve as the point for covalent attachment to the X² linking moiety and the PEG fragment respectively. In a very preferred embodiment, R is C2-alkyl substituted one time with COOH, wherein said COOH group serve as the point for covalent attachment to the X² linking moiety and the PEG fragment respectively. In another preferred embodiment, said targeting fragment is a glutamate-urea moiety of formula 1* CO₂H substituted one or more times, preferably one time with OH, SH, NH2, or COOH, wherein one of said NH2, OH or SH or COOH group serve as the point for covalent attachment to the X² linking moiety and the PEG fragment respectively, and wherein the alkyl group is optionally be interrupted by N(H), S or O. In another preferred embodiment, R is C_1-6-alkyl, preferably C₂-C₄-alkyl, substituted one time with OH, SH, NH2, or COOH, wherein said NH2, OH, or SH or COOH group serve as the point for covalent attachment to the X² linking moiety and the PEG fragment respectively. In a very preferred embodiment, R is C₂-alkyl substituted one time with COOH, wherein said COOH _{P6797PC00 – 95 –} group serve as the point for covalent attachment to the X² linking moiety and the PEG fragment respectively. In a further preferred embodiment, said targeting fragment comprises or preferably consists of the DUPA residue (HOOC-(CH₂)₂-CH(COOH)-NH-CO-NH-CH(COOH)-(CH₂)₂- CO-). In a further very preferred embodiment, said targeting fragment consists of the DUPA residue (HOOC(CH2)2-CH(COOH)-NH-CO-NH-CH(COOH)-(CH2)2-CO-), wherein both chiral C-atoms having (S)-configuration, as depicted in formula 1*. In a further preferred embodiment, said PSMA targeting fragment is a folate ligand. In a further preferred embodiment, said PSMA targeting fragment is a small molecule PSMA targeting fragment, wherein said small molecule PSMA targeting fragment is a folate ligand. In preferred embodiments, said folate ligand binds to a cell surface receptor, wherein said cell surface receptor is PSMA. As recently reported, targeting of cells expressing PSMA has been achieved by amides of folic acid (Flores O et al., Theranostics 2017, 7(9):2477-2494). As used herein, the term “folate ligand” is understood as folic acid or methotrexate or a _{derivative or analogue thereof. Preferably said folic acid or methotrexate derivative or analogue} thereof comprises a glutamate functionality R-NH-[CH(COOH)-CH2-CH2-C(O)NH]η- _{CH(COOH)-CH2-CH2-COOH, wherein η is an integer from 0 to 100, and wherein R is a group} of Formula 2: O (Formula 2), wherein R²⁰¹ is - R²⁰² is -H or -CH₃; and the wavy line indicates the point of attachment to said glutamate functionality. In preferred embodiments, η is an integer from 0 to 10, preferably η is an integer from 0 to 5, and further preferably η is 0. One of skill in the art will understand that when R²⁰¹ is -OH, in preferred embodiments said OH will tautomerize to a carbonyl group (=O), and the neighboring nitrogen atom of said R²⁰¹ will be protonated. One of skill in the art will futher understand that said glutamate functionality R-NH- [CH(COOH)-CH2-CH2-C(O)NH]η-CH(COOH)-CH2-CH2-COOH comprises at least one alpha _{P6797PC00 – 96 –} _{carboxylate group and a gamma carboxylate group. Specifically, the one or more -COOH} _{groups bonded to the same carbon as the -NH- group or groups are understood herein as alpha} carboxylate groups. When η = 0, the -COOH group bonded to the same carbon as the R-NH _{group is understood herein as the alpha carboxylate group. The -COOH group bonded to the –} _{(CH2)2- group is understood herein as the gamma carboxylate group. Moreover, one of skill in} _{the art will understand that the carboxylate groups discussed herein, e.g., the alpha and the} _{gamma carboxylate groups, can be protonated or deprotonated depending on the pH of the} surrounding solution. Accordingly, one of skill in the art will understand that although the carboxylate groups are drawn as neutral species (-COOH) for simplicity and clarity, these can exist (e.g., can primarily exist) as deprotonated, i.e., negatively charged species (-COO-) at physiological pH. I_{n some embodiments, an alpha carboxylate group of said glutamate functionality serves} as the point of covalent attachment to the X² linking moiety. In preferred embodiments, when _{said alpha carboxylate group of said glutamate functionality serves as said point of attachment} _{to the X2 linking moiety, said alpha carboxylate group is condensed with an amine group of the} _{X2 linking moiety to form an amide. In some embodiments, when said alpha carboxylate group} of said glutamate functionality serves as said point of attachment to the X² linking moiety, said _{alpha carboxylate group is condensed with a hydroxy group of the X2 linking moiety to form} an ester. I_{n preferred embodiments, the gamma carboxylate group of said glutamate functionality} serves as the point of covalent attachment to the X² linking moiety. In preferred embodiments, _{when said gamma carboxylate group of said glutamate functionality serves as said point of} _{attachment to the X2 linking moiety, said gamma carboxylate group is condensed with an amine} group of the X² linking moiety to form an amide. In some embodiments, when said gamma carboxylate group of said glutamate functionality serves as said point of attachment to the X² _{linking moiety, said gamma carboxylate group is condensed with a hydroxy group of the X2} linking moiety to form an ester. In a preferred embodiment, said folate ligand is folic acid: O CO₂H _{P6797PC00 – 97 –} _{wherein either the alpha carboxylate group or the gamma carboxylate group of said folic acid} serves as the point of covalent attachment to the X² linking moiety. I_{n some embodiments, the alpha carboxylate group of said folic acid serves as the point of} covalent attachment to the X² linking moiety. In preferred embodiments, when said alpha carboxylate group of said folic acid serves as said point of attachment to the X² linking moiety, _{said alpha carboxylate group is condensed with an amine group of the X2 linking moiety to} _{form an amide. In some embodiments, when said alpha carboxylate group of said folic acid} _{serves as said point of attachment to the X2 linking moiety, said alpha carboxylate group is} condensed with a hydroxy group of the X² linking moiety to form an ester. I_{n preferred embodiments, the gamma carboxylate group of said folic acid serves as the} point of covalent attachment to the X² linking moiety. In preferred embodiments, when said _{gamma carboxylate group of said folic acid serves as said point of attachment to the X2 linking} _{moiety, said gamma carboxylate group is condensed with an amine group of the X2 linking} _{moiety to form an amide. In some embodiments, when said gamma carboxylate group of said} _{folic acid serves as said point of attachment to the X2 linking moiety, said gamma carboxylate} group is condensed with a hydroxy group of the X² linking moiety to form an ester. In a preferred embodiment, said folate ligand is methotrexate: O CO₂H _{wherein either} _{group of said} methotrexate serves as the point of covalent attachment to the X² linking moiety. I_{n some embodiments, the alpha carboxylate group of said methotrexate serves as the} point of covalent attachment to the X² linking moiety. In preferred embodiments, when said _{alpha carboxylate group of said methotrexate serves as said point of attachment to the X2} _{linking moiety, said alpha carboxylate group is condensed with an amine group of the X2} _{linking moiety to form an amide. In some embodiments, when said alpha carboxylate group} of said methotrexate serves as said point of attachment to the X² linking moiety, said alpha carboxylate group is condensed with a hydroxy group of the X² linking moiety to form an ester. I_{n preferred embodiments, the gamma carboxylate group of said methotrexate serves as} the point of covalent attachment to the X² linking moiety. In preferred embodiments, when _{said gamma carboxylate group of said methotrexate serves as said point of attachment to the X2} _{P6797PC00 – 98 –} _{linking moiety, said gamma carboxylate group is condensed with an amine group of the X2} _{linking moiety to form an amide. In some embodiments, when said gamma carboxylate group} of said methotrexate serves as said point of attachment to the X² linking moiety, said gamma carboxylate group is condensed with a hydroxy group of the X² linking moiety to form an ester. I_{n a further aspect, the present invention provides a composition comprising a first,} second and/or third polyplex, wherein said polyplex comprise a conjugate of the Formula I* or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or enantiomer thereof, and a _{nucleic acid, wherein said nucleic acid is preferably non-covalently bound to said conjugate:} R¹-(NR²-CH₂-CH₂)_n-Z-X¹-(O-CH₂-CH₂)_m-X²-L (Formula I*); wherein n is any integer between 1 and 1500, preferably any integer between 2 and 1500; m is any integer between 1 and 200, preferably m is any integer between 1 and 100; R¹ is an initiation residue, wherein preferably R¹ is -H or -CH3; R² is independently -H or an organic residue, wherein at least 80%, preferably 90% of said R² in said -(NR²-CH₂-CH₂)_n–moieties is H; X¹ and X² are independently divalent covalent linking moieties; Z is a divalent covalent linking moiety wherein Z is not -NHC(O)-, wherein preferably Z is a divalent covalent linking moiety wherein Z is not a single bond and Z is not -NHC(O)-; L is a targeting fragment capable of binding to a cell overexpressing prostate _{specific membrane antigen (PSMA), wherein preferably said L is the DUPA residue} (HOOC(CH₂)₂-CH(COOH)-NH-CO-NH-CH(COOH)-(CH₂)₂-CO-), and wherein said nucleic acid an mRNA encoding a Cas protein, preferably Cas9; and optionally a gRNA and/or a template DNA. I_{n a further aspect, the present invention provides a composition comprising a first,} second and/or third polyplex comprising a conjugate of the Formula I* or a pharmaceutically acceptable salt, solvate, hydrate, tautomer _{or enantiomer thereof, and a nucleic acid, wherein said nucleic acid is preferably non-covalently} bound to said conjugate: R¹-(NR²-CH2-CH2)n-Z-X¹-(O-CH2-CH2)m-X²-L (Formula I*); wherein n is any integer between 1 and 1500, preferably any integer between 2 and 1500; m is any integer between 1 and 200, preferably m is any integer between 1 and 100; R¹ is an initiation residue, wherein preferably R¹ is -H or -CH₃; R² is independently -H or an organic residue, wherein at least 80%, preferably 90% of said R² in said -(NR²-CH2-CH2)n–moieties is H; X¹ and X² are independently divalent covalent linking moieties; Z is a divalent covalent linking moiety wherein Z is not -NHC(O)-, wherein preferably Z is a divalent covalent linking moiety wherein Z is not a single bond and Z is not -NHC(O)-; L is a targeting fragment capable of _{binding to prostate specific membrane antigen (PSMA), wherein preferably said L is the DUPA} _{P6797PC00 – 99 –} residue (HOOC(CH2)2-CH(COOH)-NH-CO-NH-CH(COOH)-(CH2)2-CO-), and wherein said nucleic acid an mRNA encoding a Cas protein, preferably Cas9; and optionally a gRNA and/or a template DNA I_{n a further aspect, the present invention provides a composition comprising a first,} second and/or third polyplex comprising a conjugate of the Formula I* or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or enantiomer thereof, and a nucleic acid, wherein _{said nucleic acid is preferably non-covalently bound to said conjugate: R1-(NR2-CH2-CH2)n-Z-} X¹-(O-CH₂-CH₂)_m-X²-L (Formula I*); wherein n is any integer between 1 and 1500, preferably any integer between 2 and 1500; m is any integer between 1 and 200, preferably m is any integer between 1 and 100; R¹ is an initiation residue, wherein preferably R¹ is -H or -CH3; R² is independently -H or an organic residue, wherein at least 80%, preferably 90% of said R² in said -(NR²-CH2-CH2)n–moieties is H; X¹ and X² are independently divalent covalent linking moieties; Z is a divalent covalent linking moiety wherein Z is not -NHC(O)-, wherein preferably Z is a divalent covalent linking moiety wherein Z is not a single bond and Z is not -NHC(O)-; L is a targeting fragment, wherein said targeting fragment L is the DUPA residue (HOOC(CH2)2-CH(COOH)-NH-CO-NH-CH(COOH)-(CH2)2-CO-), and wherein said nucleic acid an mRNA encoding a Cas protein, preferably Cas9; and optionally a gRNA and/or a template DNA. I_{n a further aspect, the present invention provides a composition comprising a first,} _{second and/or third polyplex comprising a conjugate of the Formula I* or a pharmaceutically} _{acceptable salt, solvate, hydrate, tautomer or enantiomer thereof, and a nucleic acid, wherein} _{said nucleic acid is preferably non-covalently bound to said conjugate:} R¹-(NR²-CH2-CH2)n-Z-X¹-(O-CH2-CH2)m-X²-L (Formula I*); wherein n is any integer _{between 1 and 1500 preferably any integer between 2 and 1500; m is any integer between 1 and} 200, preferably m is any integer between 1 and 100; R¹ is an initiation residue, wherein preferably R¹ is -H or -CH3; R² is independently -H or an organic residue, wherein at least 80%, preferably 90% of said R² in said -(NR²-CH2-CH2)n–moieties is H; X¹ and X² are independently divalent covalent linking moieties; Z is a divalent covalent linking moiety wherein Z is not - NHC(O)-, wherein preferably Z is a divalent covalent linking moiety wherein Z is not a single bond and Z is not -NHC(O)-; L is a targeting fragment capable of binding to a cell _{overexpressing prostate specific membrane antigen (PSMA), wherein preferably said L is the} DUPA residue (HOOC(CH2)2-CH(COOH)-NH-CO-NH-CH(COOH)-(CH2)2-CO-), and _{P6797PC00 – 100 –} wherein said nucleic acid an mRNA encoding a Cas protein, preferably Cas9; and optionally a gRNA and/or a template DNA. I_{n a further aspect, the present invention provides a composition comprising a first,} _{second and/or third polyplex comprising a conjugate of the Formula I* or a pharmaceutically} acceptable salt, solvate, hydrate, tautomer or enantiomer thereof, and a nucleic acid, wherein _{said nucleic acid is preferably non-covalently bound to said conjugate:} R¹-(NR²-CH2-CH2)n-Z-X¹-(O-CH2-CH2)m-X²-L (Formula I*); wherein n is any integer between 1 and 1500, preferably any integer between 2 and _{1500; m is any integer between 1 and 200, preferably m is any integer between 1 and 100; R1} _{is an initiation residue, wherein preferably R1 is -H or -CH3; R2 is independently -H or an} organic residue, wherein at least 80%, preferably 90% of said R² in said -(NR²-CH₂-CH₂)_n– _{moieties is H; X1 and X2 are independently divalent covalent linking moieties; Z is a divalent} covalent linking moiety wherein Z is not -NHC(O)-, wherein preferably Z is a divalent covalent linking moiety wherein Z is not a single bond and Z is not -NHC(O)-; L is a targeting fragment _{capable of binding to prostate specific membrane antigen (PSMA), wherein preferably L is the} _{DUPA residue (HOOC(CH2)2-CH(COOH)-NH-CO-NH-CH(COOH)-(CH2)2-CO-), and} wherein said nucleic acid an mRNA encoding a Cas protein, preferably Cas9; and optionally a gRNA and/or a template DNA. I_{n a further aspect, the present invention provides a composition comprising a first,} _{second and/or third polyplex comprising a conjugate of the Formula I* or a pharmaceutically} acceptable salt, solvate, hydrate, tautomer or enantiomer thereof, and a nucleic acid, wherein _{said nucleic acid is preferably non-covalently bound to said conjugate:} R¹-(NR²-CH2-CH2)n-Z-X¹-(O-CH2-CH2)m-X²-L (Formula I*); wherein n is any integer between 1 and 1500, preferably any integer between 2 and _{1500; m is any integer between 1 and 200, preferably m is any integer between 1 and 100; R1} _{is an initiation residue, wherein preferably R1 is -H or -CH3; R2 is independently -H or an} organic residue, wherein at least 80%, preferably 90% of said R² in said -(NR²-CH2-CH2)n– moieties is H; X¹ and X² are independently divalent covalent linking moieties; Z is a divalent covalent linking moiety wherein Z is not -NHC(O)-, wherein preferably Z is a divalent covalent linking moiety wherein Z is not a single bond and Z is not -NHC(O)-; L is a targeting fragment, wherein said targeting fragment L is the DUPA residue (HOOC(CH₂)₂-CH(COOH)-NH-CO- NH-CH(COOH)-(CH2)2-CO-), and wherein said nucleic acid an mRNA encoding a Cas protein, preferably Cas9; and optionally a gRNA and/or a template DNA. _{P6797PC00 – 101 –} _{In a further aspect, the present invention provides a composition comprising a first,} second and/or third polyplex comprising a conjugate of the Formula I, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or enantiomer thereof: R² L wherein: i_{s a single bond or a double bond, preferably a double bond;} n is any integer between 1 and 1500; m is any integer between 1 and 200, preferably any integer between 2 and 100, preferably m is 36; R¹ is an initiation residue, wherein preferably R¹ is -H or -CH3; R² is independently -H or an organic residue, wherein at least 80%, preferably wherein _{at least 90%, of said R2 in said -(NR2-CH2-CH2)n–moieties is H, further preferably said R2 is} H; Ring A is a 5 to 10-membered cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl, optionally substituted at any position with one or more R^A1; R^A1 is independently selected from C1-C6 alkyl, C1-C6 alkoxy, oxo, or halogen; or two R^A1, together with the atoms to which they are attached, can combine to form one or more fused C6-C10 aryl, C5-C6 heteroaryl, or C3-C6 cycloalkyl rings, wherein each fused aryl, heteroaryl, or cycloalkyl is optionally substituted with one or more R^A2; R^A2 is independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen -SO3H, or - OSO3H; X¹ is a linking moiety of the formula –(Y¹)_p–, wherein p is an integer between 1 and 20, and each occurrence of Y¹ is independently selected from a chemical bond, -CR¹¹R¹²-, -C(O)-, -O-, -S-, -NR¹³-, an amino acid residue, a divalent phenyl moiety, a divalent carbocycle moiety, a divalent heterocycle moiety, and a divalent heteroaryl moiety, wherein each divalent phenyl _{or heteroaryl is optionally substituted with one or more R13, and each divalent heterocycle is} optionally substituted with one or more R¹⁴; wherein R¹¹, R¹² and R¹³ are independently, at each occurrence, H, -SO₃H, -NH₂, -CO₂H, or C₁-C₆ alkyl, wherein each alkyl is optionally _{P6797PC00 – 102 –} substituted with -CO2H or -NH2; and wherein R¹⁴ is independently, at each occurrence, H, C1- C₆ alkyl, or oxo, C₆-C₁₀ aryl, or 5 to 8-membered heteroaryl; X² is a linking moiety of the formula –(Y²)q–, wherein q is an integer between 1 and 50, and each occurrence of Y² is independently selected from a chemical bond, -CR²¹R²²-, NR²³-, -O-, -S-, -C(O)-, an amino acid residue, a divalent phenyl moiety, a divalent carbocycle moiety a divalent heterocycle moiety, and a divalent heteroaryl moiety, wherein each divalent phenyl and divalent heteroaryl is optionally substituted with one or more R²³, and wherein each divalent heterocycle moiety is optionally substituted with one or more R²⁴; wherein R^21, R^22, and R²³ are each independently, at each occurrence, -H, -SO₃H, -NH₂, -CO₂H, or C₁-C₆ alkyl, wherein each C1-C6 alkyl is optionally substituted with one or more -OH, oxo, -CO2H, -NH2, C₆-C₁₀ aryl, or 5 to 8-membered heteroaryl; and wherein R²⁴ is independently, at each occurrence, -H, -CO2H, C1-C6 alkyl, or oxo; and L is a targeting fragment, wherein preferably said targeting fragment L is the DUPA residue (HOOC(CH2)2-CH(COOH)-NH-CO-NH-CH(COOH)-(CH2)2-CO-). I_{n a further aspect, the present invention provides a composition comprising a first,} second and/or third polyplex comprising a conjugate of the Formula I, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or enantiomer thereof: R² L wherein: i_{s a single bond or a double bond, preferably a double bond;} n is any integer between 1 and 1500, preferably any integer between 2 and 1500; m is a discrete number of repeating units m of 2 to 100, preferably of a discrete number of repeating units m of 4 to 60; R¹ is an initiation residue, wherein preferably R¹ is -H or -CH3; R² is independently -H or an organic residue, wherein at least 80%, preferably wherein _{at least 90%, of said R2 in said -(NR2-CH2-CH2)n– is H, further preferably said R2 is H;} Ring A is a 5 to 10-membered cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl, optionally substituted at any position with one or more R^A1; R^A1 is _{P6797PC00 – 103 –} independently selected from C1-C6 alkyl, C1-C6 alkoxy, oxo, or halogen; or two R^A1, together with the atoms to which they are attached, can combine to form one or more fused C₆-C₁₀ aryl, C5-C6 heteroaryl, or C3-C6 cycloalkyl rings, wherein each fused aryl, heteroaryl, or cycloalkyl is optionally substituted with one or more R^A2; R^A2 is independently selected from C₁-C₆ alkyl, C₁-C₆ alkoxy, halogen -SO₃H, or -OSO₃H; X¹ is a divalent covalent linking moiety; X² is a divalent covalent linking moiety; and L is a targeting fragment, wherein said targeting fragment is an PSMA targeting fragment, wherein preferably said PSMA targeting fragment is capable of specifically binding _{to a cell expressing, preferably overexpressing, PSMA. In a preferred embodiment, said R1 is -} _{H. In a preferred embodiment, said R1 is -CH3. In a further preferred embodiment, said targeting} fragment comprises or preferably consists of the DUPA residue (HOOC-(CH2)2-CH(COOH)- NH-CO-NH-CH(COOH)-(CH₂)₂-CO-). In a further very preferred embodiment, said targeting fragment consists of the DUPA residue (HOOC(CH2)2-CH(COOH)-NH-CO-NH-CH(COOH)- (CH₂)₂-CO-), wherein both chiral C-atoms having (S)-configuration, as depicted in formula 1*. In some embodiments, the conjugate of a polyplex as described herein (e.g., the first, _{second or subsequent polyplex) is a conjugate of the Formula I, or a pharmaceutically} acceptable salt, solvate, hydrate, tautomer or enantiomer thereof: R² L wherein: i_{s a single bond or a double bond, preferably a double bond;} n is any integer between 1 and 1500, preferably any integer between 2 and 1500; m is a discrete number of repeating units m of 36; R¹ is an initiation residue, wherein preferably R¹ is -H or -CH₃; R² is independently -H or an organic residue, wherein at least 80%, preferably wherein _{at least 90%, of said R2 in said -(NR2-CH2-CH2)n– is H, further preferably said R2 is H;} Ring A is a 5 to 10-membered cycloalkyl, cycloalkenyl, heterocycloalkyl, or _{heterocycloalkenyl, optionally substituted at any position with one or more RA1; RA1 is} independently selected from C1-C6 alkyl, C1-C6 alkoxy, oxo, or halogen; or two R^A1, together _{P6797PC00 – 104 –} with the atoms to which they are attached, can combine to form one or more fused C6-C10 aryl, C₅-C₆ heteroaryl, or C₃-C₆ cycloalkyl rings, wherein each fused aryl, heteroaryl, or cycloalkyl is optionally substituted with one or more R^A2; R^A2 is independently selected from C1-C6 alkyl, C₁-C₆ alkoxy, halogen -SO₃H, or -OSO₃H; X¹ is a divalent covalent linking moiety; X² is a divalent covalent linking moiety; and L is a targeting fragment, wherein said targeting fragment is an PSMA targeting fragment, wherein preferably said PSMA targeting fragment is capable of specifically binding to a cell expressing, preferably overexpressing, PSMA. In a preferred embodiment, said R¹ is - _{H. In a preferred embodiment, said R1 is -CH3. In a further preferred embodiment, said targeting} fragment comprises or preferably consists of the DUPA residue (HOOC-(CH₂)₂-CH(COOH)- NH-CO-NH-CH(COOH)-(CH2)2-CO-). In a further very preferred embodiment, said targeting fragment consists of the DUPA residue (HOOC(CH₂)₂-CH(COOH)-NH-CO-NH-CH(COOH)- (CH2)2-CO-), wherein both chiral C-atoms having (S)-configuration, as depicted in formula 1* In some embodiments, the conjugate of a polyplex as described herein (e.g., the first, second or subsequent polyplex) is a conjugate of the Formula I, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or enantiomer thereof: R² L wherein: i_{s a single bond or a double bond, preferably a double bond;} n is any integer between 1 and 1500, preferably any integer between 2 and 1500; m_{is a discrete number of contiguous repeating units wherein m is 36;} R¹ is an initiation residue, wherein preferably R¹ is -H or -CH3; R² is independently -H or an organic residue, wherein at least 80%, preferably wherein _{at least 90%, of said R2 in said -(NR2-CH2-CH2)n– is H, further preferably said R2 is H;} Ring A is a 5 to 10-membered cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl, optionally substituted at any position with one or more R^A1; R^A1 is independently selected from C₁-C₆ alkyl, C₁-C₆ alkoxy, oxo, or halogen; or two R^A1, together with the atoms to which they are attached, can combine to form one or more fused C6-C10 aryl, _{P6797PC00 – 105 –} C5-C6 heteroaryl, or C3-C6 cycloalkyl rings, wherein each fused aryl, heteroaryl, or cycloalkyl is optionally substituted with one or more R^A2; R^A2 is independently selected from C₁-C₆ alkyl, C1-C6 alkoxy, halogen -SO3H, or -OSO3H; X¹ is a linking moiety of the formula –(Y¹)_p–, wherein p is an integer between 1 and 20, and each occurrence of Y¹ is independently selected from a chemical bond, -CR¹¹R¹²-, -C(O)-, _{-O-, -S-, -NR13-, an amino acid residue, a divalent phenyl moiety, a divalent heterocycle moiety,} and a divalent heteroaryl moiety, wherein each divalent phenyl or heteroaryl is optionally substituted with one or more R¹³, and each divalent heterocycle is optionally substituted with one or more R¹⁴; wherein R¹¹, R¹² and R¹³ are independently, at each occurrence, H or C₁-C₆ alkyl; and wherein R¹⁴ is independently, at each occurrence, H, C1-C6 alkyl, or oxo; X² is a linking moiety of the formula –(Y²)_q–, wherein q is an integer between 1 and 50, and each occurrence of Y² is independently selected from a chemical bond, -CR²¹R²²-, NR²³-, -O-, -S-, -C(O)-, an amino acid residue, a divalent phenyl moiety, a divalent heterocycle moiety, and a divalent heteroaryl moiety, wherein each divalent phenyl and divalent heteroaryl is optionally substituted with one or more R²³, and wherein each divalent heterocycle moiety is optionally substituted with one or more R²⁴; wherein R^21, R^22, and R²³ are each independently, at each occurrence, -H, -CO2H, or C1-C6 alkyl, wherein each C1-C6 alkyl is optionally substituted with one or more -OH, oxo, C₆-C₁₀ aryl, or 5 to 8-membered heteroaryl; and wherein R²⁴ is independently, at each occurrence, -H, -CO₂H, C₁-C₆ alkyl, or oxo; and L is a targeting fragment, wherein said targeting fragment is an PSMA targeting fragment, wherein preferably said PSMA targeting fragment is capable of specifically binding _{to a cell expressing, preferably overexpressing, PSMA. In a preferred embodiment, said R1 is -} H. In a preferred embodiment, said R¹ is -CH3. In a further preferred embodiment, said targeting fragment comprises or preferably consists of the DUPA residue (HOOC-(CH₂)₂-CH(COOH)- NH-CO-NH-CH(COOH)-(CH2)2-CO-). In a further very preferred embodiment, said targeting fragment consists of the DUPA residue (HOOC(CH2)2-CH(COOH)-NH-CO-NH-CH(COOH)- (CH2)2-CO-), wherein both chiral C-atoms having (S)-configuration, as depicted in formula 1*. In a preferred embodiment, said DUPA residue is linked to said PEG targeting fragment by way of the linking moiety X². Such linking moieties are known to the skilled person and are disclosed in US2020/0188523A1, US2011/0288152A1, US2010/324008A1, the disclosures of said patent _{applications incorporated herein by way reference in its entirety.} In a preferred embodiment, said linking moiety X² is a peptide linker or a C₁-C₁₀ _{P6797PC00 – 106 –} alkylene linker or a combination of both. In a preferred embodiment, said linking moiety X² is a peptide linker. In a preferred embodiment, said linking moiety X² is a peptide linker, wherein said _{peptide linker comprises, preferably consists of, the sequence of SEQ ID NO:4 (-(NH-(CH2)7-} CO)-Phe-Phe-(NH-CH₂-CH(NH₂)-CO)-Asp-Cys-) or SEQ ID NO:5 (-(NH-(CH₂)₇-CO)-Phe- Gly-Trp-Trp-Gly-Cys-). In a preferred embodiment, said linking moiety X² is a peptide linker, wherein said peptide linker comprises, preferably consists of, the sequence of SEQ ID NO:5 (- (NH-(CH₂)₇-CO)-Phe-Gly-Trp-Trp-Gly-Cys-). In a further preferred embodiment, said linking _{moiety X2 comprises, preferably consists of, SEQ ID NO:5 or SEQ ID NO:4 and the targeting} _{fragment is HOOC(CH2)2-CH(COOH)-NH-CO-NH-CH(COOH)-(CH2)2-CO- (DUPA} _{residue). In a very preferred embodiment, said linking moiety X2 comprises, preferably consists} of, SEQ ID NO:5 and the targeting fragment L is HOOC(CH2)2-CH(COOH)-NH-CO-NH- _{CH(COOH)-(CH2)2-CO- (DUPA residue). In a preferred embodiment, said targeting fragment} _{L is HOOC-(CH2)2-CH(COOH)-NH-CO-NH-CH(COOH)-(CH2)2-CO- capable of binding to a} cell overexpressing PSMA, wherein said linking moiety X² comprises, preferably consists of SEQ ID NO:5. I_{n another preferred embodiment, the targeting fragment is 2-[3-(1,3-dicarboxypropyl)} ureido]pentanedioic acid (DUPA), wherein typically and preferably said coupling to the rest of said conjugate is effected via a terminal carboxyl group of said DUPA. Thus, in a further _{preferred embodiment, said targeting fragment L is the DUPA residue (HOOC(CH2)2-} _{CH(COOH)-NH-CO-NH-CH(COOH)-(CH2)2-CO-). The DUPA can be selectively taken up in} _{cells that have increased expression (e.g., overexpression) of prostate-specific membrane} antigen (PSMA). In a preferred embodiment, said targeting fragment is capable of binding to an _{asialoglycoprotein receptor (ASGPr), which is also named herein as ASGPr targeting fragment.} Thus, in some embodiments said targeting fragment is an ASGPr targeting fragment. Asialoglycoprotein receptors (ASGPr) are carbohydrate binding proteins (i.e., lectins) which _{bind asialoglycoprotein and glycoproteins, preferably galactose-terminal glycoproteins and} preferably branched galactose-terminal glycoproteins. Preferably said ASGPr targeting fragment is capable of binding to epitopes on the extracellular domain of ASGPr. Preferably, said ASGPr targeting fragment is capable of binding to a cell expressing ASGPr. In a preferred embodiment, said targeting fragment is capable of binding to a cell overexpressing ASGPr, preferably a hepatocyte. In a preferred embodiment, said targeting _{P6797PC00 – 107 –} fragment is capable of binding to a cell ASGPr expressing. In a preferred embodiment, said targeting fragment is capable of binding to a cell overexpressing ASGPr. In one embodiment, said cell overexpressing ASGPr means that the level of ASGPr expressed in said cell of a certain tissue is elevated in comparison to the level of ASGPr as measured in a normal healthy cell of the same type of tissue under analogous conditions. In one embodiment, said cell overexpressing ASGPr refers to an increase in the level of ASGPr in a cell relative to the level in the same cell or closely related non-malignant cell under normal physiological conditions. In one embodiment, said cell overexpressing ASGPr relates to expression of ASGPr that is at least 5-fold, preferably at least 10-fold, further preferably at least 20-fold, as compared to the expression of ASGPr in a normal cell or in a normal tissue. For example, ASGPr is overexpressed in liver cells, preferably hepatocytes, and liver cancer cells. In preferred _{embodiments, the ASGPr targeting fragment is capable of binding to a liver cell, preferably a} hepatocyte or cancerous liver cell and metastases thereof. Preferably said ASGPr targeting fragment is capable of specifically binding to ASGPr. Typically, specific binding refers to a binding affinity or dissociation constant (KD) of the targeting fragment between about 1 x 10^-3 M and about 1 x 10^-12 M. To detect binding of the complex or measure affinity, molecules can be analyzed using a competition binding assay, such as with a Biacore 3000 instrument (see, e.g., Kuo et al., PLoS One, 2015; 10(2): e01166610). Preferably said ASGPr targeting fragment is capable of specifically binding to ASGPr with a binding affinity equal to or greater than that of galactose. In a preferred embodiment, said ASGPr targeting fragments include small molecules or small molecule ligand, peptides, proteins, more preferably ASGPr antibodies, ASGPr affibodies, ASGPr aptamers, ASGPr targeting peptides, lactose, galactose, N- acetylgalactosamine (GalNAc), galactosamine, N-formylgalactosamine, N-acetyl- galactosamine, N-propionylgalactosamine, N-n-butanoylgalactosamine, and N-iso- butanoylgalactosamine, and combinations thereof (Iobst, S. T. and Drickamer, K. J.B.C.1996, _{271, 6686). In some embodiments, ASGPr targeting fragments are monomeric (i.e., having a} single galactosamine). In some embodiments, ASGPr targeting fragments are multimeric (i.e., having multiple galactosamines). I_{n a preferred embodiment, the ASGPr targeting fragment is a galactose cluster. A} galactose cluster is understood as a molecule having two to four terminal galactose derivatives. As used herein, the term galactose derivative includes both galactose and derivatives of _{galactose having affinity for the asialoglycoprotein receptor equal to or greater than that of} _{P6797PC00 – 108 –} galactose. Preferably the galactose derivative is selected from galactose, galactosamine, N- formylgalactosamine, N-acetylgalactosamine, N-propionyl-galactosamine, N-n- butanoylgalactosamine, and N-iso-butanoylgalactosamine. Preferably the galactose derivative is an N-acetyl-galactosamine (GalNAc). I_{n preferred embodiments, a galactose cluster contains three galactose derivatives, each} linked to a central branch point, preferably wherein each terminal galactose derivative is attached to the remainder of the galactose cluster through its C-1 carbon. In preferred embodiments, the galactose derivative is linked to the branch point via linkers or spacers, preferably flexible hydrophilic spacers, more preferably PEG spacers and yet more preferably PEG3 spacers. In preferred embodiments, a galactose cluster has three terminal galactosamines or galactosamine derivatives each having affinity for the ASGPr (i.e., is a tri-antennary galactose derivative cluster). In some embodiments the galactose cluster comprises tri-antennary galactose, tri-valent galactose and galactose trimer. Preferably the galactose cluster has three terminal N-acetyl-galactosamines. In another preferred embodiment, the targeting fragment is folic acid, wherein typically and preferably said coupling to the rest of said conjugate is effected via the terminal carboxyl group of said folic acid. In some preferred embodiments, the targeting fragment can be folate. Without wishing to be bound by theory, folate can be selectively taken up in cells that have _{increased expression (e.g., overexpression) of folate receptor.} _{In further preferred embodiments the targeting fragment are HER2 targeting ligands,} _{which in some embodiments can be selectively taken up in cells that have increased expression} _{(e.g., overexpression) of HER2.} In some embodiments, the targeting fragment can be a somatostatin receptor-targeting fragment. Without wishing to be bound by theory, the somatostatin receptor-targeting fragment can be selectively taken up by cells that have increased expression (e.g., overexpression) of somatostatin receptors such as somatostatin receptor 2 (SSTR2). In some embodiments, the targeting fragment can be an integrin-targeting fragment such as arginine-glycine-aspartic acid (RGD)-containing ligands (e.g., cyclic RGD ligands). Without wishing to be bound by theory, the integrin-targeting fragment can be selectively taken up by cells that have increased expression (e.g., overexpression) of integrins (e.g., RGD integrins such as αvβ6 integrin or αvβ8 integrin). In some embodiments, the targeting fragment can be a low pH insertion peptides _{P6797PC00 – 109 –} (pHLIP). Without wishing to be bound by theory, the low pH insertion peptide can be selectively taken up by cells that exist in a low pH microenvironment. In some embodiments, the targeting fragment can be an asialoglycoprotein receptor-targeting fragment such as asialoorosomucoid. Without wishing to be bound by theory, the asialoglycoprotein receptor- targeting fragment can be selectively taken up by cells that have increased expression (e.g., overexpression) of asialoglycoprotein receptors. In some embodiments, the targeting fragment can be an insulin-receptor targeting fragment such as insulin. Without wishing to be bound by theory, the insulin-receptor targeting fragment can be selectively taken up by cells that have increased expression (e.g., overexpression) of insulin receptors. In some embodiments, targeting fragment can be a mannose-6-phosphate receptor targeting fragment such as mannose- 6-phosphate. Without wishing to be bound by theory, the mannose-6-phosphate receptor targeting fragment can be selectively taken up by cells that have increased expression (e.g., overexpression) of mannose-6-phosphate receptors (e.g., monocytes). In some embodiments, the targeting fragment can be a mannose receptor-targeting fragment such as mannose. Without wishing to be bound by theory, the mannose-receptor-targeting fragment can be selectively taken up by cells that have increased expression (e.g., overexpression) of mannose receptors. In some embodiments, the targeting fragment can be a Sialyl Lewis^x antigen targeting fragments such as E-selectin. Without wishing to be bound by theory, the Sialyl Lewis^x antigen-targeting fragments can be selectively taken up by cells that have increased expression (e.g., overexpression) of glycosides such as Sialyl Lewis^x antigens. In some embodiments, the targeting fragment can be N-acetyllactosamine targeting fragment. Without wishing to be bound by theory, the N-acetyllactosamine targeting fragment can be selectively taken up by cells that have increased expression (e.g., overexpression) N-acetyllactosamine. In some embodiments, the targeting fragment can be a galactose targeting fragment. Without wishing to be bound by theory, the galactose targeting fragment can be selectively taken up by cells that have increased expression (e.g., overexpression) of galactose. In some embodiments, the targeting fragment can be a sigma-2 receptor agonist, such as N,N-dimethyltryptamine (DMT), a sphingolipid-derived amine, and/or a steroid (e.g., progesterone). Without wishing to be bound by theory, the sigma-2 receptor agonist can be selectively taken up by cells that have increased expression (e.g., overexpression) of sigma-2 receptors. In some embodiments, the targeting fragment can be a p32-targeting ligand such as anti-p32 antibody or p32-binding LyP- 1 tumor-homing peptide. Without wishing to be bound by theory, the p32-targeting ligand can be selectively taken up by cells that have increased expression (e.g., overexpression) of the _{P6797PC00 – 110 –} mitochondrial protein p32. In some embodiments, the targeting fragment can be a Trop-2 targeting fragment such as an anti-Trop-2 antibody and/or antibody fragment. Without wishing to be bound by theory, the Trop-2 targeting fragment can be selectively taken up by cells that have increased expression (e.g., overexpression) of Trop-2. In some embodiments, the targeting fragment is an insulin-like growth factor 1 receptor-targeting fragment, such as insulin-like _{growth factor 1. Without wishing to be bound by theory, the insulin-like growth factor 1} receptor-targeting fragment can be selectively taken up by cells that have increased expression (e.g., overexpression) of insulin-like growth factor 1 receptor. In some embodiments, the targeting fragment can be a VEGF receptor-targeting fragment such as VEGF. Without wishing to be bound by theory, the VEGF receptor-targeting fragment can be selectively taken up by cells that have increased expression (e.g., overexpression) of VEGF receptor. In some embodiments, the targeting fragment can be a platelet-derived growth factor receptor-targeting fragment such as platelet-derived growth factor. Without wishing to be bound by theory, the platelet-derived growth factor receptor-targeting fragment can be selectively taken up by cells that have increased expression (e.g., overexpression) of platelet-derived growth factor receptor. In some embodiments, the targeting fragment can be a fibroblast growth factor receptor- targeting fragment such as fibroblast growth factor. Without wishing to be bound by theory, the fibroblast growth factor receptor-targeting fragment can be selectively taken up by cells that have increased expression (e.g., overexpression) of fibroblast growth factor receptor. Coupling of PEG Fragment to Targeting fragment In some embodiments, the second terminal end of the PEG fragment is functionalized with a linking group (i.e., X²) that links the PEG fragment to a targeting fragment. Typically, _{the linking moiety X2 comprises a reactive group for coupling to an appropriate, i.e.} complementary reactive group on the targeting fragment. One of skill in the art will understand the various complementary reactive groups of such coupling reaction between said X² reactive groups and said reactive groups of the targeting fragments. In some embodiments, the targeting fragment L can be unmodified and used directly as a reactive partner for covalent coupling to a PEG fragment and linking moiety X² respectively. For example, Scheme 3 shows the nucleophilic addition of hEGF to an electrophilic tetrafluorophenyl ester bonded to a PEG fragment. As shown in Scheme 3, a nucleophilic amine of the hEGF displaces the tetrafluorophenol of the tetrafluorophenyl ester to form a covalent bond with the PEG fragment and linking moiety X² respectively. In some embodiments, the targeting fragment L can be _{P6797PC00 – 111 –} coupled to a PEG fragment by the linking moiety X² using a suitable chemical linkage such as an amide or ester bond. For example, Schemes 4 and 5 show DUPA and folate groups, respectively, that are bonded to a PEG fragment by an X² linker comprising an amide linkage. The amide groups are formed by a dehydration synthesis reaction between an appropriate carboxylic acid group on DUPA and folate and an appropriate amine on the PEG-X² fragment. In some preferred embodiments, a first end (i.e., terminus) of the PEG fragment is functionalized with an alkene or alkyne group which can in some embodiments be used to react with an azide-functionalized LPEI; and a second end (i.e., terminus) of the PEG fragment is functionalized with a targeting fragment, which in some embodiments can be used to facilitate uptake of the conjugates and corresponding polyplexes in specific cell types. Accordingly, in some preferred embodiments, the resulting conjugates of the present invention can have the general structure LPEI-PEG-Targeting fragment, arranged in a linear end-to-end fashion. The conjugates of the present invention can be prepared using a variety of different methods and steps. Schemes 1 and 2 below show different strategies for arranging the c_{onjugates of the present invention. As shown below in Scheme 1, conjugates of the present} invention can be prepared by first coupling a PEG fragment to a targeting fragment, followed by coupling targeting fragment-modified PEG fragment to the LPEI fragment. As shown below in Scheme 2, conjugates of the present invention can be prepared by first coupling a PEG fragment to the LPEI fragment, followed by coupling the LPEI-modified PEG fragment to a targeting fragment. S_{cheme 1. Exemplary coupling difunctional PEG to targeting fragment followed by} LPEI X¹ X² [Target ^{1 2} O [Electrophile] + ing X X F_{ragment "L"]} O L H X¹ X² N O L R¹ n O L a_{nd an electrophile) can be reacted first with a targeting fragment (e.g., hEGF, DUPA, or folate)} to produce a PEG fragment covalently bonded to the targeting fragment. The alkene or alkyne group of the targeting fragment-modified PEG can then be reacted with the azide group of an L_{PEI fragment via a [3+2] cycloaddition to produce a linear conjugate of the general structure} LPEI-PEG-targeting fragment. _{P6797PC00 – 112 –} Scheme 2. Exemplary coupling difunctional PEG to LPEI followed by targeting fragment. H ^N _NH H X N N X + O [Electrophile] ^R N n X X L and an electrophile) can be reacted first with the azide group of an LPEI fragment via a [3+2] cycloaddition to produce a linear conjugate of LPEI and PEG covalently attached by a 1, 2, 3 triazole or A 4,5-dihydro-1H-[1,2,3]triazole. The linear LPEI-PEG fragment can then be r_{eacted with a targeting fragment (e.g., hEGF, DUPA, or folate) to produce a linear conjugate} of the general structure LPEI-PEG-targeting fragment. S_{chemes 3-5 below show general methods for coupling a PEG fragment to various} targeting fragments. One of skill in the art will appreciate that the PEG fragment can be coupled to various targeting fragments using any suitable chemistries (e.g., nucleophilic substitution, p_{eptide coupling and the like). For example, one of skill in the art will appreciate that it is not} necessary to use a tetrafluorophenyl ester as an electrophile to couple a PEG fragment to hEGF as shown in Scheme 3, but that other electrophilic groups such as a maleate (as shown in S_{cheme 4) can also be used. Moreover, one of skill in the art will appreciate that the reactive} group of the bi-functionalized PEG fragment does not necessarily need to be an electrophilic group, but instead can be a nucleophilic group that reacts, e.g., with an electrophilic portion of a targeting fragment. Scheme 3. Exemplary coupling of bifunctional PEG to hEGF. F O_O F O _{O O} O hEGF e_{lectrophilic group such as a tetrafluorophenyl ester and/or an activated alkyne group such as} DBCO. Treatment of the tetrafluorophenyl ester-modified PEG with hEGF in solution results in a nucleophilic substitution via a nucleophilic amine of hEGF to produce an hEGF-modified PEG. The DBCO group can be used in subsequent reactions for coupling to an LPEI fragment. The variable m represents the number of repeating PEG units as described herein. _{P6797PC00 – 113 –} Scheme 4. Exemplary coupling of bifunctional PEG to DUPA. _As _{(MAL) group and/or an activated alkyne group such as DBCO. The maleimide-substituted PEG} _{can be coupled to a nucleophilic partner such as the depicted DUPA derived moiety (as depicted} _{in the scheme above comprising a peptidic spacer Aoc-Phe-Gly-Trp-Trp-Gly-Cys (SEQ ID} NO:5), N-terminally derivatized with 2-[3-(1,3-dicarboxypropyl)ureido]pentanedioic acid _{(DUPA) which due to the amino acid residue derived from cysteine contains a nucleophilic} _{group, namely a thiol. Treatment of the MAL-modified PEG in solution with the thiol-modified} _{DUPA derived moiety in solution results in a nucleophilic 1,4-addition via the nucleophilic} _{thiol of the DUPA derived moiety to produce a DUPA-modified PEG. The variable m} represents the number of repeating PEG units as described herein. _{P6797PC00 – 114 –} Scheme 5. Exemplary coupling of bifunctional PEG to folate. HO O O O O O O H N m_{aleimide (MAL) group. The maleimide-substituted PEG can be coupled to nucleophilic} partner such as a folate residue which itself is modified to contain a nucleophilic group (e.g., t_{hiol). Treatment of the MAL-modified PEG in solution with folate thiol in solution results in} _{a nucleophilic 1,4-addition via the nucleophilic thiol of folate to produce a folate-modified} PEG. The variable m represents the number of repeating PEG units as described herein. Coupling of PEG Fragment to LPEI Fragment Before or after coupling the bi-functionalized PEG fragment to a targeting fragment, the b_{i-functionalized PEG fragment can be coupled to an LPEI fragment. In preferred} embodiments, the bi-functionalized PEG fragment is coupled to LPEI using cycloaddition chemistry, e.g., a 1,3-dipolar cycloaddition or [3+2] cycloaddition between an azide and an a_{lkene or alkyne to form a 1, 2, 3 triazole or a 4,5-dihydro-1H-[1,2,3]triazole. In other preferred} embodiments, the bi-functionalized PEG fragment is coupled to LPEI using thiol-ene chemistry, between a thiol and an alkene to form a thioether. O_{ne of skill in the art will appreciate that any suitable alkene or alkyne groups can be} _{used to react with an azide group to couple the LPEI fragment to the PEG fragment. In some} preferred embodiments, incorporation of alkene or alkyne groups into ring systems introduces strain into the ring systems. The strain of the ring systems can be released upon reaction of the a_{lkene or alkyne group to produce a 1, 2, 3 triazole or a 4,5-dihydro-1H-[1,2,3]triazole,} _{preferably without the use of an added catalyst such as copper. Thus, in some preferred} embodiments, suitable ring systems include seven-, eight-, or nine-membered rings that include a_{n alkyne group, or eight-membered rings that include a trans alkene group. For example,} _{P6797PC00 – 115 –} _{suitable alkyne groups such as cyclooctyne (OCT), monofluorinated cyclooctyne (MOFO),} difluorocycloalkyne (DIFO), dibenzocyclooctynol (DIBO), dibenzoazacyclooctyne (DIBAC), _{bicyclononyne (BCN), biarylazacyclooctynone (BARAC) and tetramethylthiepinium (TMTI)} _{can be used. Additionally, suitable alkene groups such as trans cyclooctene, trans cycloheptene,} _{and maleimide can be used. For example, conjugates of the present invention can be prepared} _{from moieties comprising a PEG fragment and an alkene or alkyne group according to one of} the following formulae: R^A1 R^A1 H W_{ithout wishing to be bound by theory, the azide and the alkene or alkyne groups can} _{spontaneously (i.e., without the addition of a catalyst) react to form a 1, 2, 3 triazole or a 4,5-} dihydro-1H-[1,2,3]triazole. In some embodiments, the azide group reacts with an alkyne to form a 1, 2, 3 triazole. In some embodiments, the azide group reacts with an alkene to form a _{P6797PC00 – 116 –} 4,5-dihydro-1H-[1,2,3]triazole. One of skill in the art will appreciate that both the LPEI fragment and the PEG fragment can be functionalized to include an azide group, and both the LPEI fragment and the PEG fragment can be functionalized to include an alkene or alkyne fragment (e.g., a strained alkene or alkyne). Thus, in some embodiments, the LPEI fragment comprises the alkene or alkyne group (e.g., a strained alkene or alkyne) and the bi-functionalized PEG fragment comprises an azide group. In some preferred embodiments, the bi-functionalized PEG fragment comprises the alkene or alkyne group (e.g., a strained alkene or alkyne) and the LPEI fragment comprises an azide group. One of skill in the art will also appreciate that a [3+2] cycloaddition between an azide and an alkene or alkyne group can give adducts with different regiochemistries as shown in Schemes 6-8, below. One of skill in the art will understand that all possible regiochemistries of [3+2] cycloaddition are contemplated by this invention. In some preferred embodiments, the [3+2] azide-alkyne cycloaddition reaction takes _{place at a pH of 5 or below, preferably 4 or below. As set forth below in the Comparative} Example, no reaction occurred when a PEG fragment modified with an activated alkyne was treated with a non-azide containing LPEI fragment at a pH of 4. Without wishing to be bound by theory, these results suggest that the azide group of the LPEI fragment chemoselectively reacts with the alkyne or alkene (preferably a strained alkyne or alkene) group of the PEG _{fragment. However, at higher pH, the Comparative Example teaches that a side product was} _{formed, characterized as a hydroamination reaction between the nitrogen atoms of the LPEI} fragment and the alkene or alkyne. Without wishing to be bound by theory, the present invention teaches that an LPEI fragment (e.g., comprising a terminal azide) can be chemoselectively bonded to a PEG fragment (e.g., comprising an activated, preferably strained alkene or alkyne), at a pH below about 5, preferably about 4 or below. Thus, in another aspect, the present invention provides a method of synthesizing a conjugate of Formula I, comprising reacting an LPEI fragment comprising a thiol with a PEG fragment comprising an alkene. In another aspect, the present invention provides a method of synthesizing a conjugate as described and defined herein, and preferably a method of synthesizing a conjugate of Formula I, wherein the method comprises reacting the omega terminus of a linear _{polyethyleneimine fragment with a first terminal end of a polyethylene glycol fragment,} wherein said reaction occurs at a pH below about 5, preferably 4 or below, and wherein _{P6797PC00 – 117 –} preferably said omega terminus of said linear polyethyleneimine fragment comprises an azide, and wherein said first terminal end of said polyethylene glycol fragment comprises an alkene or an alkyne, and wherein said reaction is between said azide and said alkene or an alkyne. Scheme 6. Coupling of LPEI to Dibenzocyclooctyne (DBCO)-modified PEG H N L L _a strained alkyne group such DBCO. Treatment of the DBCO-modified PEG in solution with an azide-modified LPEI results in a [3+2] cycloaddition of the azide to the alkyne of DBCO to produce a 1, 2, 3 triazole. One of skill in the art will appreciate that the reaction shown above i_{n Scheme 6 can produce triazole adducts with different regiochemistries as shown above. The} _{variables m and n represent the number of repeating PEG and LPEI units as described herein.} Scheme 7. Coupling of LPEI to Bicyclononyne (BCN)-modified PEG H N H X L L a strained alkyne group such bicyclononyne (BCN). Treatment of the BCN-modified PEG in _{P6797PC00 – 118 –} solution with an azide-modified LPEI results in a [3+2] cycloaddition of the azide to the alkyne o_{f BCN to produce a 1, 2, 3 triazole. One of skill in the art will appreciate that the reaction} _{shown above in Scheme 7 can produce triazole adducts with different regiochemistries as} shown above. The variables m and n represent the number of repeating PEG and LPEI units as described herein. Scheme 8. Coupling of LPEI to Maleimide (MAL)-Modified PEG O H O N H X¹ X² N L a_{lkene group such as maleimide (MAL). Treatment of the MAL-modified PEG in solution with} an azide-modified LPEI will result in a [3+2] cycloaddition of the azide to the alkene of MAL to produce a 4,5-dihydro-1H-[1,2,3]triazole. The variables m and n will represent the number of repeating PEG and LPEI units as described herein. Scheme 9. Coupling LPEI to Alkene-Modified PEG H N _X1 X² H N X¹ X² L to include a terminal alkene group and LPEI can be modified to include a terminal thiol group. Treatment of the thiol-modified LPEI in solution with an alkene-modified PEG can result in a thiol-ene reaction to produce a thioether. The variables m and n will represent the number of repeating PEG and LPEI units as described herein. X¹ and X² Linking Moieties In some embodiments, the PEG fragments of the conjugates of the present invention c_{an be connected to alkene or alkyne groups and/or targeting fragments by covalent linking} moieties. X¹ Linking Moieties I_{n some embodiments, PEG fragments of the conjugates of the present invention are} connected to an activated (e.g., cyclic) alkene or alkyne group on a terminal end by a linking moiety. For instance, the X¹ linking moiety can be formed as the result of selecting a PEG fragment and an alkene or alkyne group that each contain reactive functional groups that can _{P6797PC00 – 119 –} be combined by well-known chemical reactions. For example, a PEG fragment can be coupled _{to an activated (e.g., cyclic) alkene or alkyne group by standard means such as peptide coupling} (e.g., to form an amide), nucleophilic addition, or other means known to one of skill in the art. In one aspect, X¹ is a linking moiety of the formula –(Y¹)_p–, wherein p is an integer between 1 and 20, and each occurrence of Y¹ is independently selected from a chemical bond, _{-CR11R12-, -C(O)-, -O-, -S-, -NR13-, an amino acid residue, a divalent phenyl moiety, a divalent} carbocyle moiety, a divalent heterocycle moiety, and a divalent heteroaryl moiety, wherein each divalent phenyl or heteroaryl is optionally substituted with one or more R¹¹, and each divalent heterocycle is optionally substituted with one or more R¹⁴; R¹¹, R¹² and R¹³ are independently, _{at each occurrence, H, -SO3H, -NH2, or C1-C6 alkyl, wherein each alkyl is optionally substituted} with -CO₂H or NH₂; and R¹⁴ is independently, at each occurrence, H, C₁-C₆ alkyl, or oxo, C₆- C10 aryl, or 5 to 8-membered heteroaryl. In some embodiments, when Y¹ is an amino acid residue, it can be oriented in any _{direction, i.e., -C(O)-CHR-NH- or -NH-CHR-C(O)-, wherein “R” represents the side-chain of} a naturally occurring amino acid. In some embodiments, the divalent heteroaryl moiety is a divalent heteroaryl group comprising one or more heteroatoms selected from O, N, S, and P, preferably one or two atoms selected from O and N. In some embodiments, the divalent heteroaryl moiety is a divalent furan, pyrrole, imidazole, pyrazole, triazole, pyridine, pyrimidine, pyridazine, pyrazine, thiophene, oxazole, or isoxazole; wherein the divalent heteroaryl is optionally substituted with one or more, preferably one or zero R¹⁴. In the embodiments below for X¹, unless otherwise specified, a wavy line indicates a bond in any direction, i.e., to a PEG fragment or to the divalent covalent linking moiety (e.g., “Z” or Ring A). In some embodiments, the divalent heterocycle moiety is a divalent heterocycle group comprising one or more heteroatoms selected from O, N, S, and P, preferably one or two atoms selected from O and N. In some embodiments, the divalent heterocycle moiety is a divalent tetrahydrofuran, pyrrolidine, piperidine, or 4,5-Dihydro-isoxazole, each optionally substituted with one or more R¹⁴. In some preferred embodiments, the divalent heterocycle moiety is a _{P6797PC00 – 120 –} succinimide. In some preferred embodiments, two Y¹ can combine to form a linking moiety or O partial linking moiety of the . In a further preferred combine to form a linking moiety or O partial linking moiety of the , wherein the wavy line next to the sulfur represents the direction of targeting fragment. In a further preferred embodiment, Y¹ can comprise a linking moiety or partial linking H^O ₂ ^C moiety of the In a further comprise a linking moiety or partial linking HO₂C moiety of the wherein the wavy line next to the sulfur represents the targeting fragment. In some embodiments, X¹ is a linking moiety of the formula –(Y¹)p–, wherein p is an integer between 1 and 8, and each occurrence of Y¹ is independently selected from a chemical . wherein p is an integer between 1 and 8, and each occurrence of Y¹ is independently selected from a chemical . _{P6797PC00 – 121 –} In some embodiments, X¹ is a linking moiety of the formula –(Y¹)p–, wherein p is an integer between 1 and 8, and each occurrence of Y¹ is independently selected from a chemical . p is an integer between 1 and 8, and each occurrence of Y¹ is independently selected from a chemical , wherein Y¹ i_s In some embodiments, X¹ is R¹¹ R¹² , wherein r is an integer between 1 and 8, preferably between 1 and 4, more 1 and 2; and wherein R¹¹ and R¹² are independently -H or C₁-C₆ alkyl, preferably -H or C1-C2 alkyl, more preferably -H. In some embodiments, X¹ is R^{11 R12 R11} _R ¹² R^{11 R12 R11} _R ¹² wherein the sum of r and s is less than or equal to 7; and wherein R¹¹ and R¹² are independently -_{H or C1-C6 alkyl, preferably -H or C1-C2 alkyl, more preferably -H. Preferably the wavy line} nearest to the integer “r” is a bond to the divalent covalent linking moiety (e.g., “Z” or Ring A) and the wavy line nearest to the integer “s” is a bond to the PEG fragment –[OCH2-CH2]m–. In some embodiments, X¹ is R^{11 R12 R11} _R ¹² , wherein s and t are each independently an integer between 0 and 4, 1 and 3, more preferably between 1 and 2; and wherein the sum of r and s is less than or equal to 7; and wherein R¹¹, R¹², and R¹³ are independently -H or C1-C6 alkyl, p_{referably -H or C1-C2 alkyl, more preferably -H. Preferably the wavy line nearest to the integer} “r” is a bond to the divalent covalent linking moiety (e.g., “Z” or Ring A) and the wavy line nearest to the integer “s” is a bond to the PEG fragment –[OCH₂-CH₂]_m–. _{P6797PC00 – 122 –} In some embodiments, X¹ is O_O , wherein r is an integer between 0 and 3, preferably between 1 and 1 and 2; s and t are each independently an integer between 0 and 2, preferably 0 and 1; wherein the sum of r, s, and t is less than or equal to 6; and wherein R¹¹ and R¹² are independently -H or C1-C6 alkyl, preferably -H or C1-C2 alkyl, more preferably -H. Preferably the wavy line nearest to the integer “r” is a bond to the divalent covalent linking moiety (e.g., “Z” or Ring A) and the wavy line nearest to the integer “t” is a bond to the PEG fragment –[OCH2-CH2]m–. In some embodiments, X¹ is O R¹¹ R^{12 R13} _R ¹¹ _R ¹² wherein the sum of r and s is less than or equal to 6; and wherein R¹¹, R¹² and R¹³ are i_{ndependently -H or C1-C6 alkyl, preferably -H or C1-C2 alkyl, more preferably -H. Preferably} the wavy line nearest to the integer “r” is a bond to the divalent covalent linking moiety (e.g., “Z” or Ring A) and the wavy line nearest to the integer “s” is a bond to the PEG fragment – [OCH₂-CH₂]_m–. In some embodiments, X¹ is O_{R11 R12} R¹¹ R¹² , wherein r and s are each independently an 3, more preferably between 1 and 2; and w_{herein the sum of r and s is less than or equal to 6; and wherein R11, R12 and R13 are} _{independently -H or C1-C6 alkyl, preferably -H or C1-C2 alkyl, more preferably -H. Preferably} the wavy line nearest to the integer “r” is a bond to the divalent covalent linking moiety (e.g., “Z” or Ring A) and the wavy line nearest to the integer “s” is a bond to the PEG fragment – [OCH2-CH2]m–. In some embodiments, X¹ is _{P6797PC00 – 123 –} 1^{1 12} 12 ¹¹ O O _R ^{11 R}12 ^R11 _R ¹² _R ^{R R} _R R¹³ _R ^{11 R}12 R¹¹ _R ¹² , , preferably wherein r is 0, s is 2 or 3, and t is 2; wherein the sum of r, s and t is less than or equal to 5; and wherein R¹¹, R¹² and R¹³ are independently -H or C₁-C₆ alkyl, preferably -H or C_{1-C2 alkyl, more preferably -H. Preferably the wavy line nearest to the integer “r” is a bond} to the divalent covalent linking moiety (e.g., “Z” or Ring A) and the wavy line nearest to the integer “t” is a bond to the PEG fragment –[OCH2-CH2]m–. In some embodiments, X¹ is O_{R11 R}12 ^R11 _R ¹² _R ^{11 R12 R}12 _R ^{11 O} R^{11 R}12 ^R11 _R ¹² , R¹¹ and R¹² are independently -H or C1-C6 alkyl, preferably -H or C1-C2 alkyl, more preferably -_{H. Preferably the wavy line nearest to the integer “r” is a bond to the divalent covalent linking} moiety (e.g., “Z” or Ring A) and the wavy line nearest to the integer “t” is a bond to the PEG fragment –[OCH2-CH2]m–. In some embodiments, X¹ is _{P6797PC00 – 124 –} R¹² R¹¹ O R¹² R¹¹ R¹¹ R¹² O R¹¹ R¹² _R ¹² _R ¹¹ O _R ¹² _R ¹¹ , 2; wherein the sum of r and s is less than or equal to 5; and wherein R¹¹, R¹² and R¹³ are i_{ndependently -H or C1-C6 alkyl, preferably -H or C1-C2 alkyl, more preferably -H. Preferably} the wavy line nearest to the integer “r” is a bond to the divalent covalent linking moiety (e.g., “Z” or Ring A) and the wavy line nearest to the integer “s” is a bond to the PEG fragment – [OCH₂-CH₂]_m–. In some embodiments, X¹ is R¹² R¹¹ ,_{wherein r is independently an integer between 0 and 4, preferably} between 1 and 2; and whe ^{11 12} rein R , and R are independently -_{H or C1-C6 alkyl, preferably -H or C1-C2 alkyl, more preferably -H. Preferably the wavy line} nearest to the integer “r” is a bond to the divalent covalent linking moiety (e.g., “Z” or Ring A) and the wavy line nearest to the carbonyl group is a bond to the PEG fragment –[OCH₂-CH₂]_m– . In some embodiments, X¹ is O ,_{wherein r and s are each independently an integer between 0 and} more preferably between 1 and 2; wherein the sum of r and s is less than or equal to 5; and wherein R¹¹, and R¹² are independently -H or C₁-C₆ alkyl, preferably -_{H or C1-C2 alkyl, more preferably -H. Preferably the wavy line nearest to the integer “r” is a} bond to the divalent covalent linking moiety (e.g., “Z” or Ring A) and the wavy line nearest to the carbonyl group is a bond to the PEG fragment –[OCH₂-CH₂]_m–. In some embodiments, X¹ is _{P6797PC00 – 125 –} O , wherein r and s are each independently an integer 0 and 2; wherein the sum of r and s is less than or equal to 5; and wherein R¹¹, R¹² and R¹³ are independently -H or C₁-C₆ alkyl, preferably -H or C₁-C₂ _{alkyl, more preferably -H. Preferably the wavy line nearest to the integer “r” is a bond to the} divalent covalent linking moiety (e.g., “Z” or Ring A) and the wavy line nearest to the carbonyl group is a bond to the PEG fragment –[OCH₂-CH₂]_m–. In some preferred embodiments, X¹ is selected from: R^{11 R12 R}12 R¹¹ O _R ^{11 R12 R}12 _R ¹¹ O R¹³ R^{11 R12 R}12 _R ¹¹ O O , , s is independently, at each occurrence, 0-6, preferably 0, 2, 4; t is independently, at each occurrence, 0-6, preferably 0, 1, 2, 4; _{P6797PC00 – 126 –} _{R11 and R12 are independently, at each occurrence, selected from -H, -C1-C2 alkyl, -} SO₃H, and -NH₂; more preferably -H, -SO₃H, and -NH₂; yet more preferably -H; and R¹³ is -H. Preferably the wavy line nearest to the integer “r” is a bond to the divalent covalent linking moiety (e.g., “Z” or Ring A) and the wavy line nearest to the integer “s” or “t” or carbonyl group is a bond to the PEG fragment –[OCH₂-CH₂]_m–. I_{n some preferred embodiments, X1 is selected from:} _R ^{11 R12 R}12 _R ¹¹ O ^{11 12} 12 ¹¹ O R¹³ ^{1 12} 12 O _R ^{R R} _R _R ^{1 R R} _R ¹¹ O , , s is independently, at each occurrence, 0-6, preferably 0, 2, 4; t is independently, at each occurrence, 0-6, preferably 0, 1, 2, 4; R¹¹ and R¹² are independently, at each occurrence, selected from -H and -C₁-C₂ alkyl, preferably -H; and R¹³ is -H. Preferably the wavy line nearest to the integer “r” is a bond to the divalent covalent linking moiety (e.g., “Z” or Ring A) and the wavy line nearest to the integer “s” or “t” or carbonyl group is a bond to the PEG fragment –[OCH₂-CH₂]_m–. In some preferred embodiments, X¹ is a group selected from: _{P6797PC00 – 127 –} R¹² R¹¹ O ^{12 11} ^{1 12} 12 ¹³ R ^{R12 R}12 R R R ^{1 R R} _R ^{11 R 11} _R ¹¹ O 0; s is independently, at each occurrence, 0-6, preferably 0, 2, 3, or 4; more preferably 2 or 3; t is independently, at each occurrence, 0-6, preferably 0, 1, 2, 4; more preferably 2; R¹¹ and R¹² are independently, at each occurrence, selected from -H and -C₁-C₂ alkyl, preferably -H; and R_{13 is -H. Preferably the wavy line nearest to the integer “r” is a bond to the divalent} covalent linking moiety (e.g., “Z” or Ring A) and the wavy line nearest to the integer “s” or “t” group is a bond to the PEG fragment –[OCH₂-CH₂]_m–. In some preferred embodiments, X¹ is selected from: O t_{he wavy line on the left} Ring A) and the wavy line on the right side is a bond to the PEG fragment –[OCH₂-CH₂]_m–. In some preferred embodiments, X¹ is selected from: O O O H ._{Preferably the wavy line on the left} “Z” or Ring A) and the wavy line on the right side is a bond to the PEG fragment –[OCH₂-CH₂]_m–. In some preferred embodiments, X¹ is selected from: _{P6797PC00 – 128 –} O O O H O on the right side is a bond to the PEG fragment –[OCH2-CH2]m–. I_{n some embodiments, X1 is selected from:} _{O O O O} O O ; ; ; ._{Preferably the wavy line on the left side is a bond} (e.g., “Z” or Ring A) and the wavy line on the right side is a bond to the PEG fragment –[OCH2-CH2]m–. In some preferred embodiments, X¹ is selected from: O_O O O O line on the right side is a bond to the PEG fragment –[OCH₂-CH₂]_m–. _{P6797PC00 – 129 –} In some preferred embodiments, X¹ is –(CH2)1-6-; preferably X¹ is –(CH2)2-4-; more preferably X¹ is –(CH₂)₂-. X² Linking Moieties I_{n some embodiments, PEG fragments of the conjugates of the present invention are} _{connected to a targeting fragment on a terminal end by a linking moiety. For instance, the X2} linking moiety can be formed as the result of selecting a PEG fragment and a targeting fragment that each contain reactive functional groups that can be combined by well-known chemical _{reactions. For example, a PEG fragment can be coupled to a targeting group by standard means} _{such as peptide coupling (e.g., to form an amide), nucleophilic addition, or other means known} to one of skill in the art. In one aspect, X² is a linking moiety of the formula –(Y²)_q–, wherein q is an integer between 1 and 50, and each occurrence of Y² is independently selected from a chemical bond, -CR²¹R²²-, NR²³-, -O-, -S-, -C(O)-, an amino acid residue, a divalent phenyl moiety, a divalent carbocyle moiety, a divalent heterocycle moiety, and a divalent heteroaryl moiety, wherein each divalent phenyl and divalent heteroaryl is optionally substituted with one or more R²³, and wherein each divalent heterocycle moiety is optionally substituted with one or more R²⁴; R^21, R^22, and R²³ are each independently, at each occurrence, -H, -SO3H, -NH2, -CO2H, or C₁-C₆ alkyl, wherein each C₁-C₆ alkyl is optionally substituted with one or more -OH, oxo, -CO2H, -NH2, C6-C10 aryl, or 5 to 8-membered heteroaryl; R²⁴ is independently, at each occurrence, -H, -CO₂H, C₁-C₆ alkyl, or oxo. In some embodiments, R²¹, R²² and R²³ are each independently, at each occurrence, -H, -CO₂H, or C₁-C₆ alkyl. In some embodiments, R²¹, R²² and R²³ are each, independently -H or C1-C4 alkyl, preferably C1-C2 alkyl. In some embodiments, R²¹, R²², R²³, and R²⁴ are -H. In some embodiments, R²⁴ is independently -H, C1-C6 alkyl, or oxo. In some embodiments, the divalent heteroaryl moiety is a divalent heteroaryl group comprising one or more heteroatoms selected from O, N, S, and P, preferably one or two atoms selected from O and N. In some embodiments, the divalent heteroaryl moiety is a divalent furan, pyrrole, imidazole, pyrazole, triazole, pyridine, pyrimidine, pyridazine, pyrazine, thiophene, oxazole, or isoxazole; wherein the divalent heteroaryl is optionally substituted with one or more, preferably one or zero R²¹. _{P6797PC00 – 130 –} In the embodiments below for X², unless otherwise specified, a wavy line indicates a bond in any direction, i.e., to a PEG fragment (-[OCH₂CH₂]_m-) or to a targeting fragment (i.e., “L”). In some embodiments, the divalent heterocycle moiety is a divalent heterocycle group comprising one or more heteroatoms selected from O, N, S, and P, preferably one or two atoms selected from O and N. In some embodiments, the divalent heterocycle moiety is a divalent tetrahydrofuran, pyrrolidine, piperidine, or 4,5-dihydro-isoxazole, each optionally substituted with one or more R²⁴. In some preferred embodiments, the divalent heterocycle moiety is a succinimide. In some preferred embodiments, two Y² can combine to form a linking moiety or O partial linking moiety of the . In a further preferred combine to form a linking moiety or O partial linking moiety of the , wherein the wavy line next to the sulfur represents a bond to the the wavy line next to the nitrogen represents a bond to the the PEG fragment (–[OCH2-CH2]m–). In a further preferred embodiment, two Y² can combine to form a linking moiety or O partial linking moiety of the _{, wherein the wavy line next to the} sulfur represents a bond to the CH2]m –) and the wavy line next to nitrogen represents a bond to the targeting fragment (L). In a further preferred embodiment, Y² can comprise a linking moiety or partial linking O . _{P6797PC00 – 131 –} In a further preferred embodiment, Y² can comprise a linking moiety or partial linking moiety O , wherein the wavy line next to the sulfur targeting fragment. I_{n some embodiments, X2 is a linking moiety of the formula –(Y2)q–, wherein q is an} integer between 1 and 40, and each occurrence of Y² is independently selected from a chemical O bond, -CR²¹R²²-, NH-, -O-, -S-, -C(O)-, an amino acid R²¹ and R²² are independently, at each occurrence, -H, -CO₂H, each C₁ - C₆ alkyl is optionally substituted with one or more -OH, oxo, C₆-C₁₀ aryl, or 5 to 8-membered heteroaryl. I_{n some embodiments, X2 is a linking moiety of the formula –(Y2)q–, wherein q is an} integer between 1 and 40, and each occurrence of Y² is independently selected from a chemical O bond, -CHR²¹-, NH-, -O-, -S-, -C(O)-, an amino acid R²¹ is independently, at each occurrence, -H, - C1 alkyl), wherein each C1-C4 alkyl is optionally substituted with one or more C6-C10 aryl or 5 to 8-membered heteroaryl. In some embodiments, X² is a linking moiety of the formula –(Y²)q–, wherein q is an integer between 1 and 40, and each occurrence of Y² is independently selected from a chemical O b_{ond, -CHR21-, -NH-, -O-, -S-, -C(O)-, an amino acid} R²¹ is independently, at each occurrence, -H, - C₁ alkyl), wherein each C1-C4 alkyl is optionally substituted with one or more C6-C10 aryl or 5 to 8-membered heteroaryl. _{P6797PC00 – 132 –} In some embodiments, X² is a linking moiety of the formula –(Y²)q–, wherein q is an integer between 1 and 40, and each occurrence of Y² is independently selected from a chemical O bond, -CHR²¹-, -NH-, -O-, -S-, -C(O)-, an amino acid R²¹ is independently, at each occurrence, -H, - C₁ alkyl), wherein each C1-C3 alkyl is optionally substituted with one or more phenyl or indole. In some embodiments, X² is a linking moiety of the formula –(Y²)q–, wherein q is an integer between 1 and 40, and each occurrence of Y² is independently selected from a chemical O bond, -CHR²¹-, -NH-, -O-, -S-, -C(O)-, an amino acid R²¹ is independently, at each occurrence, -H, - C1 alkyl), wherein each C1-C3 alkyl is optionally substituted with one or more phenyl or 3-indole. In some embodiments, X² is a linking moiety of the formula –(Y²)_q–, wherein q is an integer between 1 and 40, and each occurrence of Y² is independently selected from a chemical O bond, -CHR²¹-, -NH-, -O-, -S-, -C(O)-, an amino acid , wherein Y² is _{only -NH- when it is adjacent to a -C(O)- group to form a} _and R²¹ is independently, at each occurrence, -H, -CO₂H, or C₁-C₃ alkyl (preferably C₁ alkyl), wherein each C1-C3 alkyl is optionally substituted with one or more phenyl or 3-indole. In some embodiments, X² is a linking moiety of the formula –(Y²)_q–, wherein q is an integer between 1 and 40, and each occurrence of Y² is independently selected from a chemical O bond, -CHR²¹-, -NH-, -O-, -S-, -C(O)-, an amino acid , wherein Y² is _{only -NH- when it is adjacent to a -C(O)- group to form an} R²¹ is independently, at each occurrence, -H, -CO2H, or C1-C3 alkyl (preferably C1 alkyl), wherein each C1-C3 alkyl is optionally substituted with one or more phenyl or 3-indole. In some embodiments, when Y² is an amino acid residue, Y² represents a naturally _{occurring, L- amino acid residue. When Y2 is an amino acid residue, it can be oriented in any} _{P6797PC00 – 133 –} _{direction, i.e., -C(O)-CHR-NH- or -NH-CHR-C(O)-, wherein “R” represents the side-chain of} a naturally occurring amino acid. In some embodiments, X² is R²¹ R²² , wherein r is an integer between 1 and 8, preferably between 1 and 4, more 1 and 2; and wherein R²¹ and R²² are independently -H or C1-C6 alkyl, preferably -H or C₁-C₂ alkyl, more preferably -H. In some embodiments, X² is R_{21 R22 R21} _R22 _R ^{21 R22 R21} _R ²² wherein the sum of r and s is less than or equal to 7; and wherein R²¹ and R²² are independently -H or C1-C6 alkyl, preferably -H or C1-C2 alkyl, more preferably -H. In some embodiments, X² is R^{21 R22 R21} _R ²² , wherein s and t are each independently an integer between 0 and 4, and 3, more preferably between 1 and 2; and wherein the sum of r and s i_{s less than or equal to 7; and wherein R21, R22, and R23 are independently -H or C1-C6 alkyl,} preferably -H or C₁-C₂ alkyl, more preferably -H. In some embodiments, X² is O_O , wherein r is an integer between 0 and 3, preferably between 1 and 3, 1 and 2; s and t are each independently an integer between 0 and 2, preferably 0 and 1; wherein the sum of r, s, and t is less than or equal to 6; and wherein R²¹ and R²² are independently -H or C₁-C₆ alkyl, preferably -H or C₁-C₂ alkyl, more preferably -H. In some embodiments, X² is _{P6797PC00 – 134 –} O R²¹ R^{22 R23} _R ²¹ _R ²² , wherein r and s are each independently an 1 and 3, more preferably between 1 and 2; and wherein the sum of r and s is less than or equal to 6; and wherein R²¹, R²² and R²³ are i_{ndependently -H or C1-C6 alkyl, preferably -H or C1-C2 alkyl, more preferably -H. Preferably} the wavy line nearest to the integer “r” is a bond to the PEG fragment (–[OCH2-CH2]m–) and the wavy line nearest to the integer “s” is a bond to the targeting fragment (L). In some embodiments, X² is O_{R21 R22} R²¹ R²² , wherein r and s are each independently an and 3, more preferably between 1 and 2; and wherein the sum of r and s is less than or equal to 6; and wherein R²¹, R²² and R²³ are i_{ndependently -H or C1-C6 alkyl, preferably -H or C1-C2 alkyl, more preferably -H. Preferably} the wavy line nearest to the integer “r” is a bond to the PEG fragment (–[OCH₂-CH₂]_m–) and the wavy line nearest to the integer “s” is a bond to the targeting fragment (L). In some embodiments, X² is O _R ^{21 R}22 ^R21 _R ²² _R ^{21 R22 R}22 R²¹ O ^R23 _R ^{21 R}22 R²¹ _R ²² ,wherein r and t are each an integer between 0 and 3 and s is an wherein r is 0, s is 2 or 3, and t is 2; wherein the sum of r, s and t is less than or equal to 5; and wherein R²¹, R²² and R²³ are independently -H or C1-C6 a_{lkyl, preferably -H or C1-C2 alkyl, more preferably -H. Preferably the wavy line nearest to the} integer “r” is a bond to the PEG fragment (–[OCH2-CH2]m–) and the wavy line nearest to the integer “t” is a bond to the targeting fragment (L). In some embodiments, X² is _{P6797PC00 – 135 –} _{O R21 R}22 ^R21 _R ²² _R ^{21 R22 R}22 _R ^{11 O} _R ^{21 R}22 ^R21 _R ²² ,_{wherein r and t are each an integer between 0 and 3; s is an integer} the sum or r, s and t is less than or equal to 5; ²¹ and wherein R and R²² are independently -H or C₁-C₆ alkyl, preferably -H or C₁-C₂ alkyl, more preferably -H. Preferably the wavy line nearest to the integer “r” is a bond to the PEG fragment (–[OCH2- CH₂]_m–) and the wavy line nearest to the integer “t” is a bond to the targeting fragment (L). In some embodiments, X² is R²¹ R²² O R²¹ R²² R²² R²¹ O R²² R²¹ ,wherein r and s are each 0 and 2; wherein the sum of r and s is less than or equal to 5; and wherein R²¹, R²² and R²³ are independently -H or C1-C6 a_{lkyl, preferably -H or C1-C2 alkyl, more preferably -H. Preferably the wavy line nearest to the} integer “r” is a bond to the PEG fragment (–[OCH₂-CH₂]_m–) and the wavy line nearest to the integer “s” is a bond to the targeting fragment (L). In some embodiments, X² is O ,_{wherein r and s are each independently an integer between 0} 2, more preferably between 1 and 2; wherein the sum of r and s is less than or equal to 5; and wherein R²¹, and R²² are independently -H or C1-C6 alkyl, p_{referably -H or C1-C2 alkyl, more preferably -H. Preferably the wavy line nearest to the integer} “r” is a bond to the PEG fragment (–[OCH₂-CH₂]_m–) and the wavy line nearest to the carbonyl group is a bond to the targeting fragment (L). In some embodiments, X² is _{P6797PC00 – 136 –} O , wherein r and s are each independently an integer between 0 _{2; wherein the sum of r and s is less than or equal to 5; and} wherein R²¹, R²² and R²³ are independently -H or C1-C6 alkyl, preferably -H or C1-C2 alkyl, m_{ore preferably -H. Preferably the wavy line nearest to the integer “r” is a bond to the PEG} fragment (–[OCH2-CH2]m–) and the wavy line nearest to the carbonyl group is a bond to the targeting fragment (L). In some embodiments, X² is selected from: R²³ R²¹ R²² O R²³ R²¹ R²² R²¹ R²² , , , _{P6797PC00 – 137 –} R²³ R²¹ R²² O R²³ R²¹ R²² R²¹ R²² , ₀ _{and 4; v is an integer between 0 and 10; w is an integer between 0 and 10;} _{P6797PC00 – 138 –} _{AA is an amino acid residue, preferably a naturally occurring amino acid residue; yet more} preferably wherein AA is an an amino acid selected from Arg, His, Lys, Asp, Glu, Ser, Thr, Asn, Gln, Cys, Sec, Gly, Pro, Ala, Val, Ile, Leu, Met, Phe, Tyr, and Trp; a_{is an integer between 0 and 10, preferably between 0 and 6; more preferably between 0 and} 4; a_{nd wherein R21, R22 and R23 are independently –H, C1-C6 alkyl or (-COOH), preferably –H,} _{C1-C2 alkyl or (-COOH), more preferably –H or (-COOH). Preferably the wavy line on the left} side is a bond to the PEG fragment (–[OCH₂-CH₂]_m–) and the wavy line on the right side is a bond to the targeting fragment (L). In some preferred embodiments, (AA)a comprises a tri-peptide selected from Trp-Trp- G_{ly or Trp-Gly-Phe. In some preferred embodiments, (AA)a is Trp-Trp-Gly-Phe (SEQ ID} NO:6). In some embodiments, X² is selected from: R²³ _R ²¹ _R ²² O R²³ R²¹ R²² R²¹ R²² ; ; _{P6797PC00 – 139 –} R²¹ R²² O _R ²³ _{R21 R22 R21 R22} ;

_{P6797PC00 – 140 –} O _R ²³ R²¹ R²² O _R ²³ _{R21 R22 R21 R22} 0 and 4; v is an integer between 0 and 10; w is an integer between 0 and 10; AA is an amino acid residue, preferably a naturally occurring amino acid residue; yet more preferably wherein AA is an amino acid selected from Arg, His, Lys, Asp, Glu, Ser, Thr, Asn, Gln, Cys, Sec, Gly, Pro, Ala, Val, Ile, Leu, Met, Phe, Tyr, and Trp; a is an integer between 0 and 10, preferably between 0 and 6; more preferably between 0 and 4; and wherein R²¹, R²² and R²³ are independently –H, C1-C6 alkyl or (-COOH), preferably –H, C_{1-C2 alkyl or (-COOH), more preferably –H or (-COOH). Preferably the wavy line on the left} side is a bond to the PEG fragment (–[OCH₂-CH₂]_m–) and the wavy line on the right side is a bond to the targeting fragment (L). I_{n some preferred embodiments, (AA)a is Trp-Trp-Gly-Phe (SEQ ID NO:6).} In some embodiments, X² is selected from: R²³ R²¹ R²² O R²¹ R²² O ; ; _{P6797PC00 – 141 –} R²¹ R²² O R²³ R²¹ R²² O ; 2; w is an integer between 0 and 10; and wherein R²¹, R²² and R²³ are independently -H or C₁-C₆ alkyl, preferably -H or C₁-C₂ alkyl, m_{ore preferably -H. Preferably the wavy line on the left side is a bond to the PEG fragment (–} [OCH₂-CH₂]_m–) and the wavy line on the right side is a bond to the targeting fragment (L). _{P6797PC00 – 142 –} In some embodiments, X² is selected from: R²¹ R²² O R²³ _R ²¹ _R ²² O ; _{P6797PC00 – 143 –} R²¹ R²² O 2; w is an integer between 0 and 10; and wherein R²¹, R²² and R²³ are independently -H or C1-C6 alkyl, preferably -H or C1-C2 alkyl, m_{ore preferably -H. Preferably the wavy line on the left side is a bond to the PEG fragment (–} [OCH2-CH2]m–) and the wavy line on the right side is a bond to the targeting fragment (L). In some preferred embodiments, X² is selected from: R²³ R²¹ R²² O R²¹ R²² O ; _{P6797PC00 – 144 –} O R²¹ R²² O ; ; _{P6797PC00 – 145 –} R²¹ R²² O R²¹ R²² O ; r_{, s, and t, are each independently an integer between 0 and 4, preferably between 0 and 2; w is} an integer between 0 and 10; AA is an amino acid selected from Arg, His, Lys, Asp, Glu, Ser, Thr, Asn, Gln, Cys, Sec, Gly, Pro, Ala, Val, Ile, Leu, Met, Phe, Tyr, and Trp; a is an integer between 0 and 10, preferably between 0 and 6; more preferably between 0 and 4; and wherein R²¹, R²² and R²³ are independently -H or C1-C6 alkyl, preferably -H or C1-C2 alkyl, m_{ore preferably -H. Preferably the wavy line on the left side is a bond to the PEG fragment (–} [OCH2-CH2]m–) and the wavy line on the right side is a bond to the targeting fragment (L). I_{n yet more preferred embodiments, (AA)a is Trp-Trp-Gly-Phe (SEQ ID NO:6).} In some embodiments, X² comprises or alternatively is a urea, a carbamate, a carbonate, or an ester. In preferred embodiments, X² is selected from: _{P6797PC00 – 146 –} O targeting fragment (L). In a preferred embodiment said X² is H N O O . and the wavy line on the right side is a bond to the targeting fragment (L). In a further preferred embodiment said X² is H N O O _{P6797PC00 – 147 –} _{CH(COOH)-(CH2)2-CO-). Preferably the wavy line on the left side is a bond to the PEG} fragment (–[OCH₂-CH₂]_m–) and the wavy line on the right side is a bond to the DUPA residue. In a further preferred embodiment said X² is H N O O CH(COOH)-(CH2)2-CO-), wherein the terminus with the amide group of said X² is bonded to the PEG fragment (–[OCH₂-CH₂]_m–) and wherein the terminus with the amine functionality is bonded to the DUPA residue (HOOC(CH₂)₂-CH(COOH)-NH-CO-NH-CH(COOH)-(CH₂)₂- CO-). In some embodiments, X² is selected from: R²¹ O O Preferably the wavy line on the left side is a bond to the PEG fragment (–[OCH2-CH2]m–) and t_{he wavy line on the right side is a bond to the targeting fragment (L).} In some embodiments, X² is selected from: O ,_{wherein XB is -C(O)NH- or -NH-} the wavy line on the left side is a bond to the PEG fragment (–[OCH2-CH2]m–) and the wavy line on the right side is a bond to the targeting fragment (L). In some embodiments, X² is selected from: _{P6797PC00 – 148 –} O R²¹ O O R²¹ O on the right side is a bond to the targeting fragment (L). In some embodiments, X² is selected from: R²¹ H O is O H N on the left side is a bond to the PEG fragment (–[OCH₂-CH₂]_m–) and the wavy line on the right side is a bond to the targeting fragment (L). _{P6797PC00 – 149 –} In some embodiments, X² is selected from: O O ), O H N ). Preferably the wavy the wavy line on the right side is a bond to the targeting fragment (L). In some embodiments, X² is selected from: O O is O ), _{P6797PC00 – 150 –} O O O O , is H O is H O N ), _{P6797PC00 – 151 –} O H N . Preferably the wavy line on the left side is a and the wavy line on the right side is a bond to the targeting fragment (L). In some embodiments, X² is: O ,_{wherein XB is -C(O)NH- or -NH-C(O)-. Preferably the} the PEG fragment (–[OCH2-CH2]m–) and the wavy line on the right side is a bond to the targeting fragment (L). In some embodiments, X² is: O R²¹ ,_{wherein XB is -C(O)NH- or -NH-C(O)-. Preferably} to the PEG fragment (–[OCH2-CH2]m –) and the wavy line on the right side is a bond to the targeting fragment (L). Exemplary embodiments of the conjugates are given below. The conjugates described herein and below can be present in any of the polyplexes described herein, e.g., the first polyplex, the second polyplex, and/or the third (and optionally subsequent) polyplex. In some embodiments, the composition comprises a conjugate of the Formula IA: _{P6797PC00 – 152 –} R^A1 H N H X¹ X² of about 3 or less, more preferably between about 350 and about 630 with a dispersity of about 2 or less, _{and again more preferably between about 400 and 580 with a dispersity about 1.2 or less, and} _{preferably wherein m is between about 2 and about 80 and a dispersity of about 2 or less, more} _{preferably between about 2 and about 70 with a dispersity of about 1.8 or less; again more} _{preferably between about 2 and about 50 repeating units with a dispersity of about 1.5, or} alternatively m is a discrete number of repeating units, and preferably wherein m is a discrete _{number of repeating -(O-CH2-CH2)- units, wherein said discrete number m is any integer of 4} to 100, preferably of 4 to 60, and further preferably 12, 24 or 36, and again further preferably 25 to 60, preferably 36. In some embodiments, the composition comprises a conjugate of the Formula IA-1: H ^RA1 N 2: 3: of about 3 or less, more preferably between about 350 and about 630 with a dispersity of about 2 or less, _{and again more preferably between about 400 and 580 with a dispersity about 1.2 or less, and} _{P6797PC00 – 153 –} preferably wherein m is between about 2 and about 80 and a dispersity of about 2 or less, more _{preferably between about 2 and about 70 with a dispersity of about 1.8 or less; again more} preferably between about 2 and about 50 repeating units with a dispersity of about 1.5, or alternatively m is a discrete number of repeating units, preferably and preferably wherein m is _{a discrete number of repeating -(O-CH2-CH2)- units, wherein said discrete number m is any} integer of 4 to 100, preferably of 4 to 60, and further preferably 12, 24 or 36, and again further preferably 25 to 60, preferably 36. In some embodiments, the composition comprises a conjugate of the Formula IA-3a: O L Formula IA-3a. In of the Formula IA-3b: O O L Formula IA-3b. of the Formula IA-3c: O O L Formula IA-3c. of the Formula IA-3d: O O L Formula IA-3d. _{P6797PC00 – 154 –} In some embodiments, the composition comprises a conjugate of the Formula IA-4: L Formula IA-4, 700 with a dispersity of about 3 or less, more preferably between about 350 and about 630 with a dispersity of about 2 or less, _{and again more preferably between about 400 and 580 with a dispersity about 1.2 or less, and} preferably wherein m is between about 2 and about 80 and a dispersity of about 2 or less, more preferably between about 2 and about 70 with a dispersity of about 1.8 or less; again more preferably between about 2 and about 50 repeating units with a dispersity of about 1.5, or alternatively m is a discrete number of repeating units, and preferably wherein m is a discrete _{number of repeating -(O-CH2-CH2)- units, wherein said discrete number m is any integer of 4} to 100, preferably of 4 to 60, and further preferably 12, 24 or 36, and again further preferably 25 to 60, preferably 36. I_{n some embodiments, the composition comprises a conjugate of the Formula IA-4a:} O L Formula IA-4a. of the Formula IA-4b: O O L Formula IA-4b. of the Formula IA-4c: _{P6797PC00 – 155 –} O O L Formula IA-4c. of the Formula IA-4d: O O L Formula IA-4d. _{of the Formula IA-5:} SO₃H 5. In Formula IA-6: SO₃H I_n _IA-7: _{P6797PC00 – 156 –} H N X¹ X² 7. IA-7a: O_O H N L Formula IA-7a. Formula IA-8: X¹ X² N IA-8a: O O 2 9: L Formula IA-9, with a dispersity of about 3 or less, more preferably between about 350 and about 630 with a dispersity of about 2 or less, _{and again more preferably between about 400 and 580 with a dispersity about 1.2 or less, and} _{P6797PC00 – 157 –} preferably wherein m is between about 2 and about 80 and a dispersity of about 2 or less, more preferably between about 2 and about 70 with a dispersity of about 1.8 or less; again more preferably between about 2 and about 50 repeating units with a dispersity of about 1.5, or alternatively m is a discrete number of repeating units, and preferably wherein m is a discrete _{number of repeating -(O-CH2-CH2)- units, wherein said discrete number m is any integer of 4} to 100, preferably of 4 to 60, and further preferably 12, 24 or 36, and again further preferably 25 to 60, preferably 36. In some embodiments, the composition comprises a conjugate of the Formula IA-9a: L Formula IA-10, with a dispersity of about 3 or less, more preferably between about 350 and about 630 with a dispersity of about 2 or less, _{and again more preferably between about 400 and 580 with a dispersity about 1.2 or less, and} preferably wherein m is between about 2 and about 80 and a dispersity of about 2 or less, more preferably between about 2 and about 70 with a dispersity of about 1.8 or less; again more preferably between about 2 and about 50 repeating units with a dispersity of about 1.5, or _{alternatively m is a discrete number of repeating units, and preferably wherein m is a discrete} _{number of repeating -(O-CH2-CH2)- units, wherein said discrete number m is any integer of 4} to 100, preferably of 4 to 60, and further preferably 12, 24 or 36, and again further preferably _{25 to 60, preferably 36.} In some embodiments, the composition comprises a conjugate of the Formula IA-10a: _{P6797PC00 – 158 –} 3 or less, more preferably between about 350 and about 630 with a dispersity of about 2 or less, _{and again more preferably between about 400 and 580 with a dispersity about 1.2 or less, and} preferably wherein m is between about 2 and about 80 and a dispersity of about 2 or less, more preferably between about 2 and about 70 with a dispersity of about 1.8 or less; again more preferably between about 2 and about 50 repeating units with a dispersity of about 1.5, or alternatively m is a discrete number of repeating units, and preferably wherein m is a discrete _{number of repeating -(O-CH2-CH2)- units, wherein said discrete number m is any integer of 4} to 100, preferably of 4 to 60, and further preferably 12, 24 or 36, and again further preferably 25 to 60, preferably 36. In some embodiments, the composition comprises a conjugate of the Formula IB-1: R^A1 H N H 1. IB-1a: H N H IB-2: _{P6797PC00 – 159 –} R^A1 H 2. IB-2a: H N L Formula IB-2a. of the Formula IC: H O N L Formula IC, a dispersity of about 3 or less, more preferably between about 350 and about 630 with a dispersity of about 2 or less, _{and again more preferably between about 400 and 580 with a dispersity about 1.2 or less, and} _{preferably wherein m is between about 2 and about 80 and a dispersity of about 2 or less, more} preferably between about 2 and about 70 with a dispersity of about 1.8 or less; again more preferably between about 2 and about 50 repeating units with a dispersity of about 1.5, or alternatively m is a discrete number of repeating units, and preferably wherein m is a discrete _{number of repeating -(O-CH2-CH2)- units, wherein said discrete number m is any integer of 4} to 100, preferably of 4 to 60, and further preferably 12, 24 or 36, and again further preferably 25 to 60, preferably 36. In some embodiments, the composition comprises a conjugate of the Formula IC-1: H O N O _{P6797PC00 – 160 –} H R^A1 N H L F_{ormula ID,} a dispersity of about 3 or less, more preferably between about 350 and about 630 with a dispersity of about 2 or less, _{and again more preferably between about 400 and 580 with a dispersity about 1.2 or less, and} preferably wherein m is between about 2 and about 80 and a dispersity of about 2 or less, more preferably between about 2 and about 70 with a dispersity of about 1.8 or less; again more preferably between about 2 and about 50 repeating units with a dispersity of about 1.5, or alternatively m is a discrete number of repeating units, and preferably wherein m is a discrete _{number of repeating -(O-CH2-CH2)- units, wherein said discrete number m is any integer of 4} to 100, preferably of 4 to 60, and further preferably 12, 24 or 36, and again further preferably 25 to 60, preferably 36. In some embodiments, the composition comprises a conjugate of the Formula ID-1: H R^A1 N L F_{ormula ID-1.} the Formula ID-1a: H R^A1 N H L Formula ID-1a. the Formula ID-2: R^A1 L F_{ormula ID-2.} of the Formula ID-2a: _{P6797PC00 – 161 –} R^A1 H L Formula ID-2a. of the Formula ID-3: H ID-3a: H L Formula ID-3a. Formula ID-4: L F_{ormula ID-4.} of the Formula ID-4a: L Formula ID-4a. Formula IE: _{P6797PC00 – 162 –} R^A1 H H L Formula IE, a dispersity of about 3 or less, more preferably between about 350 and about 630 with a dispersity of about 2 or less, _{and again more preferably between about 400 and 580 with a dispersity about 1.2 or less, and} preferably wherein m is between about 2 and about 80 and a dispersity of about 2 or less, more preferably between about 2 and about 70 with a dispersity of about 1.8 or less; again more preferably between about 2 and about 50 repeating units with a dispersity of about 1.5, or alternatively m is a discrete number of repeating units, and preferably wherein m is a discrete _{number of repeating -(O-CH2-CH2)- units, wherein said discrete number m is any integer of 4} to 100, preferably of 4 to 60, and further preferably 12, 24 or 36, and again further preferably 25 to 60, preferably 36. In some embodiments, the composition comprises a conjugate of the Formula IE-1: H ^RA1 N 1. IE-2: R^A1 L Formula IE-2. In of the Formula IE-3: H N X¹ X² 3. IE-3a: _{P6797PC00 – 163 –} H N O L IE-4: X¹ X² N 4_. IE-4a: N O L F_{ormula IE-4a.} of the Formula IE-5: H N X¹ X² ¹ In IE-5a: O H N L Formula IE-5a. of the Formula IE-6: X¹ X² N L 6. _{P6797PC00 – 164 –} In some embodiments, the composition comprises a conjugate of the Formula IE-6a: O IE-7: In IE-7a: L Formula IE-7a. In of the Formula IE-8: In IE-8a: _{P6797PC00 – 165 –} L Formula IE-8a. of the Formula IE-9: OSO₃H 9. In IE-9a: OSO₃H In IE-10:

_{P6797PC00 – 166 –} OSO₃H L Formula IE-10. In of the Formula IE-10a: OSO₃H L Formula IE-10a. In of the Formula IE-11: F H _{F X}1 X² L Formula IE-11. of the Formula IE-11a: F H F O L IE-11b: _{P6797PC00 – 167 –} F H F N 12: F F X¹ X² L Formula IE-12. In of the Formula IE-12a: F F O L Formula IE-12a. of the Formula IE-12b: F F L Formula IE-12b. of the Formula IE-13: X¹ H₂ H₂ O C _{C X2 L} of about 3 or less, more preferably between about 350 and about 630 with a dispersity of about 2 or less, _{and again more preferably between about 400 and 580 with a dispersity about 1.2 or less, and} preferably wherein m is between about 2 and about 80 and a dispersity of about 2 or less, more _{P6797PC00 – 168 –} preferably between about 2 and about 70 with a dispersity of about 1.8 or less; again more preferably between about 2 and about 50 repeating units with a dispersity of about 1.5, or alternatively m is a discrete number of repeating units, and preferably wherein m is a discrete _{number of repeating -(O-CH2-CH2)- units, wherein said discrete number m is any integer of 4} to 100, preferably of 4 to 60, and further preferably 12, 24 or 36, and again further preferably 25 to 60, preferably 36. In some embodiments, the composition comprises a conjugate of the Formula IE-13a: O H₂ H₂ H₂ Formula IE-13a. of the Formula IE-13b: O H₂ ^H ₂ ^H ₂ 13c: O H₂ ^H ₂ _L Formula IE-13c. of the Formula IE-13d: O H₂ H₂ _L Formula IE-13d. the Formula IE-14: _{P6797PC00 – 169 –} H H X¹ _{2 2} O C _{C X2 L} Formula IE-14, 700 with a dispersity of about 3 or less, more preferably between about 350 and about 630 with a dispersity of about 2 or less, _{and again more preferably between about 400 and 580 with a dispersity about 1.2 or less, and} preferably wherein m is between about 2 and about 80 and a dispersity of about 2 or less, more preferably between about 2 and about 70 with a dispersity of about 1.8 or less; again more preferably between about 2 and about 50 repeating units with a dispersity of about 1.5, or alternatively m is a discrete number of repeating units, and preferably wherein m is a discrete _{number of repeating -(O-CH2-CH2)- units, wherein said discrete number m is any integer of 4} to 100, preferably of 4 to 60, and further preferably 12, 24 or 36, and again further preferably 25 to 60, preferably 36. In some embodiments, the composition comprises a conjugate of the Formula IE-14a: O H₂ H₂ H₂ Formula IE-14a. In conjugate of the Formula IE-14b: O H₂ ^H ₂ ^H ₂ _L Formula IE-14b. of the Formula IE-14c: _{P6797PC00 – 170 –} O H₂ H₂ _{X2 L} Formula IE-14c. of the Formula IE-14d: O H₂ ^H ₂ _L Formula IE-14d. of the Formula IH: R^A1 H X¹ X² L Formula IH, of about 3 or less, more preferably between about 350 and about 630 with a dispersity of about 2 or less, _{and again more preferably between about 400 and 580 with a dispersity about 1.2 or less, and} preferably wherein m is between about 2 and about 80 and a dispersity of about 2 or less, more preferably between about 2 and about 70 with a dispersity of about 1.8 or less; again more preferably between about 2 and about 50 repeating units with a dispersity of about 1.5, or alternatively m is a discrete number of repeating units, and preferably wherein m is a discrete _{number of repeating -(O-CH2-CH2)- units, wherein said discrete number m is any integer of 4} to 100, preferably of 4 to 60, and further preferably 12, 24 or 36, and again further preferably 25 to 60, preferably 36. In some embodiments, the composition comprises a conjugate of the Formula IH’: R^A1 H N H L Formula IH’. Formula IH-1: _{P6797PC00 – 171 –} H N X¹ 1, 3 or less, more preferably between about 350 and about 630 with a dispersity of about 2 or less, a_{nd again more preferably between about 400 and 580 with a dispersity about 1.2 or less, and} preferably wherein m is between about 2 and about 80 and a dispersity of about 2 or less, more preferably between about 2 and about 70 with a dispersity of about 1.8 or less; again more preferably between about 2 and about 50 repeating units with a dispersity of about 1.5, or alternatively m is a discrete number of repeating units, and preferably wherein m is a discrete n_{umber of repeating -(O-CH2-CH2)- units, wherein said discrete number m is any integer of 4} to 100, preferably of 4 to 60, and further preferably 12, 24 or 36, and again further preferably 25 to 60, preferably 36. I_{n some embodiments, the composition comprises a conjugate of the Formula IH-1a:} O H N N X¹ X² 2, _{about 3} or less, more preferably between about 350 and about 630 with a dispersity of about 2 or less, a_{nd again more preferably between about 400 and 580 with a dispersity about 1.2 or less, and} preferably wherein m is between about 2 and about 80 and a dispersity of about 2 or less, more preferably between about 2 and about 70 with a dispersity of about 1.8 or less; again more preferably between about 2 and about 50 repeating units with a dispersity of about 1.5, or alternatively m is a discrete number of repeating units, and preferably wherein m is a discrete n_{umber of repeating -(O-CH2-CH2)- units, wherein said discrete number m is any integer of 4} _{P6797PC00 – 172 –} to 100, preferably of 4 to 60, and further preferably 12, 24 or 36, and again further preferably 25 to 60, preferably 36. In some embodiments, the composition comprises a conjugate of the Formula IH-2a: O L Formula IH-2a. the Formula IJ: R^1A ^L Formula IJ. the Formula IJ-1: H N L Formula IJ-1. of the Formula IJ-1a: H N IJ-2: _{P6797PC00 – 173 –} N L Formula IJ-2. of the Formula IJ-2a: N L Formula IJ-2a. of the Formula IJ-3: H N 3. 4: N 4. In IK: R^1A H H N L Formula IK. of the Formula IK-1: _{P6797PC00 – 174 –} O L X¹ X² Formula IK-1. In of the Formula IK-2: O L X¹ X² Formula IK-2. In of the Formula IK-3: O L X¹ _X ² 3. In IK-4: O L X² Formula IK-4. In of the Formula IK-3a: _{P6797PC00 – 175 –} O₂S O L X² Formula IK-3a. In of the Formula IK-4a: O_{2S O} L X² Formula IK-4a. In of the Formula IL: H ^{1 2} L Formula IL. the Formula IM: O L Formula IM. In of the Formula IN: O H L Formula IN. of the Formula IO: H N X¹ X² L Formula IO. I_n _{of the Formula IP:} _{P6797PC00 – 176 –} H N S O L Formula IP. In of the Formula IQ: H H N N O L Formula IQ. of the Formula IR: H H N N O L Formula IR. of the Formula IQ: H H N N O L R^A1 H N H L _{P6797PC00 – 177 –} H R^A1 N L _L of about 3 or less, more preferably between about 350 and about 630 with a dispersity of about 2 or less, and again more preferably between about 400 and 580 with a dispersity about 1.2 or less, and preferably wherein m is between about 2 and about 80 and a dispersity of about 2 or less, more preferably between about 2 and about 70 with a dispersity of about 1.8 or less; again more _{preferably between about 2 and about 50 repeating units with a dispersity of about 1.5, or} alternatively m is a discrete number of repeating units, and preferably wherein m is a discrete _{number of repeating -(O-CH2-CH2)- units, wherein said discrete number m is any integer of 4} to 100, preferably of 4 to 60, and further preferably 12, 24 or 36, and again further preferably 25 to 60, preferably 36. In some embodiments, said conjugate of Formula I is selected from: R^A1 H _{P6797PC00 – 178 –} R^A1 H N H 3 or less, more preferably between about 350 and about 630 with a dispersity of about 2 or less, and again more preferably between about 400 and 580 with a dispersity about 1.2 or less, and preferably wherein m is between about 2 and about 80 and a dispersity of about 2 or less, more preferably between about 2 and about 70 with a dispersity of about 1.8 or less; again more preferably between about 2 and about 50 repeating units with a dispersity of about 1.5, or alternatively m is a discrete number of repeating units, and preferably wherein m is a discrete _{number of repeating -(O-CH2-CH2)- units, wherein said discrete number m is any integer of 4} to 100, preferably of 4 to 60, and further preferably 12, 24 or 36, and again further preferably 25 to 60, preferably 36. In preferred embodiments, of any of Formulae IA, IB, IC, ID, IE, and/or IH, R^A1 is -H. I_{n another preferred embodiment, said conjugate of Formula I is selected from:} _{P6797PC00 – 179 –} 3 or less, more preferably between about 350 and about 630 with a dispersity of about 2 or less, and again more preferably between about 400 and 580 with a dispersity about 1.2 or less, and preferably wherein m is between about 2 and about 80 and a dispersity of about 2 or less, more _{P6797PC00 – 180 –} preferably between about 2 and about 70 with a dispersity of about 1.8 or less; again more preferably between about 2 and about 50 repeating units with a dispersity of about 1.5, or alternatively m is a discrete number of repeating units, and preferably wherein m is a discrete _{number of repeating -(O-CH2-CH2)- units, wherein said discrete number m is any integer of 4} to 100, preferably of 4 to 60, and further preferably 12, 24 or 36, and again further preferably 25 to 60, preferably 36. In some embodiments, said conjugate of Formula I is selected from: _{P6797PC00 – 181 –} R^A1 H N H H 3 or less, more preferably between about 350 and about 630 with a dispersity of about 2 or less, _{and again more preferably between about 400 and 580 with a dispersity about 1.2 or less, and} preferably wherein m is between about 2 and about 80 and a dispersity of about 2 or less, more preferably between about 2 and about 70 with a dispersity of about 1.8 or less; again more preferably between about 2 and about 50 repeating units with a dispersity of about 1.5, or alternatively m is a discrete number of repeating units, and preferably wherein m is a discrete _{number of repeating -(O-CH2-CH2)- units, wherein said discrete number m is any integer of 4} to 100, preferably of 4 to 60, and further preferably 12, 24 or 36, and again further preferably 25 to 60, preferably 36. In some embodiments, said conjugate of Formula I is selected from:

_{P6797PC00 – 182 –} In some embodiments, said conjugate of Formula I is selected from: R^A1 H N H H L Formula IB. from: H X¹ ₂ H₂ O C _{C X2 L} In some embodiments, the composition comprises a conjugate of the formula: _{P6797PC00 – 183 –} O O O H _less. In some embodiments, the composition comprises a conjugate of the formula: O O O _{1.2 or less.} In some embodiments, the composition comprises a conjugate of the formula: O O O or less. In some embodiments, the composition comprises a conjugate of the formula: O O O _{or less.} In some embodiments, the composition comprises a conjugate of the formula: _{P6797PC00 – 184 –} H O O O H N O p_{referably wherein n is between about 400 and 580 with a dispersity about 1.2 or less.} In some embodiments, the composition comprises a conjugate of the formula: O O O O In some embodiments, the composition comprises a conjugate of the formula:

_{P6797PC00 – 185 –} H O O O H N O In some embodiments, the composition comprises a conjugate of the formula: O O O O In some embodiments, the composition comprises a conjugate of the formula: In some embodiments, the composition comprises a conjugate of the formula: _{P6797PC00 – 186 –} In some embodiments, the composition comprises a conjugate of the formula: In some embodiments, the composition comprises a conjugate of the formula: Polyplexes The inventive compositions comprise a nucleic acid, wherein said nucleic acid and said c_{onjugate form a polyplex. In a preferred embodiment, said nucleic acid is non-covalently} bound to said conjugate. This facilitates the dissociation of the nucleic acid from the targeting f_{ragment following arrival to the targeted cell or tissue and its internalization in the targeted} cell or tissue. In preferred embodiments, the nucleic acid is an mRNA encoding a Cas protein, preferably Cas9. In preferred embodiments, the polyplex can also comprise an additional nucleic acid, e.g., a gRNA and/or a template DNA. In some embodiments, the gRNA and/or template DNA form a polyplex with the first conjugate. In some embodiments, the mRNA encoding a Cas protein is polyplexed to a first conjugate to form a first polyplex, and the gRNA and/or a template DNA is polyplexed to a second and optionally subsequent conjugate to form a second and optionally subsequent polyplex. In cases where two or more types of polyplexes a_{re used, the polyplexes are preferably administered together (e.g., to a cell) to facilitate gene} editing in the cell. The inventive polyplex provides efficient delivery of the nucleic acid into cells harboring the target cell surface receptor. As described herein, the targeting fragment comprised b_{y the inventive polyplex is capable of binding to the target cell surface receptor.} _{The term "RNA" as used herein relates to a nucleic acid which comprises ribonucleotide} residues and preferably being entirely or substantially composed of ribonucleotide residues. "Ribonucleotide" relates to a nucleotide with a hydroxyl group at the 2'-position of a β-D- _{P6797PC00 – 187 –} ribofuranosyl group. The term "RNA" as used herein comprises double stranded RNA (dsRNA) and single stranded RNA (ssRNA). The term “RNA” further includes isolated RNA such as partially or completely purified RNA, essentially pure RNA, synthetic RNA, recombinantly _{generated RNA, in vitro transcribed RNA, in vivo transcribed RNA from a template such as a} DNA template, and replicon RNA, in particular self-replicating RNA, and includes modified RNA which differs from naturally occurring RNA by addition, deletion, substitution and/or alteration of one or more nucleotides. Such alterations can include addition of non-nucleotide material, such as to the end(s) of an RNA or internally. The RNA may have modified naturally occurring or synthetic ribonucleotides. Nucleotides in RNA can also comprise non-standard nucleotides, such as non-naturally occurring nucleotides or chemically synthesized nucleotides or deoxynucleotides. The term "single stranded RNA (ssRNA)" generally refers to an RNA molecule to which no complementary nucleic acid molecule (typically no complementary RNA molecule) is associated. ssRNA may contain self-complementary sequences that allow parts of the RNA to fold back and pair with itself to form double helices and secondary structure motifs including without limitation base pairs, stems, stem loops and bulges. The size of the ssRNA strand may vary from 8 nucleotides up to 120000 nucleotides, typically and preferably the size of the _{ssRNA strand may vary from 8 nucleotides up to 20000 nucleotides.} As used herein, the term “guide RNA” can be abbreviated “gRNA” is understood as _{RNA comprising (i) a sequence that is complementary to at least a portion of the DNA sequence} _{of a gene of interest (i.e., the target DNA), preferably referred to herein as “crisprRNA” or} _{“crRNA” sequence; and/or (ii) a sequence capable of serving as a binding scaffold for a Cas} _{protein, preferably referred to herein as a “tracrRNA” sequence. In some embodiments, the} inventive compositions comprise two gRNAs, preferably wherein a first gRNA comprises a crRNA sequence and a second gRNA comprises a tracrRNA sequence, and more preferably wherein said first and second gRNA each comprise an RNA sequence complimentary to a sequence of said other of said first and second gRNA. Without wishing to be bound, a system _{comprising two gRNAs can be referred to as a “2-piece gRNA” or as “cr:tracrRNA”.} In preferred embodiments, the gRNA is a “single guide RNA” or “sgRNA”. In preferred _{embodiments, said sgRNA comprises said crRNA sequence and said tracrRNA sequence} together on a single RNA strand. Preferably said sgRNA comprises a linker loop connecting said crRNA sequence and said tracrRNA sequence. Without wishing to be bound, the guide sequence of the guide RNA can hybridize to a _{P6797PC00 – 188 –} complimentary DNA sequence within the gene of interest. The guide RNA can additionally recruit a Cas protein (e.g., Cas9) to the site where it is hybridized, allowing the Cas protein to cut the DNA sequence at the desired site. In preferred embodiments, a guide RNA comprises from 50 bases to 150 bases, preferably from 75 to 125 bases in total. Preferably, the guide sequence comprises from 5 bases to 50 bases, more preferably from 10 bases to 30 bases, more preferably from 15 bases to 25 bases. As used herein, the terms “gene editing” “genome editing” and “genome engineering” are interchangeable. The term “gene editing” refers herein to a type of genetic engineering in _{which DNA is modified (e.g., inserted, deleted, modified or replaced) in the genome of a living} organism. Preferably said DNA is modified at a site-specific location within the genome (e.g., using CRISPR/Cas9). As used herein, the term “capable of eliciting gene editing”, when describing a nucleic acid or a protein, refers to a nucleic acid or protein that can alter the structure and/or sequence of a DNA molecule alone or in combination with other nucleic acids and/or proteins. In a preferred embodiment, said RNA is a "messenger-RNA" (mRNA). In preferred embodiments, the term mRNA relates to a RNA transcript which encodes a peptide or protein, wherein preferably said peptide or protein is a Cas protein, preferably Cas9. mRNA may be modified by stabilizing modifications and capping. Typically, a mRNA comprises a 5' untranslated region (5'-UTR), a protein coding region, and a 3' untranslated region (3'-UTR). Preferably, mRNA, in particular synthetic mRNA, contains a 5′ cap, UTRs embracing the coding region and a 3′ poly(A) tail. In one embodiment, the mRNA is produced by in vitro transcription using a DNA template where DNA refers to a nucleic acid that contains deoxyribonucleotides. The term "untranslated region" or "UTR" relates to a region in a DNA molecule which is transcribed but is not translated into an amino acid sequence, or to the corresponding region in an RNA molecule, such as an mRNA molecule. An untranslated region (UTR) can be present 5' (upstream) of an open reading frame (5'-UTR) and/or 3' (downstream) of an open reading frame (3'-UTR). A 3'-UTR, if present, is preferably located at the 3' end of a gene, downstream of the termination codon of a protein-encoding region, but the term "3'- UTR" does preferably not include the poly(A) tail. Thus, the 3'-UTR is preferably upstream of the poly(A) tail (if present), e.g. directly adjacent to the poly(A) tail. A 5'-UTR, if present, is preferably located at the 5' end of a gene, upstream of the start codon of a protein-encoding region. A 5'-UTR is preferably downstream of the 5'-cap (if present), e.g. directly adjacent to _{the 5'-cap. 5'- and/or 3'-untranslated regions may, according to the invention, be functionally} _{P6797PC00 – 189 –} linked to an open reading frame, so as for these regions to be associated with the open reading frame in such a way that the stability and/or translation efficiency of the RNA comprising said open reading frame are increased. The terms "poly(A) sequence" or "poly(A) tail" refer to an uninterrupted or interrupted sequence of adenylate residues which is typically located at the 3' end of an RNA molecule. An uninterrupted sequence is characterized by consecutive adenylate residues. While a poly(A) sequence is normally not encoded in eukaryotic DNA, but is attached during eukaryotic transcription in the cell nucleus to the free 3' end of the RNA by a template- independent RNA polymerase after transcription, the present invention also encompasses poly(A) sequences encoded by DNA. Terms such as "5'-cap", "cap", "5'-cap structure", or "cap structure" are used synonymously and refer preferably to a nucleotide modification at the 5’ end of the mRNA, more preferably to a dinucleotide that is found on the mRNA 5' end. A 5'- cap can be a structure wherein a (optionally modified) guanosine is bonded to the first nucleotide of an mRNA molecule via a 5' to 5' triphosphate linkage (or modified triphosphate linkage in the case of certain cap analogs). The term cap can refer to a naturally occurring cap _{or modified cap. RNA molecules may be characterized by a 5'-cap, a 5'- UTR, a 3'-UTR, a} poly(A) sequence, and/or adaptation of the codon usage. The mRNA may be generated by _{chemical synthesis, in vivo or in vitro transcription, e.g. from a DNA or other nucleic acid} template, or it may be recombinantly prepared or viral RNA. The mRNA includes non-self- amplifying mRNAs, such as endogenous mRNAs of mammalian cells, and self-amplifying mRNAs. Endogenous mRNA includes pre-mature and mature mRNA. The mRNA is preferably exogenous mRNA that has to enter the cell from outside the cell, e.g. by directly passing through the cytoplasmic membrane or by endocytosis followed by endosomal escape. mRNA preferably does not enter the nucleus, nor integrates into the genome. In a preferred embodiment, said mRNA have a size of bout and more than 100 nucleotides up to 20000 nucleotides. I_{n preferred embodiments, a first nucleic acid is a nucleic acid encoding a Cas protein,} _{preferably an mRNA encoding a Cas protein. As used herein, the term “Cas protein” is} _{understood as any RNA-guided DNA endonuclease enzyme or multisubunit enzyme complex} _{capable of selectively cleaving DNA, preferably double-stranded DNA at a specific nucleic} acid sequence and optionally in the presence of a guide RNA. As used herein, the term “Cas protein” is understood to encompass both Class 1 and Class 2 CRISPR-Cas systems. Class 1 systems are understood to encompass multiple different Cas proteins, which assemble to create a multisubunit enzyme complex. Class 1 systems include Type I, Type III, _{P6797PC00 – 190 –} and Type IV CRISPR-Cas systems. Without wishing to be bound by theory, (i) Type I CRISPR-Cas system includes the proteins Cas5, Cas6, Cas7, Cas8, and Cas11; (ii) Type III CRISPR-Cas system includes the proteins Cas5, Cas7, Cas7-like, Cas10, and Cas11; and (iii) Type IV CRISPR-Cas systems include the proteins Cas5, Cas6, Cas 7, and Csf1. In some embodiments, the “Cas protein” is a Class 1 Cas protein. In some embodiments, the “Cas _{protein” is understood to comprise multiple Cas proteins, preferably multiple Class I Cas} proteins and more preferably a grouping of Cas proteins (e.g., Type I, Type III, Type IV) capable of assembling to create a functional multisubunit enzyme complex. Accordingly, in _{some embodiments, a polyplex as described herein, e.g., a first polyplex comprising an mRNA} encoding a Cas protein can comprise one or more mRNAs encoding one or more Class I Cas proteins. For example, a first polyplex comprising an mRNA encoding a Cas protein can comprise an mRNA encoding Cas5; the first polyplex can optionally further comprise additional mRNA encoding Cas6, Cas7, Cas8 or Cas11; preferably the first polyplex further comprises additional mRNA encoding Cas6, Cas7, Cas8 and Cas11, wherein said mRNAs are _{delivered to a cell, transcribed by the cellular machinery into proteins, and assembled to create} a functional Type I multisubunit enzyme complex. Accordingly, in some embodiments, the “Cas protein” can be any of the proteins Cas5, Cas6, Cas7, Cas7-like, Cas8, Cas10, Cas11, _{Csf1, and combinations thereof. One of skill in the art will understand that multiple polyplexes} _{can be used to deliver one or more mRNAs encoding a Class 1 Cas protein, e.g., to a cell. For} example, a polyplex (e.g., a first polyplex) can comprise a single mRNA encoding one or more Class 1 Cas proteins, and a subsequent polyplex can comprise one or more additional, _{preferably different mRNAs encoding one or more additional, preferably different Class 1 Cas} proteins. Thus, in some embodiments, a single conjugate can be used to create a polyplex _{comprising multiple different mRNAs encoding multiple different Class 1 Cas proteins,} preferably wherein said multiple different Class 1 Cas proteins can assemble to create a functional Class 1 multisubunit enzyme complex. In some embodiments, multiple conjugates _{as described herein are used to each polyplex individually with a single, different Class 1 Cas} protein, preferably to create a plurality of polyplexes wherein each polyplex comprises an mRNA encoding a different Class 1 Cas protein, but wherein no individual polyplex comprises all of the mRNA necessary to create a functional Class 1 multisubunit enzyme complex. _{Preferably, said plurality of polyplexes can be combined prior to administration to a subject} _{and/or administered together to said subject, wherein the plurality of polyplexes, when} combined, comprises all the mRNA necessary to create a functional Class 1 multisubunit _{P6797PC00 – 191 –} enzyme complex. A_{s used herein, Class 2 systems are understood to contain only a single Cas protein} _{instead of a multisubunit complex. Class 2 systems include Type II, Type V, and Type VI} _{CRISPR-Cas systems. Without wishing to be bound by theory, (i) the Type II CRISPR-Cas} system includes Cas9; (ii) the Type V CRISPR-Cas system includes Cas12; and (iii) the Type VI CRISPR-Cas system includes Cas13. Accordingly, in some embodiments, a polyplex as described herein, e.g., a first polyplex comprising an mRNA encoding a Cas protein can _{comprise one or more mRNAs encoding one or more Class 2 Cas proteins. For example, in} preferred embodiments, a first polyplex comprising an mRNA encoding a Cas protein can comprise an mRNA encoding Cas9. In some embodiments, a first polyplex encoding a Cas protein can comprise an mRNA encoding Cas 12. In some embodiments, a first polyplex encoding a Cas protein can comprise an mRNA encoding Cas 13. In some embodiments, the Cas protein is Cas12. In some embodiments, the Cas protein is Cas13. In some embodiments, the Cas protein is Cas13a. In some embodiments, the Cas protein is Cas13b. In some embodiments, the Cas protein is Cas13c. In some embodiments, the Cas protein is Cas13d. In some embodiments, the Cas protein is Cas13X. In some embodiments, the Cas protein is _{Cas13Y. In preferred embodiments, the Cas protein is Cas9. In some embodiments, the Cas} protein is spCas9. As used herein, a “small nuclear RNA (snRNa)” is understood as a small (e.g., from about 100 to about 200 nucleotides in length) RNA molecule found within the splicing speckles and Cajal bodies of the cell nucleus in eukaryotic cells. As used herein, the term “base editor” is understood to mean a programmable DNA- binding protein fused to a deaminase, which enables precise nucleotide changes at targeted genomic loci without requiring a double stranded break. As used herein, a “transcription activator-like effector nuclease (TALEN)” is understood as a restriction enzyme that can be engineered to cut specific sequences of DNA. In preferred embodiments, a TALEN is made by fusing a TAL effector DNA-binding domain to a DNA cleavage domain, preferably a nuclease which cuts DNA strands. As used herein, a “zinc-finger nuclease (ZFN)” is understood as an artificial restriction enzyme generated by fusing a zinc finger DNA-binding domain to a DNA-cleavage domain. In preferred embodiments, zinc finger domains are engineered to target specific desired DNA sequences, enables zinc-finger nucleases to target unique sequences within complex genomes. As used herein, the term “template DNA” is understood as a sequence of DNA, _{P6797PC00 – 192 –} _{preferably single stranded homologous DNA, wherein said strand encodes a desired sequence} to be introduced into the genome of a subject. Without wishing to be bound by theory, in preferred embodiments, after a Cas protein selectively cleaves DNA (preferably at a specific sequence and guided by a gRNA), said cleaved DNA is repaired by native cellular machinery _{(e.g., DNA polymerases) and using the template DNA to carry out homology directed repair of} the cleaved DNA. One of skill in the art will understand that the DNA thus cleaved and repaired can be edited to include a different DNA sequence than the sequence originally present in the _{cell. Accordingly, in some embodiments, the template DNA can be used to introduce, e.g., a} healthy gene sequence, or a mutated gene sequence using homology directed repair. The formation of the inventive polyplex is typically caused by electrostatic interactions between positive charges on side of the inventive conjugate and negative charges on side of the _{polyanion, e.g., nucleic acid, preferably RNA. This results in complexation and spontaneous} formation of polyplexes. In one embodiment, an inventive polyplex refers to a particle having _{a z-average diameter suitable for parental administration.} The term "encoding" refers to the inherent property of specific sequences of nucleotides in a RNA, such as an mRNA, to serve as templates for synthesis of other polymers and _{macromolecules in biological processes having either a defined sequence of nucleotides or a} defined sequence of amino acids and the biological properties resulting therefrom. Thus, a gene encodes a protein if transcription and translation of mRNA corresponding to that gene produces the protein in a cell or other biological system. The terms "RNA encodes" or “RNA encoding”, as interchangeably used, means that the RNA, preferably the mRNA, if present in the appropriate environment, such as within cells of a target tissue, can direct the assembly of amino acids to produce the peptide or protein it encodes during the process of translation. In one embodiment, RNA is able to interact with the cellular translation machinery allowing _{translation of the peptide or protein. A cell may produce the encoded peptide or protein} intracellularly (e.g. in the cytoplasm), may secrete the encoded peptide or protein, or may produce it on the surface. With respect to RNA, and in particular with respect to mRNA, the term "expression" or "translation" relates to the process, typically in the ribosomes of a cell, by which a strand of mRNA directs the assembly of a sequence of amino acids to make a peptide or protein. The term "expression" is used in its most general meaning and comprises production of RNA and/or protein. As used herein, the terms “effective amount” and “therapeutically effective amount” are _{P6797PC00 – 193 –} used interchangeably and refer to an amount administered to a subject, either as a single dose or as part of a series of doses, which is effective to produce a desired physiological response or _{desired therapeutic effect in the subject. Examples of desired therapeutic effects include,} without limitation, improvements in the symptoms or pathology, and/or reducing the progression of symptoms or pathology in a subject suffering from an infection, disease, disorder _{and/or condition; and/or slowing, preventing or delaying the onset of symptoms or pathology} of an infection, disease, disorder and/or condition in a subject susceptible to said infection, disease, disorder and/or condition. The therapeutically effective amount will vary depending on the nature of the formulation used and the type and condition of the recipient. The determination of appropriate amounts for any given composition is within the skill in the art, through standard tests designed to assess appropriate therapeutic levels. Typical and preferred therapeutically effective amounts of the inventive triconjugates and/or polyplexes described herein range from about 0.05 to 1000 mg/kg body weight, and in particular from about 5 to 500 mg/kg body weight. T_{he term "antigen" covers any substance that will elicit an immune response. In} particular, an "antigen" relates to any substance that reacts specifically with antibodies or T- lymphocytes (T-cells). The term "antigen" comprises any molecule which comprises at least one epitope, preferably against which an immune response can be generated. Preferably, an antigen in the context of the present invention is a molecule which, optionally after processing, induces an immune reaction, which is preferably specific for the antigen, including wherein the immune reaction may be both a humoral as well as a cellular immune reaction. The antigen is preferably presented by a cell, preferably by an antigen presenting cell, in the context of MHC molecules, which results in an immune reaction against the antigen. Antigens include or may be derived from allergens, viruses, bacteria, fungi, plants, parasites and other infectious agents and pathogens or an antigen may also be a tumor antigen. In preferred embodiments, the antigen is a surface polypeptide, i.e. a polypeptide naturally displayed on the surface of a cell, a pathogen, a bacterium, a virus, a fungus, a plant, a parasite, an allergen, or a tumor. The antigen may elicit an immune response against a cell, a pathogen, a bacterium, a virus, a fungus, a plant, a parasite, an allergen, or a tumor. In one embodiment, an antigen is a self-antigen or a non-self-antigen. In another _{embodiment, said non-self-antigen is a bacterial antigen, a virus antigen, a fungus antigen, an} allergen or a parasite antigen. It is preferred that the antigen comprises an epitope that is capable of eliciting an immune response in a target organism. For example, the epitope may elicit an _{P6797PC00 – 194 –} immune response against a bacterium, a virus, a fungus, a parasite, an allergen, or a tumor. In some embodiments the non-self-antigen is a bacterial antigen. In some embodiments the non-self-antigen is a virus antigen. In some embodiments the _{non-self-antigen is a polypeptide or a protein from a fungus. In some embodiments the non-} self-antigen is a polypeptide or protein from a unicellular eukaryotic parasite. In some embodiments the antigen is a self-antigen, particularly a tumor antigen. Tumor _{antigens and their determination are known to the skilled person. In the context of the present} invention, the term "tumor antigen" or "tumor-associated antigen" relates to proteins that are under normal conditions specifically expressed in a limited number of tissues and/or organs or in specific developmental stages, for example, the tumor antigen may be under normal conditions specifically expressed in stomach tissue, preferably in the gastric mucosa, in reproductive organs, e.g., in testis, in trophoblastic tissue, e.g., in placenta, or in germ line cells, and are expressed or aberrantly expressed in one or more tumor or cancer tissues. In this context, "a limited number" preferably means not more than 3, more preferably not more than 2. The tumor antigens in the context of the present invention include, for example, differentiation antigens, preferably cell type specific differentiation antigens, i.e., proteins that are under normal conditions specifically expressed in a certain cell type at a certain differentiation stage, cancer/testis antigens, i.e., proteins that are under normal conditions specifically expressed in testis and sometimes in placenta, and germ line specific antigens. The tumor antigen is preferably associated with the cell surface of a cancer cell and is preferably not or only rarely expressed in normal tissues. Preferably, the tumor antigen or the aberrant expression of the tumor antigen identifies cancer cells. The tumor antigen that is expressed by a cancer cell in a subject, e.g., a patient suffering from a cancer disease, is preferably a self-protein in said subject. In preferred embodiments, the tumor antigen is expressed under normal conditions specifically in a tissue or organ that is non-essential, i.e., tissues or organs which when damaged by the immune system do not lead to death of the subject, or in organs or structures of the body which are not or only hardly accessible by the immune system. Preferably, the amino acid sequence of the tumor antigen is identical between the tumor antigen which is expressed in _{normal tissues and the tumor antigen which is expressed in cancer tissues. In a preferred} embodiment, said term "tumor antigen" refers to a constituent of cancer cells which may be derived from the cytoplasm, the cell surface and the cell nucleus, preferably it refers to those _{antigens which are produced intracellularly or as surface antigens on tumor cells.} _{P6797PC00 – 195 –} In a further aspect, the present invention provides a pharmaceutical composition comprising an inventive composition, an inventive conjugate, preferably said conjugate of _{Formula I* or of Formula I, or an inventive polyplex as described herein, or a pharmaceutically} acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. _{Negatively Charged Polyanions Used to Form Polyplexes} _{The triconjugates of the present disclosure can form polyplexes with polyanions such} _{as nucleic acids as described herein. For example, at physiological pH (e.g., pH 7.4), the LPEI} fragment of a triconjugate of the present invention can be at least partially protonated and can carry a net positive charge. In contrast, polyanions such nucleic acids can be at least partially _{deprotonated at physiological pH and can carry a net negative charge. Accordingly, in some} embodiments co-incubation of a triconjugate of the present invention with a negatively charged _{polyanion such as a nucleic acid, and preferably a RNA, further preferably a mRNA encoding} a Cas protein, a gRNA, and/or a template DNA, will result in a polyplex (e.g., held together by electrostatic interaction). I_{n a preferred embodiment, said Ring A is cyclooctene, succinimide, or 7- to 8-} membered heterocycloalkenyl, wherein the heterocycloalkyl or heterocycloalkenyl comprises one or two heteroatoms selected from N, O and S, and wherein each cyclooctene, _{heterocycloalkyl or heterocycloalkenyl is optionally substituted at any position with one or} more R^A1, wherein preferably R^A1 is oxo or fluorine, or wherein two R^A1 combine to form one or more fused phenyl rings, preferably one or two fused phenyl rings, wherein each phenyl ring _{is optionally substituted with one or more -SO3H or -OSO3H.} _{In a preferred embodiment of any aspects of the present disclosure and invention, said} conjugate of Formula I is a conjugate selected from: R^A1 H N X¹ X² _{P6797PC00 – 196 –} H O N embodiment described herein, be it individually related to each parameter R¹, R^A1, X¹, X², L, m and n, or collectively to some or all of R¹, R^A1, X¹, X², L, m and n. I_{n a preferred embodiment of any aspects of the present disclosure and invention, said} conjugate of Formula I is a conjugate selected from: L Formula IA-3, _{P6797PC00 – 197 –} _{P6797PC00 – 198 –} wherein R¹, R^A1, X¹, X², L, m and n are as defined herein, preferably as defined in any embodiment described herein, be it individually related to each parameter R¹, R^A1, X¹, X², L, m and n, or collectively to some or all of R¹, R^A1, X¹, X², L, m and n. I_{n a preferred embodiment of any aspects of the present disclosure and invention, said} conjugate of Formula I is a conjugate selected from: L Formula IA-3, and L Formula IA-4, _{as defined in any} embodiment described herein, be it individually related to each parameter R¹, X¹, X², L, m and n, or collectively to some or all of R¹, X¹, X², L, m and n. I_{n a preferred embodiment of any aspects of the present disclosure and invention, said} conjugate of Formula I is a conjugate selected from: R^A1 H N H embodiment described herein, be it individually related to each parameter R¹, R^A1, X¹, X², L, m and n, or collectively to some or all of R¹, R^A1, X¹, X², L, m and n. I_{n a preferred embodiment of any aspects of the present disclosure and invention, said} conjugate of Formula I is a conjugate selected from: _{P6797PC00 – 199 –} H H X¹ _{2 2} O C _{C X2 L} 14, embodiment described herein, be it individually related to each parameter R¹, R^A1, X¹, X², L, m and n, or collectively to some or all of R¹, R^A1, X¹, X², L, m and n. In a preferred embodiment, said targeting fragment comprises or preferably consists of the DUPA residue (HOOC-(CH2)2-CH(COOH)-NH-CO-NH-CH(COOH)-(CH2)2-CO-). In a further very preferred embodiment, said targeting fragment consists of the DUPA residue (HOOC(CH₂)₂-CH(COOH)-NH-CO-NH-CH(COOH)-(CH₂)₂-CO-), wherein both chiral C- atoms having (S)-configuration, as depicted in formula 1*. In another preferred embodiment, said targeting fragment is epidermal growth factor (EGF), and wherein preferably said targeting fragment is human EGF (hEGF), and wherein again further preferably said targeting fragment comprises, preferably consists of, the sequence _{of SEQ ID NO:3. In another aspect, the present invention provides a polyplex comprising a} conjugate of Formula I, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or enantiomer thereof, and a nucleic acid, wherein preferably said nucleic acid is an mRNA _{encoding a Cas protein, wherein said nucleic acid is preferably non-covalently bound to said} conjugate: R² L wherein: _{P6797PC00 – 200 –} _{is a single bond or a double bond, preferably a double bond;} n is any integer between 1 and 1500; m is a discrete number of repeating units m of 36; R¹ is an initiation residue, wherein preferably R¹ is -H or -CH₃; R² is independently -H or an organic residue, wherein at least 80%, preferably wherein _{at least 90%, of said R2 in said -(NR2-CH2-CH2)n– is H, further preferably said R2 is H;} Ring A is a 5 to 10-membered cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl, optionally substituted at any position with one or more R^A1; R^A1 is independently selected from C₁-C₆ alkyl, C₁-C₆ alkoxy, oxo, or halogen; or two R^A1, together with the atoms to which they are attached, can combine to form one or more fused C6-C10 aryl, C₅-C₆ heteroaryl, or C₃-C₆ cycloalkyl rings, wherein each fused aryl, heteroaryl, or cycloalkyl is optionally substituted with one or more R^A2; R^A2 is independently selected from C1-C6 alkyl, C₁-C₆ alkoxy, halogen -SO₃H, or -OSO₃H; X¹ is a divalent covalent linking moiety; X² is a divalent covalent linking moiety; and L is a targeting fragment, wherein preferably said targeting fragment is capable of binding to a cell, and wherein further preferably said targeting fragment is capable of binding to a cell surface receptor. In a preferred embodiment, said R¹ is -H. In a preferred embodiment, said R¹ is -CH₃. I_{n a preferred embodiment of any aspects of the present disclosure and invention,, said} _{Ring A is cyclooctene, succinimide, or 7- to 8-membered heterocycloalkenyl, wherein the} heterocycloalkyl or heterocycloalkenyl comprises one or two heteroatoms selected from N, O and S, and wherein each cyclooctene, heterocycloalkyl or heterocycloalkenyl is optionally substituted at any position with one or more R^A1, wherein preferably R^A1 is oxo or fluorine, or wherein two R^A1 combine to form one or more fused phenyl rings, preferably one or two fused phenyl rings, wherein each phenyl ring is optionally substituted with one or more -SO3H or - OSO3H. I_{n a preferred embodiment of any aspects of the present disclosure and invention, said} conjugate of Formula I is a conjugate selected from: R^A1 H N X¹ X² L Formula IA, _{P6797PC00 – 201 –} R^A1 H N H m and n, or collectively to some or all of R¹, R^A1, X¹, X², L, m and n. I_{n a preferred embodiment said conjugate of Formula I is a conjugate selected from:} L Formula IA-3, _{P6797PC00 – 202 –} Formula IE-14, _{P6797PC00 – 203 –} wherein R¹, R^A1, X¹, X², L, m and n are as defined herein, preferably as defined in any e_{mbodiment described herein, be it individually related to each parameter R1, RA1, X1, X2, L,} m and n, or collectively to some or all of R¹, R^A1, X¹, X², L, m and n. I_{n a preferred embodiment of any aspects of the present disclosure and invention, said} _{conjugate of Formula I is a conjugate selected from:} e_{mbodiment described herein, be it individually related to each parameter R1, X1, X2, L, m} and n, or collectively to some or all of R¹, X¹, X², L, m and n. I_{n a preferred embodiment of any aspects of the present disclosure and invention, said} conjugate of Formula I is a conjugate selected from: R^A1 H N H L Formula IB, as defined in any embodiment described herein, be it individually related to each parameter R¹, R^A1, X¹, X², L, m and n, or collectively to some or all of R¹, R^A1, X¹, X², L, m and n. I_{n a preferred embodiment of any aspects of the present disclosure and invention, said} conjugate of Formula I is a conjugate selected from: _{P6797PC00 – 204 –} X¹ H₂ H₂ O C _{C X2 L} 14, embodiment described herein, be it individually related to each parameter R¹, R^A1, X¹, X², L, m and n, or collectively to some or all of R¹, R^A1, X¹, X², L, m and n. In a preferred embodiment, said targeting fragment comprises or preferably consists of the DUPA residue (HOOC-(CH2)2-CH(COOH)-NH-CO-NH-CH(COOH)-(CH2)2-CO-). In a _{further very preferred embodiment, said targeting fragment consists of the DUPA residue} (HOOC(CH₂)₂-CH(COOH)-NH-CO-NH-CH(COOH)-(CH₂)₂-CO-), wherein both chiral C- atoms having (S)-configuration, as depicted in formula 1*. I_{n another preferred embodiment, said targeting fragment is epidermal growth factor} (EGF), and wherein preferably said targeting fragment is human EGF (hEGF), and wherein again further preferably said targeting fragment comprises, preferably consists of, the sequence of SEQ ID NO:3. _{Synthesis and Characterization of Polyplexes} _{The present invention relates to polyplexes comprising a linear conjugate (e.g., a linear} _{conjugate comprising LPEI, PEG, and a targeting fragment such as hEGF) polyplexed with a} _{nucleic acid. As shown in the Examples, polyplexes can be prepared by incubating the inventive} _{triconjugates together with nucleic acids such as mRNA encoding a Cas protein, and optionally} a gRNA and/or template DNA. In some embodiments, polyplexes can form spontaneously (e.g., _{within an hour or within 30 minutes) by combining the inventive triconjugates with the nucleic} _{acids in a solution of HEPES-buffered glucose at pH 7-7.4 (e.g., at room temperature), or in} _{5% glucose, or in HEPES buffered saline (HBS) pH 7.2, or in an acetate solution at pH 4-4.5} _{P6797PC00 – 205 –} containing 5% glucose e.g., at room temperature). T_{he particle size distribution (reported as the z-average diameter and PDI) and ζ-} potential of the polyplexes can be measured by dynamic light scattering (DLS) and electrophoretic mobility, respectively. DLS measures the light scatter intensity fluctuations of polyplexes caused by the Brownian motions and calculates hydrodynamic diameter (nm) using the Stokes-Einstein equation. Zeta potential (ζ-potential) measures the electrokinetic potential of the polyplexes. In some embodiments, the z-average diameter and ζ-potential can be modified as a function of the N/P ratio, defined as the ratio of nitrogen atoms in LPEI to phosphorous atoms _{in nucleic acids. In some preferred embodiments, the z-average diameter of an inventive} polyplex is below about 300 nm, more preferably below about 250 nm, yet more preferably _{below about 200 nm. Without wishing to be bound by theory, polyplexes with z-average} _{diameters below about 200 nm are believed to be well-tolerated in vivo (e.g., exhibit high} biodistribution and clearance) and are typically stable and not prone to aggregate formation. I_{n some preferred embodiments, the N/P ratio of the polyplexes is at least 2, at least 2.4,} _{at least 2.5, at least 3, at least 3.5, is at least about 4, at least 4.5, at least 5, or at least 6. In some} _{preferred embodiments, the N/P ratio is 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7, 8, 9, 10, 11 or 12. As} _{shown herein, the N/P ratios mentioned above can provide polyplexes of acceptable size and} _{stability for said polyplexes containing polyanions, such as and preferably nucleic acids.} _{In a preferred embodiment, said polyplexes of the invention have a mono- or bi-modal} diameter distribution, preferably a monomodal diameter distribution. Preferably, said monomodal diameter distribution is within the sub-micrometer range. In a preferred embodiment, said polyplexes have a z-average diameter of less than or equal to 350 nm. In a preferred embodiment, said polyplexes have a z-average diameter of less than or equal to about 300 nm. In another preferred embodiment, said polyplexes have a z- average diameter of less than or equal to 250 nm. In another preferred embodiment, said polyplexes have a z-average diameter of less than or equal to 210 nm. In another preferred embodiment, said polyplexes have a z-average diameter of less than or equal to 200 nm. In another preferred embodiment, said polyplexes have a z-average diameter of less than or equal to 180 nm. In another preferred embodiment, said polyplexes have a z-average diameter of less than or equal to 150 nm. In another preferred embodiment, said polyplexes have a z-average _{diameter of between 350 nm and 50 nm. In another preferred embodiment, said polyplexes have} a z-average diameter of between 350 nm and 70 nm. In another preferred embodiment, said _{P6797PC00 – 206 –} polyplexes have a z-average diameter of between 350 nm and 100 nm. In another preferred embodiment, said polyplexes have a z-average diameter of between 300 nm and 50 nm. In another preferred embodiment, said polyplexes have a z-average diameter of between 300 nm and 70 nm. In another preferred embodiment, said polyplexes have a z-average diameter of between 300 nm and 100 nm. In another more preferred embodiment, said polyplexes have a z-average diameter of between 250 nm and around 50 nm. In another more preferred embodiment, said polyplexes have a z-average diameter of between 250 nm and around 70 nm. In another more preferred embodiment, said polyplexes have a z-average diameter of between 250 nm and around 100 nm. In another preferred embodiment, said polyplexes have a z-average diameter of between around 200 nm and around 50 nm. In another preferred embodiment, said polyplexes have a z-average diameter of between around 200 nm and around 70 nm. In another preferred embodiment, said polyplexes have a z-average diameter of between around 200 nm and around 100 nm. In another preferred embodiment, said polyplexes have a z-average diameter of between around 180 nm and around 50 nm. In another preferred embodiment, said polyplexes have a z-average diameter of between around 180 nm and around 70 nm. Preferably, said polyplexes have a mono-modal diameter distribution, preferably within the sub- micrometer range. In a preferred embodiment, said polyplexes have a z-average diameter of less than or equal to 350 nm, and the N/P ratio of the polyplexes is at least 2, preferably at least 2.4. In a preferred embodiment, said polyplexes have a z-average diameter of less than or equal to about 300 nm, and the N/P ratio of the polyplexes is at least 2, preferably at least 2.4. In a preferred embodiment, said polyplexes have a z-average diameter of less than or equal to about 250 nm, and the N/P ratio of the polyplexes is at least 2, preferably at least 2.4. In a preferred embodiment, said polyplexes have a z-average diameter of less than or equal to about 220 nm, and the N/P ratio of the polyplexes is at least 2.4, more preferably at least 3, yet more preferably at least 4. In another preferred embodiment, said polyplexes have a z-average diameter of less than or equal to 200 nm, and the N/P ratio of the polyplexes is at least 3, preferably at least 4. _{In another preferred embodiment, said polyplexes have a z-average diameter of less than or} equal to 180 nm, and the N/P ratio of the polyplexes is at least 3, preferably at least 4. In another preferred embodiment, said polyplexes have a z-average diameter of less than or equal to 150 _{nm. In another preferred embodiment, said polyplexes have a z-average diameter of between} 350 nm and 100 nm, and the N/P ratio of the polyplexes is at least 3, preferably at least 4. In another preferred embodiment, said polyplexes have a z-average diameter of between 300 nm _{P6797PC00 – 207 –} _{and 100 nm, and the N/P ratio of the polyplexes is at least 3, preferably at least 4. In another} more preferred embodiment, said polyplexes have a z-average diameter of between 250 nm and around 100 nm, and the N/P ratio of the polyplexes is at least 3, preferably at least 4. In another preferred embodiment, said polyplexes have a z-average diameter of between around 200 nm and around 100 nm, and the N/P ratio of the polyplexes is at least 3, preferably at least 4. Preferably, said polyplexes have a mono-modal diameter distribution, preferably within the sub-micrometer range. In a preferred embodiment, the composition of the invention has a polydispersity index _{(PDI) of 0.7 or less. More preferably, said PDI is 0.5 or less, e.g. between 0.5 and 0.05. Again} _{more preferably, said PDI is 0.35 or less, e.g. between 0.35 and 0.05. In another preferred} embodiment, said PDI is 0.25 or less, e.g. between 0.25 and 0.05. In another preferred embodiment, said PDI is 0.2 or less, e.g. between 0.2 and 0.05. In another preferred embodiment said PDI is less than 0.2, e.g. between 0.19 and 0.05. In another more preferred embodiment said PDI is between 0.2 and 0.1. In another preferred embodiment said PDI is between 0.25 and _{0.1. Preferably, said polyplexes have a mono-modal diameter distribution, preferably within the} sub-micrometer range. In a preferred embodiment, the composition of the invention has a polydispersity index _{(PDI) of 0.7 or less, and the N/P ratio of the polyplexes is at least 2, preferably at least 2.4.} More preferably, said PDI is 0.5 or less, e.g. between 0.5 and 0.05. Again more preferably, said PDI is 0.35 or less, e.g. between 0.35 and 0.05, and the N/P ratio of the polyplexes is at least 2, preferably at least 2.4. In another preferred embodiment, said PDI is 0.25 or less, e.g. between 0.25 and 0.05, and the N/P ratio of the polyplexes is at least 2.4, more preferably at least 3, yet more preferably at least 4. In another preferred embodiment, said PDI is 0.2 or less, e.g. between 0.2 and 0.05, and the N/P ratio of the polyplexes is at least 3, preferably at least 4. In another preferred embodiment said PDI is less than 0.2, e.g. between 0.19 and 0.05, and the N/P ratio of the polyplexes is at least 3, preferably at least 4. In another more preferred embodiment said PDI is between 0.2 and 0.1. In another preferred embodiment said PDI is between 0.25 and 0.1, and the N/P ratio of the polyplexes is at least 3, preferably at least 4. Preferably, said polyplexes have a mono-modal diameter distribution, preferably within the sub-micrometer range. In a preferred embodiment, said polyplexes have a z-average diameter of less than or equal to 350 nm, the PDI is 0.5 or less and the N/P ratio of the polyplexes is at least 2, preferably at least 2.4. In a preferred embodiment, said polyplexes have a z-average diameter of less than or equal to 350 nm, the PDI is 0.4 or less and the N/P ratio of the polyplexes is at least 2, _{P6797PC00 – 208 –} preferably at least 2.4. In a preferred embodiment, said polyplexes have a z-average diameter of less than or equal to about 300 nm, the PDI is 0.4 and the N/P ratio of the polyplexes is at least 2, preferably at least 2.4. In another preferred embodiment, said polyplexes have a z- average diameter of less than or equal to about 250 nm, the PDI is 0.2 or less and the N/P ratio of the polyplexes is at least 2, preferably at least 2.4. In a preferred embodiment, said polyplexes have a z-average diameter of less than or equal to about 220 nm, the PDI is 0.2 or _{less, and the N/P ratio of the polyplexes is at least 2.4, more preferably at least 3, yet more} preferably at least 4. In another preferred embodiment, said polyplexes have a z-average diameter of less than or equal to 200 nm, the PDI is 0.2 or less, and the N/P ratio of the polyplexes is at least 3, preferably at least 4. In another preferred embodiment, said polyplexes have a z-average diameter of less than or equal to 180 nm, the PDI is 0.2 or less, and the N/P ratio of the polyplexes is at least 3, preferably at least 4. In another preferred embodiment, said polyplexes have a z-average diameter of less than or equal to 150 nm, the PDI is 0.2 or less, and the N/P ratio of the polyplexes is at least 3, preferably at least 4. In another preferred embodiment, said polyplexes have a z-average diameter of between 350 nm and 100 nm, the PDI is 0.2 or less, and the N/P ratio of the polyplexes is at least 3, preferably at least 4. In another preferred embodiment, said polyplexes have a z-average diameter of between 300 nm and 100 nm, the PDI is 0.2 or less, and the N/P ratio of the polyplexes is at least 3, preferably at least 4. In another more preferred embodiment, said polyplexes have a z-average diameter of between 250 nm and around 100 nm, the PDI is 0.2 or less, and the N/P ratio of the polyplexes is at least 3, preferably at least 4. In another preferred embodiment, said polyplexes have a z- average diameter of between around 200 nm and around 100 nm, the PDI is 0.2 or less, and the N/P ratio of the polyplexes is at least 3, preferably at least 4. Preferably, said polyplexes have a mono-modal diameter distribution, preferably within the sub-micrometer range. In a preferred embodiment, the composition of the invention has a zeta potential of _{greater than or equal to 18 mV, e.g. between 18 mV and 50 or 60 mV. In a preferred} embodiment, the composition of the invention has a zeta potential of greater than or equal to _{18 mV, e.g. between 18 mV and 60 mV. In a preferred embodiment, the composition of the} _{invention has a zeta potential of greater than or equal to 18 mV, e.g. between 18 mV and 45} mV. In another preferred embodiment, the composition of the invention has a zeta potential of _{greater than or equal to 18 mV, e.g. between 18 mV and 42 mV. In another preferred} _{embodiment, the composition of the invention has a zeta potential between 20 mV and 50 mV.} In another preferred embodiment, the composition of the invention has a zeta potential between _{P6797PC00 – 209 –} _{20 mV and around 45 mV. In another preferred embodiment, the composition of the invention} _{has a zeta potential between 20 mV and around 42 mV. In another preferred embodiment, the} composition of the invention has a zeta potential between around 20 mV and around 40 mV. Preferably, said polyplexes have a mono-modal diameter distribution, preferably within the sub-micrometer range. In a preferred embodiment, the composition of the invention has a zeta potential of _{greater than or equal to 18 mV, preferably between 18 mV and 50 mV, and the N/P ratio of the} polyplexes is at least 2, preferably at least 2.4. In a more preferred embodiment, the composition _{of the invention has a zeta potential of greater than or equal to 18 mV, preferably between 18} mV and 45 mV, and the N/P ratio of the polyplexes is at least 2.4, more preferably at least 3, yet more preferably at least 4. In another preferred embodiment, the composition of the _{invention has a zeta potential of greater than or equal to 18 mV, e.g. between 18 mV and 42} mV, and the N/P ratio of the polyplexes is at least 3, preferably at least 4. In another preferred _{embodiment, the composition of the invention has a zeta potential between 20 mV and 50 mV,} and the N/P ratio of the polyplexes is at least 3, preferably at least 4. In another preferred embodiment, the composition of the invention has a zeta potential between 30 mV and around 40 mV, and the N/P ratio of the polyplexes is at least 3, preferably at least 4. In another more _{preferred embodiment, the composition of the invention has a zeta potential between 18 mV} and around 40 mV, and the N/P ratio of the polyplexes is at least 3, preferably at least 4. In another even more preferred embodiment, the composition of the invention has a zeta potential between around 20 mV and around 40 mV, and the N/P ratio of the polyplexes is at least 3, preferably at least 4. Preferably, said polyplexes have a mono-modal diameter distribution, preferably within the sub-micrometer range. I_{n a preferred embodiment, said polyplexes have a z-average diameter of less than or} equal to 350 nm, and the N/P ratio of the polyplexes is at least 2, preferably at least 2.4, and the _{composition of the invention has a zeta potential of between 18 mV and 50 mV. In a preferred} embodiment, said polyplexes have a z-average diameter of less than or equal to about 300 nm, and the N/P ratio of the polyplexes is at least 2, preferably at least 2.4, and the composition of _{the invention has a zeta potential of between 20 mV and 50 mV. In a preferred embodiment,} said polyplexes have a z-average diameter of less than or equal to about 250 nm, and the N/P ratio of the polyplexes is at least 2, preferably at least 2.4, and the composition of the invention has a zeta potential of between 20 mV and 50 mV. In a preferred embodiment, said polyplexes have a z-average diameter of less than or equal to about 220 nm, and the N/P ratio of the _{P6797PC00 – 210 –} polyplexes is at least 2.4, more preferably at least 3, yet more preferably at least 4, and the _{composition of the invention has a zeta potential of between 18 mV and 45 mV. In another} preferred embodiment, said polyplexes have a z-average diameter of less than or equal to 200 nm, and the N/P ratio of the polyplexes is at least 3, preferably at least 4, and the composition _{of the invention has a zeta potential of between 18 mV and 45 mV. In another preferred} embodiment, said polyplexes have a z-average diameter of less than or equal to 180 nm, and _{the N/P ratio of the polyplexes is at least 3, preferably at least 4, and the composition of the} _{invention has a zeta potential of between 18 mV and 45 mV. In another preferred embodiment,} said polyplexes have a z-average diameter of less than or equal to 150 nm, and the N/P ratio of _{the polyplexes is at least 3, preferably at least 4 and the composition of the invention has a zeta} _{potential of between 18 mV and 45 mV. In another preferred embodiment, said polyplexes have} a z-average diameter of between 350 nm and 100 nm, and the N/P ratio of the polyplexes is at least 3, preferably at least 4, and the composition of the invention has a zeta potential of between _{18 mV and 45 mV. In another preferred embodiment, said polyplexes have a z-average diameter} of between 300 nm and 100 nm, and the N/P ratio of the polyplexes is at least 3, preferably at _{least 4, and the composition of the invention has a zeta potential of between 18 mV and 45 mV.} In another more preferred embodiment, said polyplexes have a z-average diameter of between 250 nm and around 100 nm, and the N/P ratio of the polyplexes is at least 3, preferably at least _{4, and the composition of the invention has a zeta potential of between 18 mV and 45 mV. In} another preferred embodiment, said polyplexes have a z-average diameter of between around 200 nm and around 100 nm, and the N/P ratio of the polyplexes is at least 3, preferably at least _{4, and the composition of the invention has a zeta potential of between 18 mV and 45 mV.} Preferably, said polyplexes have a mono-modal diameter distribution, preferably within the sub-micrometer range. In a preferred embodiment, said polyplexes have a z-average diameter of less than or equal to 350 nm, the PDI is between 0.5 and 0.05, the N/P ratio of the polyplexes is at least 2, preferably at least 2.4, and the composition of the invention has a zeta potential of between 18 mV and 50 mV. In a preferred embodiment, said polyplexes have a z-average diameter of less than or equal to about 300 nm, the PDI is between 0.5 and 0.05, and the N/P ratio of the _{polyplexes is at least 2, preferably at least 2.4, and the composition of the invention has a zeta} _{potential of between 18 mV and 50 mV. In a preferred embodiment, said polyplexes have a z-} average diameter of less than or equal to about 250 nm, the PDI is between 0.35 and 0.05, the _{N/P ratio of the polyplexes is at least 2, preferably at least 2.4, and the composition of the} _{P6797PC00 – 211 –} _{invention has a zeta potential of between 18 mV and 50 mV. In a preferred embodiment, said} _{polyplexes have a z-average diameter of less than or equal to about 220 nm, the PDI is 0.3 or} less, e.g. between 0.3 and 0.05, the N/P ratio of the polyplexes is at least 2.4, more preferably at least 3, yet more preferably at least 4, and the composition of the invention has a zeta potential _{of between 18 mV and 45 mV. In another preferred embodiment, said polyplexes have a z-} average diameter of less than or equal to 200 nm, the PDI is 0.2 or less, e.g. between 0.2 and 0.05, the N/P ratio of the polyplexes is at least 3, preferably at least 4, and the composition of _{the invention has a zeta potential of between 18 mV and 45 mV. In another preferred} embodiment, said polyplexes have a z-average diameter of less than or equal to 180 nm, the PDI is 0.2 or less, e.g. between 0.2 and 0.05, and the N/P ratio of the polyplexes is at least 3, preferably at least 4, and the composition of the invention has a zeta potential of between 18 mV and 45 mV. In another preferred embodiment, said polyplexes have a z-average diameter of less than or equal to 150 nm, the PDI is 0.2 or less, e.g. between 0.2 and 0.05, the N/P ratio of the polyplexes is at least 3, preferably at least, and the composition of the invention has a _{zeta potential of between 18 mV and 45 mV. In another preferred embodiment, said polyplexes} _{have a z-average diameter of between 350 nm and 100 nm, the PDI is 0.2 or less, e.g. between} 0.2 and 0.05, the N/P ratio of the polyplexes is at least 3, preferably at least 4, and the _{composition of the invention has a zeta potential of between 18 mV and 45 mV. In another} preferred embodiment, said polyplexes have a z-average diameter of between 300 nm and 100 nm, the PDI is 0.2 or less, e.g. between 0.2 and 0.05, the N/P ratio of the polyplexes is at least 3, preferably at least 4, and the composition of the invention has a zeta potential of between 25 mV and 45 mV. In another more preferred embodiment, said polyplexes have a z-average diameter of between 250 nm and around 100 nm, the PDI is 0.2 or less, e.g. between 0.2 and 0.05, the N/P ratio of the polyplexes is at least 3, preferably at least 4, and the composition of _{the invention has a zeta potential of between 18 mV and 45 mV. In another preferred} embodiment, said polyplexes have a z-average diameter of between around 200 nm and around 100 nm, the PDI is 0.2 or less, e.g. between 0.2 and 0.05, the N/P ratio of the polyplexes is at least 3, preferably at least 4, and the composition of the invention has a zeta potential of between _{18 mV and 45 mV. Preferably, said polyplexes have a mono-modal diameter distribution,} preferably within the sub-micrometer range. I_{n some embodiments, the polyplex has a z-average diameter below about 200 nm. In} _{some embodiments, the N/P ratio of the polyplex is between about 3 and about 10, preferably} wherein the N/P ratio of the polyplex is between about 4 and about 7. In some embodiments, _{P6797PC00 – 212 –} the N/P ratio of the polyplex is about 4, 5 or 7. In some preferred embodiments, the polyplexes of the present disclosure have a ζ-potential between about 15 and about 70 mV, between about _{20 and about 70 mV; preferably between about 15 and about 50 mV; preferably between about} 15 and about 40 mV. Polyplexes for Use in Gene Editing or Treating Disease In one aspect, the present invention provides compositions comprising polyplexes described herein for use in gene editing. In one aspect, the present invention provides a method of gene editing in a subject in need thereof, the method comprising administering to said subject an effective amount of a composition comprising a polyplex as described herein. In preferred embodiments, said gene editing causes a therapeutic effect in a subject. In one aspect, the present invention provides compositions comprising polyplexes described herein for use in the treatment of a disease or disorder. In another aspect, the present invention provides the use of compositions comprising polyplexes described herein for use in the manufacture of a medicament for the treatment of a disease or disorder. In another aspect, the present invention provides a method of treating a disease or disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of a composition comprising a polyplex as described herein. In preferred embodiments, said disease or disorder is cancer. Without wishing to be _{bound by theory, the compositions and polyplexes described herein are used to target genetic} mutations that drive the growth and spread of tumors. For instance, the compositions and _{polyplexes described herein are used to inactivate the genes (e.g., oncogenes) that cause tumor} growth. I_{n some embodiments, the compositions and polyplexes described herein are used to} enhance the immune response to cancer cells. In some embodiments, the compositions and _{polyplexes described herein are for use to repair genetic mutations that cause cancer. In some} _{embodiments, the compositions and polyplexes described herein are for use in an} immunotherapeutic strategy, preferably wherein T cells are engineered to express receptors that specifically target tumor cells, preferably enhancing a body’s immune response against cancer (e.g., by engineering CAR-T cells, preferably to target CD19, CD20, and/or CD22). In some _{embodiments, the compositions and polyplexes described herein are for use in engineering NK} _{cells to specifically target tumor cells (e.g., by engineering CAR-NK cells). In some} _{P6797PC00 – 213 –} _{embodiments, the compositions and polyplexes described herein are for use in engineering B} _{cells to specifically target tumor cells (e.g., by engineering CAR-B cells). In some} _{embodiments, the compositions and polyplexes described herein are for use in engineering} _{dendritic cells to specifically target tumor cells. In some embodiments, the compositions and} polyplexes described herein are for use in engineering stem cells. In some embodiments, the present disclosure provides the compositions and polyplexes described herein for use in stem cell therapy. In some embodiments, the cancer can be characterized by cells that express, highly _{express, or overexpress one or more cell surface receptors and/or antigens. Without wishing to} be bound by theory, the triconjugates and/or polyplexes of the present invention can be targeted to a particular cell type (e.g., cancer cell type) by selecting an appropriate targeting fragment and coupling the appropriate targeting fragment to the PEG fragment to form a targeted triconjugate as described above. The cell surface receptor and/or antigen may be, but is not limited to, EGFR; HER2; an integrin (e.g., an RGD integrin); a sigma-2 receptor; Trop-2; folate receptor; prostate-specific membrane antigen (PSMA); p32 protein; a somatostatin receptor such as somatostatin receptor 2 (SSTR2); an insulin-like growth factor 1 receptor (IGF1R); a vascular endothelial growth factor receptor (VEGFR); a platelet-derived growth factor receptor (PDGFR); and/or a fibroblast growth factor receptor (FGFR). In some embodiments, the cancer can be characterized by cells that have increased expression (e.g., overexpression or high expression) of EGFR. In some preferred embodiments, cancers characterized by cells that have increased expression of EGFR can be treated with polyplexes comprising an EGFR-targeting fragment such as hEGF. In certain embodiments, the cancer characterized by EGFR-overexpressing cells is an adenocarcinoma, squamous cell carcinoma, lung cancer (e.g., non-small-cell-lung-carcinoma), breast cancer, glioblastoma, head and neck cancer (e.g., head and neck squamous cell carcinoma), renal cancer, colorectal cancer, ovarian cancer, cervical cancer, bladder cancer or prostate cancer, and/or metastases thereof. In certain embodiments, the cancer can be characterized by cells that have increased expression (e.g., overexpression or high expression) of HER2. In some preferred embodiments, cancers characterized by cells that have increased expression of HER2 can be treated with polyplexes comprising a HER2-targeting fragment such as anti-HER2 peptide (e.g., an anti- HER2 antibody or affibody). In some embodiments, the cancer characterized by HER2- overexpressing cells is breast cancer, ovarian cancer, stomach (gastric) cancer, and/or uterine _{P6797PC00 – 214 –} cancer (e.g., aggressive forms of uterine cancer, such as uterine serous endometrial carcinoma) and/or metastases thereof. In certain embodiments, the HER2 overexpressing cells are treatment-resistant cells (e.g., Herceptin/trastusumab resistant cells). Thus, the polyplex of the present invention may be for use in the treatment of Herceptin/trastusumab resistant cancer, i.e. cancer comprising cells that do not respond or respond to a lesser extent to exposure to Herceptin/trastusumab. In some embodiments, the cancer can be characterized by cells that have increased expression (e.g., overexpression or high expression) of prostate-specific membrane antigen. In some preferred embodiments, cancers characterized by cells that have increased expression of prostate-specific membrane antigen (PSMA) can be treated with polyplexes comprising a PSMA-targeting fragment such as DUPA. In certain embodiments, the cancer characterized by PSMA-overexpressing cells is prostate cancer and/or metastases thereof. In a preferred embodiment, said cancer is prostate cancer. I_{n some embodiments, cancer-associated neovasculature can be characterized by} increased expression (e.g., overexpression or high expression) of PSMA (see., e.g., Van de Wiele et al., Histol Histopathol., (2020); 35(9):919-927). In some preferred embodiments, cancers characterized by neovasculature that has increased expression of prostate-specific membrane antigen (PSMA) can be treated with polyplexes comprising a PSMA-targeting fragment such as DUPA. In some preferred embodiments, the cancers characterized by association with PSMA-overexpressing neovasculature are glioblastoma, breast cancer, bladder cancer and/or metastases thereof. In some embodiments, the cancer can be characterized by cells that have increased expression (e.g., overexpression or high expression) of folate receptor. In some preferred embodiments, cancers characterized by cells that have increased expression of folate receptor can be treated with polyplexes comprising folate and/or folic acid as a targeting fragment. In certain embodiments, the cancer characterized by folate receptor-overexpressing cells is gynecological, breast, cervical, uterine, colorectal, renal, nasopharyngeal, ovarian, endometrial cancers and/or metastases thereof. In some embodiments, the cancer can be characterized by cells that have increased _{expression (e.g., overexpression or high expression) of somatostatin receptors such as} somatostatin receptor 2 (SSTR2). In some embodiments, cancers characterized by increased expression of SSTR2 can be treated with polyplexes comprising a somatostatin receptor- targeting fragment such as somatostatin and/or octreotide. In certain embodiments, cancers _{P6797PC00 – 215 –} characterized by increased expression of somatostatin receptors (e.g., SSTR2) include colorectal cancer and/or metastases thereof. In some embodiments, the cancer can be characterized by cells that have increased expression of integrins (e.g., RGD integrins such as α_vβ₆ integrin or α_vβ₈ integrin). In some embodiments, cancers characterized by increased expression of integrins such as RGD integrins can be treated with polyplexes comprising an integrin-targeting fragment such as arginine- glycine-aspartic acid (RGD)-containing ligands (e.g., cyclic RGD ligands). In some preferred embodiments, the integrin-targeting fragment can be a peptide such as SFITGv6, SFFN1, _{SFTNC, SFVTN, SFLAP1, SFLAP3, A20FMDV2 (see, e.g., Roesch et al., J. Nucl. Med.2018,} _{59 (11) 1679-1685). In some embodiments, the integrin-targeting fragment can be an anti-} integrin antibodies such as anti α_vβ₆ integrin antibodies, anti-integrin diabodies, or knottins. In some embodiments, the integrin-targeting fragment can be latent transforming growth factor-ß (TGFß). In some embodiments, cancer cells characterized by increased expression of integrins such as RGD integrins can include solid tumor, breast cancer, ovarian cancer, cervical cancer, pancreatic cancer, non-small cell lung cancer (NSCLC), colon cancer, oral squamous cell cancer, astrocytoma, head and neck squamous cell carcinoma and/or metastases thereof. In some embodiments, the cancer can be characterized by cells that exist in a low pH microenvironment. In some embodiments, cancers characterized by a low pH microenvironment can be treated with polyplexes comprising low pH insertion peptides (pHLIPs) as a targeting fragment. In some preferred embodiments, cancers characterized by cells exist in a low pH microenvironment include breast cancer and/or metastases thereof. In some embodiments, the cancer can be characterized by cells that have increased expression of asialoglycoprotein receptors. In some embodiments, cancers characterized by increased expression of asialoglycoprotein receptors can be treated with polyplexes comprising an asialoglycoprotein receptor-targeting fragment such as asialoorosomucoid. In certain _{embodiments, the cancer characterized by increased expression of asialoglycoprotein receptors} is liver cancer, gallbladder cancer, stomach cancer and/or metastases thereof. In some embodiments, the cancer can be characterized by cells that have increased expression of insulin receptors. In some embodiments, cancers characterized by increased expression of insulin receptors can be treated with polyplexes comprising an insulin-receptor targeting fragment such as insulin. In certain embodiments, the cancer characterized by insulin- receptor overexpressing cells is breast cancer, prostate cancer, endometrial cancer, ovarian cancer, liver cancer, bladder cancer, lung cancer, colon cancer, thyroid cancer and/or metastases _{P6797PC00 – 216 –} thereof. In some embodiments, the cancer can be characterized by cells that have increased expression of mannose-6-phosphate receptors (e.g., monocytes). In some embodiments, cancers characterized by increased expression of mannose-6-phosphate receptors can be treated with polyplexes comprising a mannose-6-phosphate receptor targeting fragment such as mannose-6-phosphate. In some embodiments, the cancer characterized by overexpression of mannose-6-phosphate receptor is leukemia. In some embodiments, the cancer can be characterized by cells that have increased expression of mannose receptors. In some embodiments, cancers characterized by increased expression of mannose receptors can be treated with polyplexes comprising a mannose-receptor targeting fragment such as mannose. In some embodiments, cancers characterized by increased expression of mannose receptors include gastric cancer and/or metastases thereof. In some embodiments, the cancer can be characterized by cells that have increased expression of glycosides such as Sialyl Lewis^x antigens. In some embodiments, cancers characterized by increased expression of Sialyl Lewis^x antigens can be treated with polyplexes comprising Sialyl Lewis^x antigen targeting fragments such as E-selectin. In some embodiments, the cancer can be characterized by cells that have increased expression of N-acetyllactosamine. In some embodiments, cancers characterized by increased expression of N-acetyllactosamine can be treated with polyplexes comprising an N- acetyllactosamine targeting fragment. In some embodiments, the cancer can be characterized by cells that have increased expression of galactose. In some embodiments, cancers characterized by increased expression of galactose can be treated with polyplexes comprising a galactose targeting fragment. In some embodiments, cancers characterized by increased expression of galactose include colon carcinoma and/or metastases thereof. In some embodiments, the cancer can be characterized by cells that have increased expression of sigma-2 receptors. In some embodiments, cancers characterized by increased expression of sigma-2 receptors can be treated with polyplexes comprising sigma-2 receptor agonists, such as N,N-dimethyltryptamine (DMT), sphingolipid-derived amines, and/or steroids (e.g., progesterone). In some embodiments, cancers characterized by increased expression of sigma-2 receptors include pancreatic cancer, lung cancer, breast cancer, melanoma, prostate cancer, ovarian cancer and/or metastases thereof. In some embodiments, the cancer can be characterized by cells that have increased _{P6797PC00 – 217 –} expression of the mitochondrial protein p32. In some embodiments, cancers characterized by increased expression of p32 can be treated with polyplexes comprising p32-targeting ligands such as anti-p32 antibody or p32-binding LyP-1 tumor-homing peptide. In some embodiments, cancers characterized by increased expression of p32 include glioma, breast cancer, melanoma, endometrioid carcinoma, adenocarcinoma, colon cancer and/or metastases thereof. In some embodiments, the cancer can be characterized by cells that have increased expression of Trop-2. In some embodiments, cancers characterized by increased expression of Trop-2 can be treated with polyplexes comprising a Trop-2 targeting fragment such as an anti- Trop-2 antibody and/or antibody fragment. In some embodiments, cancers characterized by increased expression of Trop-2 include breast cancer, squamous cell carcinoma, esophageal squamous cell carcinoma (SCC), pancreatic cancer, hilar cholangiocarcinoma, colorectal cancer, bladder cancer, cervical cancer, ovarian cancer, thyroid cancer, non-small-cell lung cancer (NSCLC), hepatocellular cancer, small cell lung cancer, prostate cancer, head and neck cancer, renal cell cancer, endometrial cancer, glioblastoma, gastric cancer and/or metastases thereof. In some embodiments, the cancer can be characterized by cells that have increased expression (e.g., overexpression or high expression) of insulin-like growth factor 1 receptor. In some preferred embodiments, cancers characterized by cells that have increased expression of insulin-like growth factor 1 receptor can be treated with polyplexes comprising an insulin-like growth factor 1 receptor-targeting fragment, such as insulin-like growth factor 1. In some embodiments, the cancer characterized by insulin-like growth factor 1 receptor overexpressing cells is breast cancer, prostate cancer, lung cancer and/or metastases thereof. In some embodiments, the cancer can be characterized by cells that have increased _{expression (e.g., overexpression or high expression) of VEGF receptor. In some preferred} embodiments, cancers characterized by cells that have increased expression of VEGF receptor can be treated with polyplexes comprising a VEGF receptor-targeting fragment such as VEGF. In some embodiments, the cancer can be characterized by cells that have increased expression (e.g., overexpression) of platelet-derived growth factor receptor. In some preferred embodiments, cancers characterized by cells that have increased expression of platelet-derived growth factor receptor can be treated with polyplexes comprising an platelet-derived growth factor receptor-targeting fragment such as platelet-derived growth factor. In some preferred embodiments, cancers characterized by cells that have increased expression of platelet-derived growth factor receptor include breast cancer and/or metastases thereof. _{P6797PC00 – 218 –} In some embodiments, the cancer can be characterized by cells that have increased expression (e.g., overexpression or high expression) of fibroblast growth factor receptor. In _{some preferred embodiments, cancers characterized by cells that have increased expression of} fibroblast growth factor receptor can be treated with polyplexes comprising a fibroblast growth factor receptor-targeting fragment such as fibroblast growth factor. In some embodiments, the cancer to be treated is characterized by a particular mutation, wherein said cancer can be treated by repairing a mutation therein. For example, in some embodiments the compositions and polyplexes described herein are for use in treating solid _{tumors including ovarian cancer, breast cancer (e.g., by targeting HER,2,BRCA1/2, CDH1,} _{MLLT4, TBX3, RUNX1, GATA3, ZFP36L1, and/or MEN1), colon cancer (e.g., by targeting} _{APC), retinoblastoma (e.g., by targeting RB1), neurofibromatosis Type 1 (e.g., by targeting} NF1), Li-Fraumeni Syndrome (e.g. by targeting TP53), Lynch Syndrome (e.g., by targeting _{MLH1, MSH2, MSH6, and/or PMS2), Wilms tumors (e.g. by targeting WT1 or WTX), thyroid} _{cancer, melanoma, prostate cancer, lung cancer, and liver cancer.} In some embodiments, said compositions and polyplexes described herein can be used to _{treat non-solid tumors such as Lymphomas, including B-cell acute lymphoblastic leukemia,} _{Non-Hodgkin lymphoma (e.g., by targeting TCR and/or B2M) lung cancer, esophageal cancer,} and multiple myeloma. In some embodiments, the cancer is retinoblastoma. In some embodiments, the disease or disorder is a metabolic disease, e.g., diabetes. In some embodiments, the disease or disorder is a viral disease, e.g., HIV or COVID. In some embodiments, the disease or disorder is a monogenic inherited disease. In some embodiments, the disease or disorder is a neurodegenerative disease, e.g., Huntington’s disease. In some embodiments, said disease or disorder is a heritable genetic disorder. Without wishing to be bound, in some embodiments the compositions comprising polyplexes disclosed herein can be used to repair (e.g., provide a functional copy of) a mutated gene in a subject in need thereof. Exemplary heritable genetic disorders that can be treated by the compositions comprising polyplexes of the present disclosure include, without limitation, albinism, Angelman syndrome, ankylosing spondylitis, Apert syndrome, Charcot-Marie Tooth disease, _{Congenital adrenal hyperplasia, cystic fibrosis (preferably by repairing CFTR), Down} _{syndrome, Duchenne muscular dystrophy (preferably by repairing DMD), Ehler’s Danlos} syndrome, Fabry disease, Fragile X syndrome, haemochromatosis, haemophilia, Huntington’s _{disease (preferably by repairing HTT), Klinefelter syndrome, Marfan syndrome,} _{P6797PC00 – 219 –} neurofibromatosis, Noonan syndrome, Prader-Willi syndrome, Rett syndrome, Tay-Sachs _{disease (preferably by repairing HEXA), Thalassaemia, Tourette syndrome, Turner syndrome,} _{von Willebrand disease, sickle cell anemia (preferably by repairing HBB), familial} _{hypercholesterolemia (preferably by repairing LDLR, APOB, and/or PCSK9), cystinuria} (preferably by repairing SLC3A1 and/or SLC7A9), hereditary tyrosinemia type 1 (preferably by repairing Fah) and Williams syndrome. In some embodiments, the compositions and polyplexes described herein are for use in tissue and organ engineering, e.g., for disease modeling and drug testing. In some embodiments, the compositions and polyplexes described herein are for use in treating sickle cell anemia, and/or ß-thalassemia, e.g., by repairing a defective copy of the BCL11A gene. In some embodiments, the compositions and polyplexes described herein target PD-1. In some embodiments, the compositions and polyplexes described herein target CCR5. As described herein, a first polyplex of the invention can comprise multiple nucleic acids, preferably an mRNA encoding a Cas protein such as Cas9; a gRNA; and optionally a _{template DNA). In such embodiments, said first polyplex is administered to said subject in} _{need thereof to cause gene editing and/or to treat a disease. When said first polyplex comprises} multiple nucleic acids, e.g., all nucleic acids necessary to bring about gene editing in a subject, and preferably when said first polyplex comprises an mRNA encoding a Cas protein such as Cas9; a gRNA and optionally a template DNA, said polyplex (or a composition comprising said polyplex) may be administered by an intravenous, intra-brain (intracerebral), oral, intramuscular, subcutaneous, transdermal, intradermal, transmucosal, intranasal, sublingual, _{intraperitoneal or intraocular route. In a preferred embodiment, the first polyplex is systemically} _{administered, i.e. enterally or parenterally. More preferably, the first polyplex is intravenously,} subcutaneously or intraperitoneally administered. I_{n a more preferred embodiment, the first polyplex is for systemic administration. More} _{preferably, said first polyplex is intravenously or intraperitoneally administered, again more} preferably intravenously administered. I_{n some embodiments, multiple polyplexes (e.g., a first polyplex and a second polyplex,} _{optionally a third polyplex) containing different nucleic acids can be used, wherein the} polyplexes are prepared individually and mixed together to prepare a single composition. For _{instance, the composition can comprise a first polyplex comprising a first conjugate and an} mRNA encoding a Cas protein such as Cas9, a second polyplex comprising a second conjugate and a gRNA. The composition can optionally comprise a third polyplex comprising a third _{P6797PC00 – 220 –} conjugate and a template DNA. In preferred embodiments, when multiple polyplexes are used to prepare a single composition, the conjugates comprising the conjugates all comprise the same targeting fragment and are thus all targeted to the same cell type. In preferred embodiments, _{when multiple polyplexes are used to prepare a single composition, the various polyplexes can} be mixed together prior to administration (e.g., to a subject or a cell). In some embodiments, a single composition comprising multiple polyplexes (e.g., a first polyplex, a second polyplex, and optionally a third polyplex) may be administered by an intravenous, intra-brain (intracerebral), oral, intramuscular, subcutaneous, transdermal, intradermal, transmucosal, intranasal, sublingual, intraperitoneal or intraocular route. In a preferred embodiment, the composition comprising multiple polyplexes is systemically administered, i.e. enterally or parenterally. More preferably, the composition comprising multiple polyplexes is intravenously, subcutaneously or intraperitoneally administered. I_{n a more preferred embodiment, the composition comprising multiple polyplexes is for} _{systemic administration. More preferably, said composition comprising multiple polyplexex is} intravenously or intraperitoneally administered, again more preferably intravenously administered. I_{n some embodiments, said a first polyplex as described herein (e.g., comprising mRNA} _{encoding a Cas protein) is administered separately from a second polyplex as described herein} _{(e.g., comprising a gRNA) and optionally a third polyplex as described herein (e.g., comprising} a template DNA). I_{n some embodiments, the invention provides use of a first and optionally a second and} _{a third polyplex, wherein said first polyplex is administered to a patient in a therapeutically} _{effective amount and said second polyplex and optionally said third polyplex is administered} _{to said patient in a therapeutically effective amount.} _{In a preferred embodiment, use of compositions as described herein for gene editing} _{comprises independent dosing of the first polyplex and said second and optionally third} _{polyplex. Said first polyplex and said second and optionally third polyplex can be administered} simultaneously or sequentially (consecutive), i.e. chronologically staggered. Said first polyplex and said second and optionally third polyplex, e.g., as included in the kit-of-parts of the _{invention, can be combined prior to administration and can be administered together as a} _{composition or can be administered separately. In some preferred embodiments, said first} polyplex and second and optionally third polyplex, as included in the kit-of-parts of the _{invention, are administered separately.} _{P6797PC00 – 221 –} _{In certain embodiments, the first, second and optionally third polyplexes for use} according to the invention are administered by any suitable route. The polyplexes for use according to the invention may be administered by an intravenous, intra-brain (intracerebral), oral, intramuscular, subcutaneous, transdermal, intradermal, transmucosal, intranasal, sublingual, intraperitoneal or intraocular route. In a preferred embodiment, the first, second and _{optionally third compositions or the polyplexes contained therein for use according to the} invention are systemically administered, i.e. enterally or parenterally. More preferably, first, second and optionally third compositions or the polyplexes contained therein for use according to the invention are intravenously, subcutaneously or intraperitoneally administered. I_{n a more preferred embodiment, the first, second and optionally third compositions or} the polyplexes contained therein for use according to the invention are for systemic _{administration. More preferably, first, second and optionally third compositions or the} polyplexes contained therein for use according to the invention are intravenously or intraperitoneally administered, again more preferably intravenously administered. S_{aid first polyplex and said second polyplex and optionally said third polyplex can be} administered via the same route or preferably via different routes. More preferably, said first _{polyplex and said second and optionally said third polyplex are administered via the same route} or routes. In a preferred embodiment, said first polyplex and second polyplex and optionally _{said third polyplex are administered sequentially or simultaneously, preferably sequentially. In} a preferred embodiment, said first polyplex and second polyplex and optionally said third _{polyplex are administered sequentially via different routes. More preferably, said first polyplex} _{and said second polyplex and optionally said third polyplex are administered simultaneously} via the same route or routes. In a preferred embodiment, said first polyplex and said second and optionally third _{polyplex are administered sequentially, or simultaneously, preferably sequentially, wherein one} _{polyplex is administered via intraperitoneal injection and at least one other polyplex (e.g., the} second and/or third polyplex) is administered via intravenous injection. In a preferred _{embodiment, said first polyplex and said second and optionally third polyplex are administered} sequentially or simultaneously, preferably sequentially, wherein the first polyplex is _{administered via intravenous injection and second and optionally third polyplexes are} administered via intraperitoneal or intravenous injection. In another preferred embodiment, the first polyplex is administered prior to said second and optionally third polyplex. In another preferred embodiment, the first polyplex and said _{P6797PC00 – 222 –} _{second and optionally third polyplex are administered sequentially, wherein the first polyplex} _{is administered via intravenous injection and said second and optionally third polyplex are} _{administered via intraperitoneal or intravenous injection, and wherein the first polyplex is} administered prior to the second and optionally third polyplex. T_{he ratio of the amount or concentration of the first polyplex to the amount or} _{concentration second and optionally third polyplex can be varied, e.g. in order to cope with the} needs of a single patient or a patient sub-population to be treated, wherein the needs can be different due to patient’s age, sex, body weight, condition etc. Equivalents W_{hile the present invention has been described in conjunction with the specific} embodiments set forth above, many alternatives, modifications and other variations thereof will be apparent to those of ordinary skill in the art. All such alternatives, modifications, and variations are intended to fall within the scope and spirit of the present invention. EXAMPLES The invention is further illustrated by the following examples and synthesis schemes, which are not to be construed as limiting this invention in scope or spirit to the specific procedures herein described. It is to be understood that the examples are provided to illustrate certain embodiments and that no limitation to the scope of the invention is intended thereby. It is to be further understood that resort may be had to various other embodiments, modifications, and equivalents thereof which may suggest themselves to those skilled in the art without departing from the spirit of the present invention and/or scope of the appended claims. Abbreviations used in the following examples and elsewhere herein are: ACN Acetonitrile Aoc 8-aminooctanoic acid _{Aq. aqueous} _{ASGPr Asialoglycoprotein Receptor} _{BCN Bicyclononyne} _{D Dispersity} _{DBCO Dibenzocyclooctyne} _{DCM Dichloromethane} _{DIEA N,N-Diisopropylethylamine (Hünig’s Base)} _{P6797PC00 – 223 –} _{DLS Dynamic light scattering} _{DMSO Dimethyl sulfoxide} DTT Dithiothreitol (reducing agent) _{DUPA 2-[3-(1,3-dicarboxypropyl)ureido]pentanedioic acid} _{EGF Epidermal growth factor} _{ELSD Evaporative light scattering detector} _{Endo-BCN (1alpha,8alpha,9beta)-bicyclo[6.1.0]non-4-yne} _{Epsilon (ε) Extinction coefficient} _{Eq Equivalent} FLuc Firefly Luciferase _{FLuc mRNA Firefly Luc messenger RNA} _{HATU O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium-} hexafluorphosphate _{HBG HEPES buffered glucose solution} _{hEGF Human epidermal growth factor} _{HEPES 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid} LC Liquid chromatography _{LPEI Linear polyethyleneimine} _{LPEI-l-PEG-hEGF Linear polyethyleneimine-PEG-human epidermal growth factor conjugate} _{MADOPA N10-Methyl-4-amino-4-deoxypteroic acid} _{MAL Maleimide} _{NHS N-hydroxysuccinimide} _{PEG Polyethylene glycol} _{PDI Polydispersity Index} _{PyBOP Benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate} _{RENCA Renal Carcinoma} _{RP-HPLC Reversed phase high pressure liquid chromatography} _{RP-HPLC-MS Reversed phase high pressure liquid chromatography mass spectrometry} _{qTOF MS Quadrupole time of flight mass spectrometry} _{SSTR2 Somatostatin receptor 2} _{TCEP Tris(2-carboxyethyl)phosphine} _{TFA Trifluoroacetic acid} _{P6797PC00 – 224 –} _{TFF Tangential flow filtration} _{TIS Triisopropylsilane} Unless otherwise noted, the following polymer naming conventions are used herein. Linear (i.e., unbranched) polymers are denoted with “l” and random (i.e., branched) polymers are denoted with “r”. Conjugates are further using an abbreviation for each fragment of the conjugate (e.g., PEG or LPEI) and/or targeting group (e.g., hEGF) in the orientation in which they are connected. Subscripts, when used, after each fragment within the conjugate indicate the number of monomer units (e.g., LPEI or PEG units) in each fragment. The linking moieties, and in particular the divalent covalent linking moiety Z of Formula I* connecting the LPEI and PEG fragments (e.g., a 1, 2, 3 triazole or a 4,5-dihydro-1H-[1,2,3]triazole) are defined by the reactive groups that formed the linking moieties and the divalent covalent linking moiety Z of Formula I*, respectively. For example, the conjugate abbreviated “LPEI-l-[N3:DBCO]- PEG₃₆-hEGF” is an unbranched (i.e., linear) conjugate comprising LPEI connected to a 36-unit PEG chain through a 1, 2, 3 triazole formed by the reaction of an azide comprised by the LPEI fragment and DBCO comprised by the PEG fragment, while the terminal end of the PEG fragment is bonded to hEGF. _{Analytical Methods, Materials, and Instrumentation. Unless otherwise noted, reagents and} solvents were used as received from commercial suppliers. Starting materials are either commercially available or made by known procedures in the reported literature or as illustrated. ^-Hydrogen-^-azido-poly(iminoethylene) (H-(NC2H5)n-N3; LPEI-N3) ULTROXA^® (MW = 22 KDa; dispersity ≤ 1.25) and ^-Methyl-^-azido-poly(iminoethylene) (CH3-(NC2H5)n-N3; Me- LPEI-N3) ULTROXA^® (MW = 25.3 KDa; dispersity ≤ 1.25) were obtained from AVROXA BV (Belgium). CliCr^®-beta-Ala-NH₂ (Product No. RL-4190), HOOC-dPEG₃₆-NH₂ (Product No. PEG3340, CAS No. 196936-04-6) was purchased from IRIS BIOTECH GMBH (Germany). DUPA-Aoc-Phe-Gly-Trp-Trp-Gly-Cys ((C₅₇H₇₁N₁₁O₁₆S; Mw 1198.3; SEQ ID NO:12), and hEGF peptides, were synthesized by CBL Patras S.A. (Greece). Acetate buffer was 50 mM sodium acetate (aq.) supplemented with 5% glucose at pH 4-4.5. HEPES buffer was HEPES at a concentration of 20 mM (aq.) at a pH of 7-7.4. JetPEI was purchased from Polyplus (Cat# 101000053). I_{nventive conjugates (e.g., triconjugates) can be prepared as described in} PCT/EP0222/080986, published as WO 2023/079142 on 05. May 2023, particularly at _{Examples 1-20; and/or PCT/EP2022/080986, filed November 7, 2023, the contents of each of} _{P6797PC00 – 225 –} which are hereby incorporated by reference in their entirety. UV spectrophotometry of samples comprising hEGF. Measurements of hEGF content in reagent solutions and in conjugated samples are performed on a microplate reader (Spectramax Paradigm, Molecular Devices) using Brand^® pureGrade UV-transparent _{microplates at 280 nm. UV absorption of a 100 mL solution of sample in its buffer is measured} and the absorbance of the sample is corrected by subtracting the absorbance of buffer solution alone (blank). ε (280 nm) of hEGF was calculated with the following formula: ε(280 nm) = (#Trp)*(5500) + (#Tyr)*(1490) + (#cystine)*(125) = 2*(5500) + 5*(1490) + 2*(125) = The c(hEGF) [mol/L] = A₂₈₀ [AU]/ (ε₂₈₀ [L*mol^-1*cm^-1]*0.28 cm). U_{V spectrophotometry of samples comprising HER2. For measurements of HER2} content in samples, UV spectrophotometry is performed on a Thermofischer Nanodrop One C device at 280 nm.2 mL of the sample are analysed and the absorbance of the sample is corrected for by subtracting the absorbance of 2 mL of the appropriate buffer solution alone (blank). ε (280 nm) of HER2 is 16600 cm^-1∙M^-1. The concentration of total HER2 is calculated using this formula: c(HER2) [mol/L] = A280 [AU]/ (ε280 [L*mol^-1*cm^-1]*1 cm). U_{V spectrophotometry of samples comprising DUPA. For measurements of DUPA} _{content, UV spectrophotometry is performed on a microplate reader (Spectramax Paradigm,} Molecular Devices) at 280 nm. 100 µL of solution are analysed in Brand puregrade 98 UVtransp F as well as 100 µL of the appropriate buffer (blank). The absorbance of the sample _{is corrected for the blank. ε (280 nm) of DUPA is (theoretically determined): ε (280 nm) =} 11’000 cm^-1∙M^-1. The concentration of DUPA is calculated using this formula: c(DUPA) _{[mol/L] = A280 [AU]/ (ε [L*mol-1*cm-1]*0,28 cm).} UV spectrophotometry of samples comprising DBCO. Measurements of DBCO content of reagent solution and conjugated samples are performed on a microplate reader (Spectramax _{Paradigm, Molecular Devices) using Brand® pureGrade UV-transparent microplates at 309 nm.} UV absorption of a 100 mL buffered solution is measured and the absorbance of the sample is corrected by subtracting the absorbance of buffer solution alone (blank). ε (309 nm) of DBCO was 12,000 cm^-1∙M^-1. The concentration of total DBCO is calculated using this formula: c(DBCO) [mol/L] = A309 [AU]/ (ε309 [L*mol^-1*cm^-1]*0.28 cm). _{P6797PC00 – 226 –} _{RP-HPLC-coupled Mass Spectrometry. Samples are analyzed by LC-MS using an} Agilent 1260 Infinity II HPLC system or an Agilent UHPLC 1290 system. The Agilent 1260 Infinity II HPLC system is connected to an Agilent iFunnel 6550B qTOF equipped with an Agilent Jet Stream electrospray ionization (AJS ESI) source. The _{sample is separated on a Phenomenex Aeris Widepore column XB-C8 – 3.6µm, 100x2.1mm} (P/N: 00D-4481-AN) at 40°C. 1-5 μL are injected and elution is achieved with the eluent gradient shown in Table 1 with a flowrate of 0.3 mL/min, where solvent A is 100% H2O with 0.1% HCOOH and solvent B 100% ACN with 0.1% HCOOH. The AJS ESI source is operated with a capillary voltage of 3000 V and a nozzle voltage of 1000 V with a drying gas temperature of 200°C and a flow rate of 14 L/min, nebulizing gas pressure of 20 psig, and a sheath gas temperature of 325°C and flow rate of 12 L/min. MS data are acquired in the positive ion mode in the range of 100-3200 m/z in the standard mass range at 4Ghz high resolution mode between 2 and 12 min. The fragmentor and octupole RF voltages are set at 380, 750 V respectively. Table 1. Eluent Gradient for RP-HPLC-MS using Agilent 1260 Infinity II HPLC System T_{ime [min] A [%] B [%]} _{0.00 95.00 5.00} _{1.00 95.00 5.00} _{8.00 50.00 50.00} _{9.00 5.00 95.00} _{13.00 5.00 95.00} _{The Agilent UHPLC 1290 system comprises an Agilent 1290 binary pump (G4220A),} _{Agilent 1290 HiP Sampler (G4226A), Agilent 1290 Column compartment (G1316C), Agilent} 1290 DAD UV modules (G4212A), and Agilent Quadrupole LC/MS (6130) at 40 °C using a _{Phenomenex BioZen column XB-C8 (3.6 µm, 150 × 2.1mm (00F-4766-AN) equipped with a} pre-column filter of the same material (AJ0-9812).5 µL of sample are injected. The flow is 0.4 mL/min. Signal is monitored at 210 nm, 215 nm, 240 nm and 280 nm. The mobile phases are: A) H₂O with 0.1% (vol.) HCOOH and B) ACN. The eluent gradient to be used is given in Table 2. Table 2. Eluent Gradient for RP-HPLC-MS using Agilent UHPLC 1290 System T_{ime [min] A [%] B [%]} _{0.00 95.00 5.00} _{1.00 95.00 5.00} _{8.00 50.00 50.00} _{9.00 5.00 95.00} _{11.00 5.00 95.00} _{P6797PC00 – 227 –} Analytical RP-HPLC. RP-HPLC experiments are performed on an Agilent UHPLC 1290 system comprising an Agilent 1290 binary pump (G4220A), Agilent 1290 HiP Sampler (G4226A), Agilent 1290 Column Compartment (G1316C), and Agilent 1290 DAD UV (G4212A) modules at 40 °C using a Phenomenex BioZen^TM XB-C8 column (3.6 µm, 150 × _{2.1mm (00F-4766-AN) equipped with a pre-column filter of the same material (AJ0-9812). 20} µL of sample are injected. The flow is 0.4 mL/min. Signal is monitored at 210 nm, 214 nm, 220 _{nm, 230 nm, 240 nm and 280 nm. The mobile phases are A) H2O + 0.1% TFA (vol.) and B)} _{ACN + 0.1% TFA (vol.). The eluent gradient to be used is given in Table 3.} Table 3. Eluent Gradient for Analytical RP-HPLC T_{ime [min] A [%] B [%]} _{0.00 95.00 5.00} _{1.00 95.00 5.00} _{8.00 50.00 50.00} _{9.00 5.00 95.00} _{11.00 5.00 95.00} Preparative RP-HPLC. Preparative RP-HPLC experiments are performed on a Waters preparative system or a PuriFlash RP preparative system. The Waters system comprises a Waters 515 HPLC Pump, Waters 2545 Binary Gradient Module, Waters 2777C Sampler, Waters Fraction Collector III and Waters 2487 Dual λ Absorbance Detector module using a Phenomenex Kinetex 5 mm XB-C18 column (100Å, 100 x 21.0 mm, 00D-4605-P0-AX) equipped with a Phenomenex SecurityGuard PREP Cartridge Core-shell C18 pre-column (15 x 21.2 mm, G16-007037). The flow rate is 35 mL/min and the signal is monitored at 240 nm. The fractions collector collects from 0.1 min to 30 min volumes of ~8 mL/tube (88% total filling) according to the following profile: Eluent A: H2O with 0.1%(vol.) TFA. Eluent B: CAN with 0.1% (vol) TFA. The eluent gradient to be used is given in Table 4. Table 4. Eluent Gradient for Preparative RP-HPLC Using Waters Preparative System T_{ime [min] A [%] B [%]} _{0.00 90.00 10.00} _{30.00 50.00 50.00} _{35.00 2.00 98.00} _{36.00 2.00 98.00} _{38.00 90.00 10.00} _{P6797PC00 – 228 –} _{The PuriFlash system comprises an Interchim Inc. PuriFlash 1 Serie system comprising} an injector, pump, detector and fraction collector using a Phenomenex Kinetex 5 mm XB-C18 column (100Å, 100 x 21.0mm, 00D-4605-PO-AX) equipped with a Phenomenex SecurityGuard PREP Cartridge Core-shell pre-column (C18 15 x 21.2 mm, G16-007037). When injecting (from 00 s to 04 s), the flow rate is 10 mL/min and then was 35 mL/min until _{the end of run. The signal is monitored at 210 nm. The mobile phases are: Eluent A: H2O with} _{0.1% (vol) TFA. Eluent B: ACN with 0.1% (vol.) TFA. The eluent gradient to be used is given} in Table 5. Table 5. Eluent Gradient for Preparative RP-HPLC Using PuriFlash Preparative System N_{° Time Flow [mL/min] A [%] B [%]} _{01 00 s 10.0 90 10} _{02 01 s 10.0 90 10} _{03 04 s 10.0 90 10} _{04 01:03 10.0 89 11} _{05 01:06 10.0 89 11} _{06 01:35 10.0 88 12} _{07 01:38 35.0 88 12} _{08 30:00 35.0 50 50} _{09 35:00 35.0 02 98} _{10 36:00 35.0 02 98} _{11 38:00 35.0 90 10} _{12 40:00 35.0 90 10} Copper Assay. The copper assay provides the concentration in mg/mL of total LPEI present in the solution (Ungaro et al., J. Pharm. Biomed. Anal. 31; 143-9 (2003)). A stock solution of copper reagent (10x) is prepared by dissolving 23.0 mg of CuSO4•5H2O in 10.0 mL acetate buffer (100 mM; pH 5.4). This stock solution is stored at 4 °C. Prior to analysis, this reagent is diluted ten-fold with acetate buffer (100 mM pH 5.4) and used directly. As a control, a solution of known concentration of LPEI (in vivo-jetPEI; 150mM nitrogen concentration; Polyplus 201-50G) is used.6.7 µL aliquots of the in vivo-jetPEI solution are prepared in plastic tubes and frozen for use as control samples which are freshly thawed and diluted 15x with Milli- Q water (93.3 µL) prior to use. The solutions of experimental samples and control samples are dispensed in a UV- compatible 96 well microplate (BRANDplates, pureGrade) as shown in Table 6 and are measured in triplicate. Table 6. Solutions Used in Copper Assay. _{P6797PC00 – 229 –} _{Sample Sample volume [µl] Water volume [µl] CuSO4 volume [µl]} In vivo-Jet LPEI (15x; _{8 92 100} Control) LPEI-l-PEG-[Targeting _{8 92 100} Fragment] A blank consisting of 100 µL water and 100 µL CuSO4 reagent is also measured in _{triplicate and the mean absorbance of the blank is subtracted from the absorbance values} recorded for the experimental samples and the control sample. Solutions are left to react for 20 minutes at room temperature and their absorbance is then measured at 285 nm in a microplate reader (Spectramax Paradigm, Molecular Devices). Individual measurements are validated if the absorbance values are in the calibration range and were otherwise further diluted. Individual measurements are not validated if the coefficient of variation of the measurement is greater than 10.0% but were instead repeated. The measurement run is validated if the value of the control was within 10% of 150 mM. Concentrations are calculated using the following formula using _{the calibration slope k = 0.0179:} _{c(LPEI total) [mg/L] = (Acorr, average [AU] / k [L*mg-1]) * (200/8) * dilution factor} _{Lyophilization. Lyophilization is performed on a freeze-drying device from Christ} _{(Alpha 2-4 LP Plus). Because of the presence of acetonitrile in some samples, the samples are} _{cooled for about three minutes with liquid nitrogen at -196 °C before lyophilization.} _{Samples are lyophilized at -82 °C (condenser temperature) and 100 mbar (75 Torr). The} time of lyophilization is adjusted based on the properties of the lyophilized compound. Buffer Exchange general method. For preparation of triconjugates in a HEPES buffer, the resuspended TFA-lyophilisate solution is pH adjusted with NaOH to pH 6.5 before exchanging the buffer with 20 mM HEPES at pH 7.2. F_{or preparation of triconjugates in an acetate buffer, the resuspended TFA-lyophilisate} solution is pH adjusted with NaOH to pH 4.5 before exchanging the buffer with 50 mM acetate at pH 4.3. Polyplex Sizing Measurements and Characterization. Triconjugates (e.g., LPEI-l-[N3:DBCO]-PEG36-DUPA) are complexed with nucleic acids _{to form polyplexes (e.g., LPEI-l-[N3:DBCO]-PEG36-DUPA:hIL-2 mRNA). The N/P ratio of} the polyplexes, as referred herein, corresponds to the molar ratio of the nitrogen (N) content of _{the triconjugate to the phosphorus (P) content of nucleic acid measured prior to preparing} _{polyplexes by mixing at the specified N/P ratio. Polyplex size distribution and ζ-potential are} _{P6797PC00 – 230 –} measured by DLS and ELS according to Hickey et al., J. Control. Release, 2015, 219, 536-47. The size of the polyplexes is measured by DLS with a Zetasizer Nano ZS instrument (Malvern Instruments Ltd., UK), working at 633 nm at 25 °C and equipped with a backscatter detector (173°), for example in HBG buffer (20 mM HEPES, 5% glucose, pH 7.2). Each sample is _{measured in triplicate. Briefly, polyplexes in HBT, HBG or HBS buffer are transferred into a} _{quartz cuvette, typically and preferably using particle RI of 1.59 and absorption of 0.01 in HBG} _{or 5% glucose (wt/vol) at 25° C with viscosity of (0.98 mPa.s or 1.078 mPa.s) and RI of 1.330.} Measurements are made using a 173° Backscatter angle of detection previously equilibrated to 25° C for at least 30 seconds, typically and preferably 60 seconds in triplicate, each with _{automatic run duration, without delay between measurements. Each measurement is performed} seeking optimum position with an automatic attenuation selection. Data is analyzed using a General-Purpose model with normal resolution. The calculations for particle size and PDI are _{determined according to the ISO standard document ISO 22412:2017. The ζ-potential of} _{polyplexes is measured by phase-analysis light scattering (PALS) (for example in HBG buffer} at 25 °C), and/or electrophoretic light scattering (ELS) as described by instrument supplier (https://www.malvernpanalytical.com/en/products/technology/light-scattering/electrophoretic- light-scattering). Briefly, polyplex samples in the indicated formulation buffer (e.g. 5% glucose) are transferred into a folded capillary cell and measured in 3-5 replicates. For nanoparticle material, settings of polystyrene latex are used: R.I. of 1.59 and absorption of 0.01. _{For dispersant, the experimentally determined viscosity of the formulation buffer are used (e.g.} R.I. of 1.33 and viscosity 1.078 mPa.s for 5% glucose). Measurements are performed after at least 30 s incubation at 25°C using the auto mode. U_{nless otherwise stated, when a concentration is indicated for a polyplex, the} _{concentration refers to the final nucleic acid concentration.} EXAMPLE 1 SYNTHESIS OF LPEI-l-[N₃:DBCO]-PEG₃₆-hEGF L_{PEI-l-[N3:DBCO]-PEG36-hEGF was prepared as a mixture of regioisomers according} to the schemes below. DBCO-PEG36-TFP was condensed with hEGF, and the resulting DBCO- PEG₃₆-hEGF was reacted with LPEI-N₃ to give LPEI-l-[N₃:DBCO]-PEG₃₆-hEGF. _{P6797PC00 – 231 –} Step 1. Synthesis of DBCO-PEG36-hEGF F DMSO (2.0 mL) was slowly added to a solution of hEGF (92 µmol, 1.0 eq, 2.6 mM) in 20 mM HEPES pH 7.5 (35 mL). The reaction mixture was stirred in a round-bottom flask and the reaction was monitored by RP-C₈-HPLC. After one hour, an additional amount of DBCO-PEG₃₆-TFP (140 µL, 9 µmol, 0_{.1 eq, 64 mM) was added. After a total of 1.5 hrs, acetonitrile (4 mL) was added to the reaction} mixture and the pH adjusted to 3.5. DBCO-PEG36-hEGF was isolated following RP-C18 preparative HPLC. Pooled fractions were lyophilized to give 310 mg of a fluffy white solid w_{hich was analyzed by RP-HPLC-ELSD and RP-HPLC – ESI+ qTOF mass spectrometry} (DBCO-PEG₃₆-hEGF calculated monoisotopic mass: 8168.79 Da; measured: 8168.80 Da).

_{P6797PC00 – 232 –} Step 2. Synthesis of LPEI-l-[N3:DBCO]-PEG36-hEGF H H N buffer pH 4.0 was slowly added to a solution of DBCO-PEG36-hEGF (16 mL, 22 µmol, 1.0 eq) in 50 mM acetate buffer pH 4.0. The reaction mixture was stirred in a round-bottom flask and monitored b_{y RP-C8-HPLC. After a total of 72 hours, acetonitrile (4 mL) and TFA (400 µL) were added} to the reaction mixture. LPEI-l-[N₃:DBCO]-PEG₃₆-hEGF was isolated as a mixture of regioisomers using RP-C18 preparative HPLC. Pooled fractions were lyophilized (505 mg) and characterized by RP-C₈-HPLC, copper assay and spectrophotometry at 280 nm for determination of the hEGF content. T_{he lyophilizate was dissolved in 50 mM acetate, pH 4.5 and processed by TFF (10 kDa} MWCO membrane) to remove TFA residues. A solution of LPEI-l-[N₃:DBCO]-PEG₃₆-hEGF acetate (42 mL) was recovered and characterized by RP-C₈-HPLC, copper assay and spectrophotometry at 280 nm for determination of the hEGF content. The solution had a concentration of 2.6 mg/mL in total LPEI and a LPEI to hEGF ratio of 1/1.0. _{P6797PC00 – 233 –} EXAMPLE 2 SYNTHESIS OF Me-LPEI-l-[N₃:BCN]-PEG₃₆-DUPA Me-LPEI-l-[N3:BCN]-PEG36-DUPA was synthesized according to the schemes below. In a first step, HOOC-PEG₃₆-NH₂ was coupled to N-succinimidyl 3-maleimidopropionate by amide formation to produce HOOC-PEG36-MAL. Endo-BCN-PEG36-MAL was prepared by condensing HOOC-PEG36-MAL with endo-BCN-PEG2-NH2. In a next step, Endo-BCN- PEG₃₆-MAL was condensed with DUPA-Aoc-Phe-Gly-Trp-Trp-Gly-Cys, and the resulting endo-BCN-PEG36-[MAL-S]-DUPA was reacted with Me-LPEI-N3 to give Me-LPEI-l- [N₃:BCN]-PEG₃₆-DUPA. Step 1: Synthesis of HOOC-PEG36-MAL O O O O O O m_{ixed with a solution of N-succinimidyl 3-maleimidopropionate (85 µmol, 0.9 eq, 184 mM) in} DCM (0.83 mL). The reaction mixture was shaken on a Stuart rotator at room temperature and t_{he reaction was monitored by RP-C8 HPLC. At one hour into reaction, an additional amount} _{of N-succinimidyl 3-maleimidopropionate (137 µL, 14 µmol, 0.15 eq) was added and at 1h 15} _{min into reaction, an additional amount of N-succinimidyl 3-maleimidopropionate (83 µL, 9} µmol, 0.1 eq) was added. After a total of 1.5 hours, 4.5 mL of cold diethyl ether were added to induce precipitation followed by centrifugation. The precipitate was washed with 4.5 mL cold diethyl ether and 183 mg of HOOC-PEG₃₆-MAL were recovered (calculated monoisotopic mass: 1825.03 Da; measured: 1825.02 Da). Step 2. Synthesis of endo-BCN-PEG₃₆-MAL _{P6797PC00 – 234 –} A solution of HOOC-PEG36-MAL (40 µmol, 1.0 eq, 99 mM) in DCM (0.40 mL) was mixed with a solution of HATU (36 µmol, 0.9 eq, 325 mM) in DMF (111 µL). The mixture was stirred for one minute and DIEA (14 µL, 80 µmol, 2.0 eq) was added. The mixture was stirred for three minutes and was mixed with a solution of endo-BCN-PEG₂-NH₂ (32 µmol, 0.8 eq, 370 mM) in DCM (86 µL). The reaction mixture was shaken on a Stuart rotator at room temperature and the reaction was monitored by RP-C8-HPLC. At 15 minutes into reaction, an additional amount of endo-BCN-PEG2-NH2 (54 µL, 20 µmol, 0.5 eq) was added and at 30 minutes into reaction, a further amount of endo-BCN-PEG₂-NH2 (32 µL, 12 µmol, 0.3 eq) was added. After a total of 45 minutes, 4.5 mL of n-hexane were added to induce precipitation followed by centrifugation. The precipitate was washed with 4.5 mL cold diethyl ether and 103 mg of endo-BCN-PEG₃₆-MAL solid material were recovered (calculated monoisotopic mass: 2131.21 Da; measured: 2131.22 Da. Step 3. Synthesis of endo-BCN-PEG36-[MAL-S]-DUPA m_{ixed with a solution of DUPA-Aoc-Phe-Gly-Trp-Trp-Gly-Cys (13 µmol, 0.7 eq, 77 mM) in} _{P6797PC00 – 235 –} DMF (173 µL) and DIEA (6 µL, 38 µmol, 2.0 eq). The reaction mixture was shaken on a Stuart rotator at room temperature and the reaction was monitored by RP-C₈ HPLC. At 1 hour into r_{eaction, an additional amount of DUPA-Aoc-Phe-Gly-Trp-Trp-Gly-Cys (26 µL, 2 µmol, 0.1} eq) was added. After a total of 2 hours the mixture was purified using RP-C₁₈ preparative chromatography and pooled fractions containing endo-BCN-PEG₃₆-[MAL-S]-DUPA were lyophilized to give 12 mg lyophilized product. The lyophilisate was analyzed by RP-HPLC- E_{LSD and RP-HPLC – ESI+ qTOF mass spectrometry. The solid mainly contained endo-BCN-} PEG₃₆-[MAL-S]-DUPA (calculated monoisotopic mass: 3328.69 Da; measured: 3328.71 Da). Step 4. Synthesis of Me-LPEI-l-[N₃:BCN]-PEG₃₆-DUPA H O O O O O O O N N O N N H N s_{lowly added to a solution of endo-BCN-PEG36-[MAL-S]-DUPA (3.3 µmol, 0.7 eq, 1.1 mM)} in acetate buffer (50 mM, 3.0 mL, pH 4.0). The mixture was shaken for about 45 hrs at room temperature on a Stuart rotator and protected from light. To the reaction mixture were added acetonitrile (0.66 mL) and TFA (70 µL) and the resultant mixture was purified using RP-C18 preparative chromatography. Me-LPEI-l-[N₃:BCN]-PEG₃₆-DUPA was lyophilized to give 55 mg lyophilized product and characterized by analytical RP-C8 HPLC, copper assay and spectrophotometry at 280 nm for determination of the DUPA content. The product was found _{P6797PC00 – 236 –} to have a weight percentage in LPEI of 28%w/w and a LPEI to DUPA ratio of 1/0.90. Step 5. Preparation of Me-LPEI-l-[N₃:BCN]-PEG₃₆-DUPA HEPES salt 24.8 mg of Me-LPEI-l-[N3:BCN]-PEG36-DUPA TFA salt (wLPEI = 28%, 6.9 mg in total LPEI) _{were dissolved in 0.8 mL 20 mM HEPES pH 7.2. Two centrifugal filters (Amicon Ultra – 0.5} mL, 10kDa MWCO) were filled with 400 μL of Me-LPEI-l-[N₃:BCN]-PEG₃₆-DUPA solution each. They were centrifuged one time at 14000 g for 30 minutes and then three times after addition of 400 µL 20 mM HEPES, pH 7.2. About 253 μL of concentrated solution were recovered and supplemented with 2.5 mL 20 mM HEPES, pH 7.2. The concentration of the solution was determined by copper assay to be 2.3 mg/mL in total LPEI (LPEI/DUPA ratio = 1/0.97). EXAMPLE 3 SYNTHESIS OF Me-LPEI-l-[N3:DBCO]-PEG36-DUPA Me-LPEI-l-[N₃:DBCO]-PEG₃₆-DUPA was synthesized according to the schemes below. In a first step, DBCO-PEG36-MAL was coupled to DUPA-Aoc-Phe-Gly-Trp-Trp-Gly-Cys (SEQ ID NO:12) by a Michael addition to produce DBCO-PEG36-DUPA. In a next step, DBCO-PEG₃₆-DUPA was coupled to Me-LPEI-N₃ by a [2+3] cycloaddition to produce Me- _{LPEI-l-[N3:DBCO]-PEG36-DUPA as a mixture of regioisomers.}

_{P6797PC00 – 237 –} Step 1: Synthesis of DBCO-PEG36-DUPA O O O O mixed with a solution of DUPA-Aoc-Phe-Gly-Trp-Trp-Gly-Cys (SEQ ID NO:12) (10 µmol, 1.0 eq, 82 mM) (151 µL) and DIEA (3 µL, 20 µmol, 2.0 eq) in DMF. The mixture was shaken for about 30 minutes at room temperature on a Stuart rotator and protected from light and the r_{eaction was monitored by RP-C8 HPLC. The resultant mixture was purified using RP-C18} preparative chromatography and pooled fractions containing DBCO-PEG₃₆-DUPA were lyophilized to give 20 mg of DBCO-PEG₃₆-DUPA. A sample was analyzed by analytical RP- H_{PLC-ELSD and HPLC – ESI+ qTOF mass spectrometry (calculated monoisotopic mass:} _{P6797PC00 – 238 –} 3280.61 Da; measured: 3280.64 Da) Step 2: Synthesis of Me-LPEI-l-[N₃:DBCO]-PEG₃₆-DUPA O O O O 4.0) was slowly added to a solution of DBCO-PEG36-DUPA (6.6 µmol, 1.5 eq, 2.2 mM) in _{P6797PC00 – 239 –} acetate buffer (50 mM, 3.0 mL, pH 4.0). The mixture was shaken for about 20 hrs at room temperature on a Stuart rotator and protected from light. To the reaction mixture were added acetonitrile (0.70 mL) and TFA (70 µL). The resultant mixture was purified using RP-C18 preparative chromatography and pooled fractions containing Me-LPEI-l-[N₃:DBCO]-PEG₃₆- DUPA were lyophilized to give 70 mg lyophilized product and characterized by RP-C₈ HPLC, copper assay and spectrophotometry at 280 nm for determination of the DUPA content. The p_{roduct was found to have a weight percentage in LPEI of 28% w/w and a LPEI to DUPA ratio} of 1/1.17. Step 3. Preparation of Me-LPEI-l-[N₃:DBCO]-PEG₃₆-DUPA HEPES salt 25.0 mg of Me-LPEI-l-[N3:DBCO]-PEG36-DUPA TFA salt (wLPEI = 28%, 7.0 mg in total LPEI) were dissolved in 0.8 mL 20 mM HEPES pH 7.2. The pH was adjusted to pH 7.2. Two c_{entrifugal filters (Amicon Ultra – 0.5 mL, 10kDa MWCO) were filled with 400 μL of Me-} LPEI-l-[N₃:DBCO]-PEG₃₆-DUPA solution each. They were centrifuged one time at 14000 g for 30 minutes and then three times after addition of 400 µL 20 mM HEPES, pH 7.2. About 254 μL of the concentrated solution were recovered after buffer exchange and were supplemented with 2.5 mL 20 mM HEPES, pH 7.2. The concentration of the solution was determined by copper assay to be 2.3 mg/mL in total LPEI and an LPEI to DUPA molar ratio of = 1/1.19 was determined. EXAMPLE 4 SYNTHESIS OF LPEI-l-[N3:CliCr^®]-PEG36-DUPA (COMPOUND 83) LPEI-l-[N3:CliCr^®]-PEG36-DUPA was synthesized according to the schemes below. In a first step, CliCr^®-beta-Ala-NH₂ was coupled to HOOC-PEG₃₆-MAL to produce CliCr^®-PEG₃₆- MAL. Subsequently, CliCr^®-PEG36-MAL was coupled to DUPA-Aoc-Phe-Gly-Trp-Trp-Gly- Cys (SEQ ID NO:12) by a Michael addition to produce CliCr^®-PEG₃₆-DUPA. In a final step, CliCr^®-PEG36-DUPA was reacted with LPEI-N3 in a [2+3] cycloaddition reaction to produce LPEI-l-[N3:CliCr^®]-PEG36-DUPA. Step 1: Synthesis of HOOC-PEG₃₆-MAL O O m_{ixed with a solution of N-succinimidyl 3-maleimidopropionate (85 µmol, 0.9 eq, 184 mM) in} _{P6797PC00 – 240 –} DCM (0.83 mL). The reaction mixture was shaken for one hour on a Stuart rotator at room temperature and the reaction was monitored by RP-C₈ HPLC. An additional amount of N- s_{uccinimidyl 3-maleimidopropionate (220 µL, 23 µmol, 0.25 eq) was added. After a total of} 3.5 hours mixing, 4.5 mL of cold diethyl ether were added to induce precipitation followed by centrifugation. The precipitate was washed with 4.5 mL cold diethyl ether and 183 mg of HOOC-PEG36-MAL were recovered (calculated monoisotopic mass: 1825.03 Da; measured: 1825.02 Da). Step 2: Synthesis of CliCr^®-PEG₃₆-MAL O _O O HATU, mixed with a solution of HATU (17 µmol, 1.0 eq, 89 mM) and DIEA (6 µL, 34 µmol, 2.0 eq) in DMF (191 µL). A solution of CliCr^®-beta-Ala-NH₂ (20 µmol, 1.2 eq, 163 mM) in DMF (123 µL) was then added. The mixture was shaken for about 30 minutes at room temperature on a Stuart rotator and the reaction was monitored by RP-C₈ HPLC. The resultant mixture was purified using RP-C₁₈ preparative chromatography and pooled fractions containing CliCr^®- PEG36-MAL were lyophilized to give 11 mg of CliCr^®-PEG36-MAL. A sample was analyzed b_{y analytical RP-HPLC ELSD and HPLC – ESI+ qTOF mass spectrometry (calculated} monoisotopic mass: 2077.15 Da; measured: 2077.17 Da).

_{P6797PC00 – 241 –} Step 3: Synthesis of CliCr^®-PEG36-DUPA O O O O mixed with a solution of DUPA-Aoc-Phe-Gly-Trp-Trp-Gly-Cys (SEQ ID NO:12) (5.3 µmol, 1.0 eq, 44 mM) (120 µL) and DIEA (1.8 µL, 11 µmol, 2.0 eq) in DMF. The mixture was shaken for about 30 minutes at room temperature on a Stuart rotator and the reaction was monitored by RP-C₈ HPLC. The resultant mixture was purified using RP-C₁₈ preparative chromatography and pooled fractions containing CliCr^®-PEG36-DUPA were lyophilized to give 11 mg of C_{liCr®-PEG36-DUPA. A sample was analyzed by analytical RP-HPLC ELSD and HPLC – ESI+} qTOF mass spectrometry (calculated monoisotopic mass: 3274.63 Da; measured: 3274.66 Da). _{P6797PC00 – 242 –} Step 4: Synthesis of LPEI-l-[N3:CliCr^®]-PEG36-DUPA O O O O w_{as slowly added to a solution of CliCr®-PEG36-DUPA (3.9 µmol, 1.0 eq, 3.9 mM) in acetate} buffer (50 mM, 1.0 mL, pH 4.0). The mixture was shaken for about 3 hrs at room temperature on a Stuart rotator. To the reaction mixture were added acetonitrile (0.67 mL) and TFA (67 µL). The resultant mixture was purified using RP-C₁₈ preparative chromatography and pooled fractions containing LPEI-l-[N3:CliCr^®]-PEG36-DUPA were lyophilized to give 85 mg lyophilized product and characterized by RP-C₈ HPLC, copper assay and spectrophotometry at 280 nm for determination of the DUPA content. The product was found to have a weight p_{ercentage in LPEI of 29% w/w and a LPEI to DUPA ratio of 1/1.0.} Step 5: Preparation of LPEI-l-[N3:CliCr^®]-PEG36-DUPA HEPES salt 27.0 mg of LPEI-l-[N₃:CliCr^®]-PEG₃₆-DUPA TFA salt (w_LPEI = 29%, 7.8 mg in total LPEI) were dissolved in 0.8 mL 20 mM HEPES pH 7.2. The pH was adjusted to pH 7.2. Two _{P6797PC00 – 243 –} _{centrifugal filters (Amicon Ultra – 0.5 mL, 10kDa MWCO) were filled with 400 μL of LPEI-} l-[N₃:CliCr^®]-PEG₃₆-DUPA solution each. They were centrifuged one time at 14000 g for 30 minutes and then three times after addition of 400 µL 20 mM HEPES, pH 7.2. About 249 μL of the concentrated solution were recovered after buffer exchange and were supplemented with 3.0 mL 20 mM HEPES, pH 7.2. The concentration of the solution was determined by copper assay to be 2.0 mg/mL in total LPEI and an LPEI to DUPA molar ratio of = 1/1.0 was determined. EXAMPLE 5 POLYPLEX FORMATION, POLYPLEX SIZING AND ZETA POTENTIAL MEASUREMENTS General Procedure for Polyplex Formation with mRNA. For the preparation of preferred polyplexes, the respective triconjugates are complexed with selected mRNAs at various N/P ratios in 5% glucose (wt/vol) or HBS (HEPES-buffered saline pH 7.2). Nitrogen to phosphorus (N/P) ratios are calculated based on the nitrogen content _{in the LPEI portion of the used triconjugates and the phosphorus content in the mRNA.} _{gRNA targeting mouse transthyretin (mTTR) gene is synthesized chemically. The} sgRNA has a purity of > 75% intact oligonucleotide by HPLC analysis using UV detection at _{260 nm and +/1 0.05% of calculated mass by MS analysis. The total sgRNA, including the} scaffold and modifications, is given below: 5’-ususasCAGCCAC GUCUACAGCA GUUUUAGAgc uagaaauagc AAGUUAAAAU AAGGCUAGUC CGUUAUCAac uugaaaaagu ggcaccgagu cggugcusususu-3’ (SEQ ID NO: 13), wherein “s” indicates phosphorothioate backbone modification; “n” indicates 2’-O-methyl residues; and “N” indicates standard RNA residues. The guide sequence of the sgRNA targeting the mouse transthyretin (mTTR) gene is given below: 5'-UUACAGCCACGUCUACAGCA-3' (SEQ ID NO: 14). S_{pCas9 mRNA (encoding Streptococcus pyogenes SF370 Cas9 protein) is purchased} _{commercially. In some embodiments, mRNA encoding Streptococcus pyogenes SF370 Cas9} protein is purchased from TriLink BioTechnologies LLC, and has the sequence given in SEQ ID NO:15. Template DNA is synthesized chemically and/or obtained commercially. _{P6797PC00 – 244 –} Embodiment 1: Polyplex comprising LPEI-l-[N3:DBCO]-PEG36-hEGF and SpCas9 mRNA S_{tock solutions of LPEI-l-[N3:DBCO]-PEG36-hEGF and SpCas9 mRNA are each} _{diluted with HBT, HBG, 5% glucose or HBS to the appropriate concentrations for the selected} N/P ratio prior to mixing. The diluted triconjugate solution is added to an equal volume of _{SpCas9 mRNA solution and mixed vigorously. The mixture is incubated at RT for 30 min for} polyplex formation prior to use. Five preparations are made at an N/P ratio of 4, with final concentrations of 0.2 μg/mL, _{0.4 μg/mL, 0.6 μg/mL, 0.8 μg/mL, 1.0 μg/mL, of SpCas9 mRNA in the polyplex preparation} (total volume in 96-well: 100 μL). Five additional preparations are made at an N/P ratio of 6, with final concentrations of 0.2 μg/mL, 0.4 μg/mL, 0.6 μg/mL, 0.8 μg/mL, 1.0 μg/mL, of _{SpCas9 mRNA in the polyplex preparation (total volume in 96-well: 100 μL).} Embodiment 2: Polyplex comprising LPEI-l-[N3:DBCO]-PEG36-hEGF, SpCas9 mRNA, and mTTR sgRNA. A_{stock solution of LPEI-l-[N3:DBCO]-PEG36-hEGF is diluted with HBT, HBG, 5%} glucose or HBS to the appropriate concentration for the selected N/P ratio prior to mixing. A second stock solution comprising SpCas9 mRNA and mTTR sgRNA (ratio: 1:1 w/w) is diluted _{with HBT, HBG, 5% glucose or HBS to the appropriate concentration for the selected N/P ratio} prior to mixing. The diluted triconjugate solution is added to an equal volume of SpCas9 mRNA and mTTR sgRNA solution and mixed vigorously. The mixture is incubated at RT for 30 min for polyplex formation prior to use. Five preparations are made at an N/P ratio of 4, with final concentrations of 0.2 μg/mL, 0.4 μg/mL, 0.6 μg/mL, 0.8 μg/mL, 1.0 μg/mL, of total mRNA (i.e., SpCas9 mRNA and mTTR sgRNA) in the polyplex preparation (total volume in 96-well: 100 μL). Five additional preparations are made at an N/P ratio of 6, with final concentrations of 0.2 μg/mL, 0.4 μg/mL, 0.6 μg/mL, 0.8 μg/mL, 1.0 μg/mL, of total mRNA (i.e., SpCas9 mRNA and mTTR sgRNA) in the polyplex preparation (total volume in 96-well: 100 μL). Embodiment 3: Polyplex comprising LPEI-l-[N3:DBCO]-PEG36-hEGF, SpCas9 mRNA, mTTR sgRNA, and template DNA. A_{stock solution of LPEI-l-[N3:DBCO]-PEG36-hEGF is diluted with HBT, HBG, 5%} glucose or HBS to the appropriate concentration for the selected N/P ratio prior to mixing. A _{P6797PC00 – 245 –} second stock solution comprising SpCas9 mRNA, mTTR sgRNA, and template DNA (ratio: _{1:1:1 w/w/w) is diluted with HBT, HBG, 5% glucose or HBS to the appropriate concentration} for the selected N/P ratio prior to mixing. The diluted triconjugate solution is added to an equal _{volume of nucleic acid (i.e., SpCas9 mRNA, mTTR sgRNA, and template DNA) solution and} mixed vigorously. The mixture is incubated at RT for 30 min for polyplex formation prior to use. Five preparations are made at an N/P ratio of 4, with final concentrations of 0.2 μg/mL, 0.4 μg/mL, 0.6 μg/mL, 0.8 μg/mL, 1.0 μg/mL, of total mRNA (i.e., SpCas9 mRNA, mTTR sgRNA, and template DNA) in the polyplex preparation (total volume in 96-well: 100 μL). Five additional preparations are made at an N/P ratio of 6, with final concentrations of 0.2 μg/mL, 0.4 μg/mL, 0.6 μg/mL, 0.8 μg/mL, 1.0 μg/mL, of total mRNA (i.e., SpCas9 mRNA, mTTR sgRNA, and template DNA) in the polyplex preparation (total volume in 96-well: 100 μL). Embodiment 4: Polyplex comprising LPEI-l-[N3:DBCO]-PEG36-hEGF and mTTR sgRNA Stock solutions of LPEI-l-[N₃:DBCO]-PEG₃₆-hEGF and mTTR sgRNA are each _{diluted with HBT, HBG, 5% glucose or HBS to the appropriate concentrations for the selected} N/P ratio prior to mixing. The diluted triconjugate solution is added to an equal volume of SpCas9 mRNA solution and mixed vigorously. The mixture is incubated at RT for 30 min for polyplex formation prior to use. F_{ive preparations are made at an N/P ratio of 4, with final concentrations of 0.2 μg/mL,} 0.4 μg/mL, 0.6 μg/mL, 0.8 μg/mL, 1.0 μg/mL, of mTTR sgRNA in the polyplex preparation (total volume in 96-well: 100 μL). Five additional preparations are made at an N/P ratio of 6, with final concentrations of 0.2 μg/mL, 0.4 μg/mL, 0.6 μg/mL, 0.8 μg/mL, 1.0 μg/mL, of mTTR sgRNA in the polyplex preparation (total volume in 96-well: 100 μL). Embodiment 5: Polyplex comprising LPEI-l-[N3:DBCO]-PEG36-hEGF and template DNA Stock solutions of LPEI-l-[N3:DBCO]-PEG36-hEGF and template DNA are each diluted _{with HBT, HBG, 5% glucose or HBS to the appropriate concentrations for the selected N/P} ratio prior to mixing. The diluted triconjugate solution is added to an equal volume of template DNA solution and mixed vigorously. The mixture is incubated at RT for 30 min for polyplex formation prior to use. Five preparations are made at an N/P ratio of 4, with final concentrations of 0.2 μg/mL, _{P6797PC00 – 246 –} 0.4 μg/mL, 0.6 μg/mL, 0.8 μg/mL, 1.0 μg/mL, of template DNA in the polyplex preparation (total volume in 96-well: 100 μL). Five additional preparations are made at an N/P ratio of 6, with final concentrations of 0.2 μg/mL, 0.4 μg/mL, 0.6 μg/mL, 0.8 μg/mL, 1.0 μg/mL, of template DNA in the polyplex preparation (total volume in 96-well: 100 μL). Embodiment 6: Mixture of polyplexes comprising LPEI-l-[N₃:DBCO]-PEG₃₆-hEGF and SpCas9 mRNA; and polyplexes comprising LPEI-l-[N3:DBCO]-PEG36-hEGF and mTTR sgRNA. A_{preparation of polyplexes comprising LPEI-l-[N3:DBCO]-PEG36-hEGF and SpCas9} _{mRNA (Embodiment 1) is added to an equal volume of polyplexes comprising LPEI-l-} [N3:DBCO]-PEG36-hEGF and mTTR sgRNA (Embodiment 4) and stirred. Appropriate _{volumes of polyplex preparations are combined such that the final ratio of SpCas9 mRNA to} _{mTTR sgRNA is 1:1 (w/w). Appropriate preparations of polyplexes are selected to ensure the} same N/P ratio (e.g., 4 or 6) and the same concentration of total nucleic acid (e.g., 0.2 μg/mL, 0.4 μg/mL, 0.6 μg/mL, 0.8 μg/mL, 1.0 μg/mL) of the combined polyplex preparations. Embodiment 7: Mixture of polyplexes comprising LPEI-l-[N₃:DBCO]-PEG₃₆-hEGF, SpCas9 mRNA, and mTTR sgRNA; and polyplexes comprising LPEI-l-[N3:DBCO]-PEG36- hEGF and template DNA. A_{preparation of polyplexes comprising LPEI-l-[N3:DBCO]-PEG36-hEGF, SpCas9} _{mRNA, and mTTR sgRNA (Embodiment 2) is added to an equal volume of polyplexes} _{comprising LPEI-l-[N3:DBCO]-PEG36-hEGF and template DNA (Embodiment 5) and stirred.} Appropriate volumes of polyplex preparations are combined such that the final ratio of SpCas9 _{mRNA to mTTR sgRNA to template DNA is 1:1:1 (w/w/w). Appropriate preparations of} polyplexes are selected to ensure the same N/P ratio (e.g., 4 or 6) and the same concentration of total nucleic acid (e.g., 0.2 μg/mL, 0.4 μg/mL, 0.6 μg/mL, 0.8 μg/mL, 1.0 μg/mL) of the combined polyplex preparations. Embodiment 8: Mixture of polyplexes comprising LPEI-l-[N₃:DBCO]-PEG₃₆-hEGF and SpCas9 mRNA; polyplexes comprising LPEI-l-[N3:DBCO]-PEG36-hEGF and mTTR sgRNA; and polyplexes comprising LPEI-l-[N₃:DBCO]-PEG₃₆-hEGF and template DNA. Three separate preparations of polyplexes comprising (i) LPEI-l-[N₃:DBCO]-PEG₃₆- hEGF and SpCas9 mRNA (Embodiment 1); LPEI-l-[N3:DBCO]-PEG36-hEGF and mTTR sgRNA (Embodiment 4); and (iii) LPEI-l-[N₃:DBCO]-PEG₃₆-hEGF and template DNA (Embodiment 5) are combined together in equal volume and stirred. Appropriate volumes of _{P6797PC00 – 247 –} polyplex preparations are combined such that the final ratio of SpCas9 mRNA to mTTR sgRNA to template DNA is 1:1:1 (w/w/w). Appropriate preparations of polyplexes are selected to ensure the same N/P ratio (e.g., 4 or 6) and the same concentration of total nucleic acid (e.g., 0.2 μg/mL, 0.4 μg/mL, 0.6 μg/mL, 0.8 μg/mL, 1.0 μg/mL) of the combined polyplex preparations. The polyplexes are further characterized with respect to particle size distribution and ζ- potential. Physico-chemical characterization by Dynamic Light Scattering (DLS) of polyplexes comprising various mRNA and various inventive triconjugates shows a mean Z-average diameter in the range between about 50 nm and about 200 nm low monodispersity, preferably _{with a PDI value <0.3. In all samples positive mean ζ-potential in the range of about 15 mV to} _{about 60 mV is observed. The polyplexes are further characterized with respect to encapsulation} _{efficiency using a RiboGreen RNA assay (see Goldsmith et al, Nature Comm. 2018, 9: 4493 |} DOI: 10.1038/s41467-018-06936-1). The polyplexes show high encapsulation efficiency of the nucleic acids. EXAMPLE 6 _{SELECTIVE GENE EDITING OF TTR USING THE INVENTIVE POLYPLEXES} TARGETING EGFR-EXPRESSING CELLS The efficiency and selectivity of gene disruption by LPEI-l-[N3:DBCO]-PEG36-hEGF _{polyplexes comprising SpCas9 mRNA and mTTR sgRNA (see Embodiment 2) in cells (e.g.,} _{BT-20, HUH7, RENCA-EGFR, Neuro2A-EGFR) will be assessed by quantifying the percent} of gene-edited TTR genomic sequences by sequence analysis. Cells in 90 μL media are incubated with 10x formulated polyplexes in 10 μL to achieve final concentrations of 0.2 μg/mL, 0.4 μg/mL, 0.6 μg/mL, 0.8 μg/mL, and 1.0 μg/mL total nucleic acid (SpCas9 mRNA). The cells are incubated at 37°C, 5% CO₂ in a humidified _{incubator for 48-72 hr.} As a control for the effect of the inventive triconjugates, cells are transfected with SpCas9 mRNA and mTTR gRNA (1:1 w/w ratio) at 1 μg/mL using MessengerMax^TM transfection _{reagent (purchased from ThermoFisher Scientific®). As a control, cells will be treated with} vehicle alone. Appropriate primers for the genomic target region and readout assay of interest are designed and confirmed by end-point PCR on genomic DNA isolated from both engineered cell lines followed by amplicon study on agarose gels. Genomic DNA is isolated from cells, _{P6797PC00 – 248 –} followed by QC and amplification of the region around the estimated editing site by PCR. Mismatch efficacy is measured by genome sequencing and/or T7E1 assay. All data is generated in biological quadruplicates. A second assay is performed as described above using the mixture of polyplexes comprising LPEI-l-[N₃:DBCO]-PEG₃₆-hEGF and SpCas9 mRNA; and polyplexes comprising LPEI-l-[N3:DBCO]-PEG36-hEGF and mTTR sgRNA (embodiment 6). EXAMPLE 7 POLYPLEX FORMATION, POLYPLEX SIZING AND ZETA POTENTIAL MEASUREMENTS General Procedure for Polyplex Formation with mRNA. For the preparation of preferred polyplexes, the LPEI-l-[N3:DBCO]-PEG36-hEGF triconjugate of Example 1 was complexed with Cas9 mRNA and mouse sgTTR at N/P ratios _{of 6, 8 and 12 in HBT (HEPES-buffered Trehalose pH 7.0). Nitrogen to phosphorus (N/P) ratios} were calculated based on the nitrogen content in the LPEI portion of the LPEI-l-[N₃:DBCO]- PEG36-hEGF triconjugate being used and the phosphorus content in the RNA. sgRNA targeting the mouse transthyretin (mTTR) gene (X22881) was synthesized chemically. The complete sgRNA sequence, including the scaffold and modifications, is given below: 5’-ususasCAGCCAC GUCUACAGCA GUUUUAGAgc uagaaauagc AAGUUAAAAU AAGGCUAGUC CGUUAUCAac uugaaaaagu ggcaccgagu cggugcusususu-3’ (SEQ ID NO: 13), wherein “s” indicates phosphorothioate backbone modification; “n” indicates 2’-O-methyl residues; and “N” indicates standard ribonucleotides. The guide sequence of the sgRNA targeting the mouse transthyretin (mTTR) gene is given below: 5'-UUACAGCCACGUCUACAGCA-3' (SEQ ID NO: 14). Cas9 mRNA was purchased from TriLink Biotechnologies (Cat. no: L-8106) or PackGene (Cat. No: 9009-85-2). The sgRNA for mouse TTR (mTTR sgRNA) was synthesized by Axolabs (Kulmbach, Germany). Embodiment 1: Polyplex comprising LPEI-l-[N₃:DBCO]-PEG₃₆-hEGF, Cas9 mRNA, and mTTR sgRNA. A stock solution of LPEI-l-[N3:DBCO]-PEG36-hEGF was diluted with HBT to the _{P6797PC00 – 249 –} appropriate concentration for the selected N/P ratio (6, 8 or 12) prior to mixing. A second stock _{solution comprising Cas9 mRNA and mTTR sgRNA at the concentrations indicated below} (ratio: 1:1 w/w) was diluted with HBT to the appropriate concentration for the selected N/P ratio (6, 8 or 12) prior to mixing. The diluted triconjugate solution was added to an equal _{volume of solution containing Cas9 mRNA and mTTR sgRNA and mixed vigorously. The} mixture was incubated at RT for 30 min for polyplex formation prior to use. Table 7. Amounts of Triconjugate and mRNA used in Embodiment 1 _{N/P ratio 6 8 12} _{Conc of mRNA+sgRNA (mg/mL) 0.25 0.5 0.25 0.5 0.25 0.5} Conc of LPEI-l-[N3:DBCO]-PEG36- _{0.195 0.39 0.26 0.52 0.39 0.78} hEGF (mg/mL) Embodiment 2: Polyplex comprising LPEI-l-[N3:DBCO]-PEG36-hEGF, and Cas9 mRNA. A stock solution of LPEI-l-[N₃:DBCO]-PEG₃₆-hEGF was diluted with HBT to the appropriate concentration for the selected N/P ratio (6, 8 or 12) prior to mixing. A second stock solution comprising Cas9 mRNA at the concentrations indicated below was diluted with HBT to the appropriate concentration for the selected N/P ratio (6, 8 or 12) prior to mixing. The diluted triconjugate LPEI-l-[N3:DBCO]-PEG36-hEGF solution was added to an equal volume of Cas9 mRNA solution and mixed vigorously. The mixture was incubated at RT for 30 min for polyplex formation prior to use. Table 8. Amounts of Triconjugate and mRNA used in Embodiment 2 _{N/P ratio 6 8 12} _{Conc of mRNA (mg/mL) 0.25 0.5 0.25 0.5 0.25 0.5} Conc of LPEI-l-[N₃:DBCO]-PEG₃₆- _{0.195 0.39 0.26 0.52 0.39 0.78} hEGF (mg/mL) Physico-chemical characterization by Dynamic Light Scattering (DLS) of polyplexes comprising various mRNA and various inventive triconjugates showed a mean Z-average diameter in the range between about 150 nm and about 200 nm and low monodispersity, with a PDI value <0.3. In all samples positive mean ζ-potential in the range of 37-42 mV was _{observed (Table 9). The polyplexes were further characterized with respect to encapsulation} _{efficiency using a RiboGreen RNA assay (see Goldsmith et al, Nature Comm. 2018, 9: 4493 |} _{P6797PC00 – 250 –} DOI: 10.1038/s41467-018-06936-1). The polyplexes showed high encapsulation efficiency (≥ _{97%) of the nucleic acids (Table 10). Similar data was obtained with polyplexes of Embodiment} 2. Table 9: Particle size (nm), polydispersity (PDI), and ζ-potential (mV) P_{olyplexes Z-average PDI Zeta potential (mV)} (nm) N_{/P 6 at 0.25 mg/mL 153±2.1 0.12±0.02 37±0.4} _{N/P 8 at 0.25 mg/mL 161±0.7 0.11±0.01 39±0.4} _{N/P 12 at 0.25 mg/mL 144±1.5 0.18±0.02 42±0.8} _{N/P 6 at 0.5 mg/mL 206±4.3 0.28±0.01 37±1.0} _{N/P 8 at 0.5 mg/mL 159±2.4 0.14±0.02 39±0.3} _{N/P 12 at 0.5 mg/mL 148±4.1 0.17±0.01 42±0.9} _{Table 9 shows Z-average hydrodynamic diameter (nm), polydispersity index (PDI), and} _{ζ-potential (mV) measured by Dynamic Light Scattering (DLS), of polyplexes generated with} LPEI-l-[N3:DBCO]-PEG36-hEGF, and Cas9 mRNA and mouse sgTTR (Embodiment 1) at the indicated formulation concentration (0.25 or 0.5 mg/mL), in HBT and at the indicated N/P ratios (6, 8 or 12). Values are presented as Average ± Standard deviation (n=3). FIG 1 shows exemplary DLS back scatter plots (prepared in triplicate) of polyplexes generated with LPEI-l-[N3:DBCO]-PEG36-hEGF, Cas9 mRNA and mouse sgTTR in HBT. FIG _{1A is a DLS back scatter plot of polyplexes generated with LPEI-l-[N3:DBCO]-PEG36-hEGF,} _{Cas9 mRNA and mouse sgTTR at 0.25 mg/mL and N/P 6. FIG 1B is a DLS back scatter plot} of polyplexes generated with LPEI-l-[N3:DBCO]-PEG36-hEGF, Cas9 mRNA and mouse _{sgTTR at 0. 5 mg/mL and N/P 8.} Results from the physicochemical characterization of LPEI-l-[N3:DBCO]-PEG36-hEGF CAS9 mRNA-mouse sgTTR polyplexes are summarized in Table 9. Polyplexes formulated in HBT, at N/P ratios of 6, 8 and 12, had Z-average hydrodynamic diameters in a range between _{140 nm and 206 nm and particles were found to be monodispersed (PDI <0.3) (Table 9 and} _{FIGs 1A and 1B). In all samples ζ-potential in the range of +37 mV to +42 mV was observed} (Table 9). Method: P_{article size distribution and polydispersity (Polydispersity index, PDI) of polyplexes} were measured in triplicate in quartz or disposable cuvettes using Dynamic Light Scattering _{P6797PC00 – 251 –} (DLS). Measurements were performed at 173° (back scatter) angle of detection after at least 30 s incubation at 25°C in a fixed position with automatic attenuation and measurement process. For data analysis, a general purpose analysis model was applied. ζ-Potential of polyplexes was measured using Electrophoretic Light Scattering (ELS) technique. Polyplex samples were diluted 5-fold in the formulation buffer and transferred into a folded capillary cell and measured in 3-5 replicates. For nanoparticle material, settings of polystyrene latex were used: R.I. of 1.59 and absorption of 0.01. Measurements were performed _{after at least 30 s incubation at 25°C using the auto mode.} The experimentally determined viscosity for dispersant HBT was: 1.025 mPa.s, RI: 1.33 was used for both DLS and ζ-potential. _{Table 10: Encapsulation efficiency of mRNA LPEI-l-[N3:DBCO]-PEG36-hEGF CAS 9-sgTTR} _{polyplexes measured using the RiboGreen assay} N_{/P 6 N/P 8} _{Encapsulation efficiency (%) 97.1 97.2} _{RNA Recovery (%) 99.9 102.5} _{Table 10 shows the encapsulation efficiency of RNA in LPEI-l-[N3:DBCO]-PEG36-} _{hEGF:CAS-9-sgTTR polyplexes measured using the RiboGreen assay. RNA mixtures/} combinations (Cas9 + sgTTR) with or without heparin were used for calibration. As controls, calibration curves with single RNAs with or without heparin were included. The encapsulation efficiency was calculated by comparison to untreated and disrupted polyplexes (incubated with 40 mg/mL heparin for 1 h at room temperature). L_{PEI-l-[N3:DBCO]-PEG36-hEGF - CAS-9 + sgTTR polyplexes at N/P 6 and N/P 8} showed encapsulation efficiencies >97% and RNA recovery values between 99.9-102.5%. Encapsulation efficiency results confirm that both Cas-9 and sgTTR are complexed with LPEI- l-[N3:DBCO]-PEG36-hEGF to form the polyplexes (Table 10). Methods: Encapsulation efficiency of the polyplexes was quantified using the Quant-IT _{RiboGreen RNA Assay kit (ThermoFisher Cat. No: R11490 Lot.: 2668603) according to the} manufacturer’s instructions and as previously described by (Veiga, N., Goldsmith, M., Granot, _{P6797PC00 – 252 –} Y. et al. Cell specific delivery of modified mRNA expressing therapeutic proteins to leukocytes. Nat Commun 9, 4493 (2018)). To assess unbound (free) RNA in polyplex formulations (X_RNA unbound), 100 µL of the untreated polyplex solution was directly transferred in triplicates to a 96- well plate without further dilution. To quantify total RNA, including RNA encapsulated or bound within polyplexes (X_{RNA total}), 100 µL of the polyplex formulation was mixed with 100 µL of 40 mg/mL heparin (Heparin sodium salt, PanReac AppliChem, Cat# A3004.0001) in a _{1.5 mL microcentrifuge tube. The mixture was pipetted up and down at least ten times and} incubated at room temperature for 60 minutes. After incubation, samples were diluted to a final RNA concentration of 0.5 µg/mL or further diluted to the final concentration used. A 100 µL _{aliquot of the diluted, heparin-treated sample was then transferred to the 96-well plate in} triplicates. 100 µL of a freshly prepared RiboGreen reagent was added to all wells. The plate was covered to protect from light and incubated for 10 minutes at RT. Fluorescence was measured using Biotek H1 multi-mode Reader with excitation at 485 nm and emission at 530 nm, according to the manufacturer protocol. Calibration curve preparation: Two calibration curves were prepared, a calibration curve of the intact polyplexes without heparin which was used to determine the concentration of unbound, free RNA (XRNA unbound) and the calibration curve containing heparin which is used to determine total RNA (X_{RNA total}) concentration following polyplex disruption. Encapsulation efficiency and RNA recovery were calculated as follows: Equation 1. Encapsulation Efficiency of RNA in Polyplexes ^_{^^^^^^^^^^^^ ^^^^^^^^^^ [%] =} ^_{^^^ ^^^^^}−^_{^^^ ^^^^^^^} ^ _{∗ 100} _{^^^ ^^^^^} Equation 2. Percent Recovery of RNA from Polyplexes ^_{^^ ^^^^. ^^^^^ ^^^^^^^^ ^^^^^^^^^^} _{^^^ ^^^^^^^^ [%] =} _{^^^ ∗ 100} EXAMPLE 8 SELECTIVE GENE EDITING OF TTR USING THE INVENTIVE POLYPLEXES TARGETING EGFR-OVEREXPRESSING CELLS The selectivity and efficiency of RNA delivery by LPEI-l-[N3:DBCO]-PEG36-hEGF _{P6797PC00 – 253 –} _{polyplexes comprising Cas9 mRNA and mTTR sgRNA (see Example 7, Embodiment 1) and} protein expression was assessed by western blot analysis in cells with differential expression of EGFR: in parental RENCA cells (“RENCA parental” cells with low EGFR expression) and in RESC cells (RENCA parental cells that were transfected to stably express EGFR and were selected for high EGFR expression). Selective delivery of LPEI-l-[N3:DBCO]-PEG36-hEGF:Cas9 mRNA:mTTR sgRNA polyplexes resulted in expression of the Cas9 protein in high EGFR expressing cells (RESC) at _{all the tested N/P ratios in a dose-dependent manner (FIG 2). In contrast, Cas9 expression was} _{not detected in RENCA parental cells.} Furthermore, cell survival assay demonstrated minimal cytotoxicity in the cell lines following treatment with the inventive polyplexes for 48h (FIG 3). These results demonstrate the selective delivery of Cas9 mRNA to cancer cells with high expresssion of EGFR and efficient protein translation in these cells. F_{IG 2 is a Western blot assay showing Cas9 expression in RENCA parental and RESC} cells transfected with EGFR targeting polyplexes containing Cas9 mRNA and mTTR sgRNA using polyplexes prepared at a concentration of 0.25 mg/mL and 0.5 mL. The images in FIG 2 demonstrate the detection of Cas9 protein in murine cancer cell lysates by western blot analysis. Murine cancer cell lines with differential expression of human EGFR (RENCA parental (low EGFR expression); RESC: (high EGFR expression)) were transfected with EGFR targeting polyplexes containing mRNA encoding the Cas9 protein (Trilink) and mTTR sgRNA. Selective expression of Cas9 protein by EGFR overexpressing _{cells was demonstrated. GAPDH was used as a loading control.} _{FIG 3 is a plot of percent cell survival in RENCA parental cells and RESC cells treated} for 48h with LPEI-l-[N₃:DBCO]-PEG₃₆-hEGF polyplexes comprising Cas9 mRNA and mTTR sgRNA at N/P ratios of 6 and 8, and at final concentrations from 0.5, 1 and 2 µg/mL and compared to Lipofectamine MessengerMAX (MM) containing Cas9 mRNA and mTTR sgRNA 2 µg/mL. Results in RENCA Parental cells are shown at left with bars containing diagonal stripes, and results in RESC cells are shown at right with bars shaded black. Percent cell survival was calculated relative to vehicle-treated cells (UT). Method: For the western blot analysis, 400,000 cells of murine cancer cell lines RENCA parental and RESC were seeded into 6-well plates and grown overnight at 37°C and 5% CO2. Cas9 mRNA (Trilink Biotechnology, Cat.No: L-8106-1000, SEQ ID NO: 15) and mTTR sgRNA _{P6797PC00 – 254 –} (Axolabs, X22881, SEQ ID NO: 13) were formulated with LPEI-l-[N3:DBCO]-PEG36-hEGF _{in HBT (HEPES buffered trehalose (HEPES 20 mM, Trehalose 10%)) at 0.25 or 0.5 mg/mL} (1:1 w/w ratio of Cas9 mRNA and mTTR sgRNA) as described in Example 7, Embodiment 1. The mRNA and sgRNA mix were first diluted with HBT to a total concentration of 0.5 _{or 1 mg/mL for all N/P ratios. LPEI-l-[N3:DBCO]-PEG36-hEGF was diluted with HBT to 0.39} or 0.78 mg/mL (N/P 6); 0.52 or 1.04 mg/mL (N/P 8) and 0.78 or 1.56 mg/mL (N/P 12). The diluted LPEI-l-[N3:DBCO]-PEG36-hEGF was added to the diluted mRNA+sgRNA and mixed by pipetting and incubated for 30 minutes at room temperature to form polyplexes. The polyplexes were diluted and added to the cells to obtain the indicated final concentrations (1.0 and 2.0 μg/mL) of the mRNA/sgRNA mix. Cells were lysed after 24 hours of treatment and lysates were prepared. Protein lysates were run on 4-20% Mini-PROTEAN^® TGX™ Precast Protein Gels (BioRad) before being transferred onto 0.2 µm PVDF membranes (BioRad). Cas9 protein expression was detected by an anti-Cas9 antibody (CST, Cat. No: 14697) and GAPDH (CST, Cat. No: 2188) was used as a loading control. Cell survival was analyzed in parallel to the western blot analysis.10’000 cells per well of RENCA parental or RESC were plated in triplicate in 96-well plates and incubated overnight _{at 37°C and 5% CO2. Cells were treated with the different polyplexes (formulated as above for} the western blot) at the indicated concentrations (0.5 to 2.0 μg/mL, reflecting the nucleic acid concentration in the polyplexes). After 48 hours of treatment, cell viability was quantified using CellTiter Glo® (Promega) and the signal was assessed by Synergy H1 plate reader (Biotek). _{Selective gene editing by LPEI-l-[N3:DBCO]-PEG36-hEGF polyplexes comprising Cas9} mRNA and mTTR sgRNA The efficiency and selectivity of gene disruption by LPEI-l-[N₃:DBCO]-PEG₃₆-hEGF _{polyplexes comprising Cas9 mRNA and mTTR sgRNA (see Example 7, Embodiment 1) in} RENCA Parental and RESC cells were assessed by quantifying the percentage of gene-edited _{TTR genomic sequences, as identified by sequence analysis. Only changes that resulted in} _{frameshifts, i.e. insertions or deletions of 1 or 2 base pairs, were considered.} _{Selective delivery of LPEI-l-[N3:DBCO]-PEG36-hEGF:Cas9 mRNA:mTTR sgRNA} polyplexes resulted in increased induction of frameshift mutations in high EGFR expressing cells (RESC) compared to low EGFR expressing RENCA parental cells at all the tested N/P _{ratios (Table 11 and FIG 4 (as indicated by the increase in fold-change in frameshift mutations} in RENCA EGFR (RESC) cells compared to RENCA parental)). These results demonstrate _{P6797PC00 – 255 –} _{the selective gene-editing of TTR genomic sequences in cancer cells with high expression of} EGFR. FIG 4 is a bar graph showing the fold-change in frameshift mutations in RENCA EGFR (RESC) cells compared to RENCA parental cells following treatment with the inventive polyplexes after 24 h and 48 h. _{Table 11. Percentage of Gene-Edited Sequences in RENCA Parental and RESC Cells after 24} h and 48 h N/P ratio _{N/P 6 N/P 6 N/P 6 N/P 8 N/P 8 N/P 8} MM (µg RNA/mL) (0.5) (1) (2) (0.5) (1) (2) (2) RENCA _{Parental (24 h) 0.73 2.45 3.12 0.51 1.20 1.88 11.47} _{RESC (24 h) 4.37 11.20 10.24 6.26 7.62 4.13 24.96} RENCA _{Parental (48 h) 0.79 3.00 4.31 0.78 1.86 2.86 15.75} _{RESC (48 h) 3.50 13.52 9.39 1.29 10.96 7.75 26.49} _{Table 11 shows quantification of the percentage of gene-edited TTR genomic sequences} _{of RENCA parental and RESC cells transfected with EGFR-targeting polyplexes containing} Cas9 mRNA and mTTR sgRNA or with Lipofectamine MessengerMax^TM (MM) containing _{Cas9 mRNA and mTTR sgRNA, after 24 h and 48 h. Gene-edited sequences were identified} _{by Next Generation Sequencing. Different N/P ratios and total RNA concentrations were} _{tested. FIG 4 shows the fold-change in % frameshift in RESC cells compared to RENCA} _{parental cells.} Method: 1_{0x formulated polyplexes in 10 μL were added to cells in 90 µL medium, to achieve} final concentrations of 0.5 μg/mL, 1.0 μg/mL, and 2.0 μg/mL total nucleic acid (1:1 w/w ratio of Cas9 mRNA and mTTR sgRNA). The cells were incubated at 37°C, 5% CO₂ in a humidified incubator for 24 and 48 hr. As a control, cells were transfected with Cas9 mRNA and mTTR gRNA (1:1 w/w ratio) at 2.0 μg/mL using Lipofectamine MessengerMax^TM transfection reagent (purchased from ThermoFisher Scientific^®). As additional controls, the cells were treated with vehicle (HBT alone). _{P6797PC00 – 256 –} Cells were lysed after 24 h or 48 h. Cell lysates were prepared using DirectPCR®-Cell Lysis Reagent (Viagen) as follows. Cells were washed twice with PBS.140 μL of the lysis buffer was added per well. The plate was then sealed and incubated at 55°C for 1 hr. The lysates were then transferred to 96-well PCR plates and incubated at 85°C for 45 min. DNA extraction was performed using Quick-DNA Miniprep Plus Kit (Zymo Research, D4068). Next Generation Sequencing was performed by Azenta Life Sciences using Paired- _{End, Illumina sequencing. Frame shift mutations were identified and increases over background} _{were reported.} Selective delivery of LPEI-l-[N3:DBCO]-PEG36-hEGF, and Cas9 mRNA To demonstrate delivery of Cas9 mRNA alone, polyplexes comprising LPEI-l- [N3:DBCO]-PEG36-hEGF and Cas9 mRNA were utilized (Example 7, Embodiment 2). FIG 5 is a Western blot assay showing Cas9 expression from cells transfected with EGFR- targeting polyplexes containing RNA encoding the Cas9 mRNA. Selective delivery of LPEI-l-[N₃:DBCO]-PEG₃₆-hEGF:Cas9 mRNA polyplexes induced the expression of the Cas9 protein in high EGFR expressing cells (RESC) at all the tested N/P ratios in a dose-dependent manner (FIG 5A). In contrast, lower expression of the Cas9 protein was detected in RENCA parental cells. Selective delivery of LPEI-l-[N₃:DBCO]-PEG₃₆-hEGF:Cas9 mRNA polyplexes resulted _{in expression of the Cas9 protein in high EGFR expressing cells (RESC) at all the tested N/P} _{ratios as early as 8 h (FIG 5B). Similar expression levels of Cas9 protein were detected} following transfection with Lipofectamine MessengerMax (MM). These results demonstrate that the polyplexes are as efficient in delivering Cas9 mRNA as the non-selective commercially available transfection reagent. F_{IG 5 demonstrates the detection of Cas9 protein in murine cancer cell lysates by western} _{blot analysis. In FIG 5A, murine cancer cell lines with differential expression of human EGFR} (RENCA parental (low EGFR expression); RESC (high EGFR expression)) were transfected with EGFR-targeting polyplexes containing mRNA encoding the Cas9 protein (PackGene). The 8 h and 48 h samples were run on separate gels, while the 24 h samples were run on both gels _{to allow comparison between the time points. In FIG 5B, the lysates from all the time points} from the high EGFR expressing RESC cells of FIG 5A were run on a separate gel, alongside _{control lysates from cells transfected with Lipofectamine MessengerMax containing mRNA} _{encoding the Cas9 protein (PackGene (PG) or TriLink (TL)). The N/P 12 and MM(TL) lysates} _{P6797PC00 – 257 –} were from separate experiments. Method: 400,000 cells of murine cancer cell lines RENCA parental and RESC were seeded into 6-well plates and grown overnight. Cas9 mRNA (PackGene (PG) or TriLink (TL)) was formulated with LPEI-l-[N₃:DBCO]-PEG₃₆-hEGF in HBT (HEPES buffered _{trehalose (HEPES 20mM, Trehalose 10%)) at the N/P ratios indicated in Table 12.} Table 12. Amounts of Triconjugate and mRNA used for Selective Cas9 Delivery _{N/P ratio 4 6 8} _{Conc of mRNA (mg/mL) 0.25 0.25 0.25} Conc of LPEI-l-[N3:DBCO]-PEG36- _{0.13 0.195 0.26} hEGF (mg/mL) The mRNA was first diluted with HBT to a total concentration of 0.5 mg/mL for all N/P ratios. LPEI-l-[N₃:DBCO]-PEG₃₆-hEGF was diluted with HBT to 0.26 mg/mL (N/P 4); 0.39 mg/mL (N/P 6) and 0.52 mg/mL (N/P 8). The diluted LPEI-l-[N3:DBCO]-PEG36-hEGF was added to the diluted mRNA and mixed by pipetting and incubated for 30 minutes at room temperature to form polyplexes. The polyplexes were serially diluted and added to the cells (using 10X dilution) to obtain the indicated final concentration (1.0 μg/mL) of the mRNA. Cells were lysed after 24 or 48 hours of treatment and lysates were prepared. Protein lysates were run on 8-16% Mini-PROTEAN^® TGX™ Precast Protein Gels (BioRad) before being transferred onto 0.2 µm PVDF membranes (BioRad). Cas9 protein expression was detected by an anti- Cas9 antibody (CST, Cat. No: 14697) and α-tubulin (CST, Cat. No: 2144) was used as a loading control.

Claims

_{P6797PC00 – 258 –1. A composition comprising a first polyplex, wherein said first polyplex comprises a first} _{conjugate and a first nucleic acid, and} _{wherein said first conjugate comprises:} a linear polyethyleneimine fragment comprising an alpha terminus and an omega terminus; wherein the alpha terminus of said polyethyleneimine fragment is an initiation residue; a polyethylene glycol fragment comprising a first terminal end and a second terminal end; and wherein the omega terminus of the polyethyleneimine fragment is connected to t_{he first terminal end of the polyethylene glycol fragment by a divalent covalent linking} _{group -Z-X1-, wherein -Z-X1- is not a single bond and -Z- is not an amide; and} wherein the second terminal end of the polyethylene glycol fragment is c_{onnected to a targeting fragment by a divalent covalent linking moiety X2, and} _{wherein said first nucleic acid is an mRNA encoding a Cas protein, preferably wherein} said Cas protein is Cas9. 2_{. The composition of claim 1, wherein said first conjugate is of the Formula I* or} a pharmaceutically acceptable salt, solvate, hydrate, tautomer or enantiomer thereof R_{1-(NR2-CH2-CH2)n-Z-X1-(O-CH2-CH2)m-X2-L (Formula I*);} wherein n is any integer between 1 and 1500; m is any integer between 1 and 200; R¹ is an initiation residue, wherein preferably R¹ is -H or -CH₃; R² is independently -H or an organic residue, wherein at least 80%, preferably 90%, of _{said R2 in said -(NR2-CH2-CH2)n- is H;} X¹ and X² are independently divalent covalent linking moieties; Z is a divalent covalent linking moiety wherein Z is not a single bond and Z is not - NHC(O)-; L_{is a targeting fragment, wherein preferably said targeting fragment is capable of binding} to a cell. _{P6797PC00 – 259 –} _{3. The composition of claim 1 or claim 2, wherein said first conjugate is of the Formula I,} or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or enantiomer thereof: R² L wherein: i_{s a single bond or a double bond, preferably a double bond;} n is any integer between 1 and 1500; m is any integer between 1 and 200; R¹ is an initiation residue, wherein preferably R¹ is -H or -CH3; R² is independently -H or an organic residue, wherein at least 80%, preferably wherein at l_{east 90%, of said R2 in said -(NR2-CH2-CH2)n– is H, further preferably said R2 is H;} Ring A is a 5 to 10-membered cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl, optionally substituted with one or more R^A1; R^A1 is independently selected from C₁-C₆ alkyl, C₁-C₆ alkoxy, oxo, or halogen; or two R^A1, together with the atoms to which they are attached, can combine to form one or more fused C6-C10 aryl, C₅-C₆ heteroaryl, or C₃-C₆ cycloalkyl rings, wherein each fused aryl, heteroaryl, or cycloalkyl is optionally substituted with one or more R^A2; R^A2 is independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen -SO3H, or -OSO3H; X_{1 is a divalent covalent linking moiety;} X² is a divalent covalent linking moiety; and L is a targeting fragment, wherein preferably said targeting fragment is capable of binding to a cell. _{4. The composition of any one of the claims 2 to 3, wherein said -(O-CH2-CH2)m-moiety} consists of a discrete number of repeating units m of 4 to 60, wherein preferably said d_{iscrete number m of repeating -(O-CH2-CH2)- units is 36.} _{5. The composition of any one of the claims 3 to 4, wherein said first conjugate is a} conjugate selected from: _{P6797PC00 – 260 –} R^A1 H N H X¹ X² _{6. The composition of any one of the claims 3 to 5, wherein said first conjugate is a} conjugate selected from: _{P6797PC00 – 261 –} _{P6797PC00 – 262 –} H₂ H X¹ ₂ O C _{C X2 L} Formula IE-14. _{7. The composition of any one of the claims 3 to 6, wherein said first conjugate is a} conjugate selected from: H L Formula IA-3, and L Formula IA-4. _{8. The composition of any one of the claims 3 to 6, wherein said first conjugate is a} conjugate selected from: R^A1 H N H H L Formula IB. _{9. The composition of any one of the claims 3 to 7, wherein said first conjugate is} _{P6797PC00 – 263 –} H _{O O} O L ; H _{O O} O L _{10. The composition of any one of the claims 3 to 9, wherein said first conjugate is} H _{O O} O ; H _{O O} O _{P6797PC00 – 264 –} _{O O} O . _{11. The composition of any one of the preceding claims, wherein said first polyplex} comprises a second nucleic acid, wherein said second nucleic acid is a gRNA. _{12. The composition of claim 11, wherein a ratio of said first nucleic acid to said second} _{nucleic acid is 1:1 (w/w).} _{13. The composition of any one of the preceding claims, wherein said first polyplex} comprises a third nucleic acid, preferably wherein said third nucleic acid is a template DNA. _{14. The composition of any one of claims 1 to 10, wherein said composition comprises a} second polyplex, wherein said second polyplex comprises a second conjugate and a second nucleic acid, wherein said second conjugate comprises: a linear polyethyleneimine fragment comprising an alpha terminus and an omega terminus; wherein the alpha terminus of said polyethyleneimine fragment is an initiation residue; a polyethylene glycol fragment comprising a first terminal end and a second terminal end; and wherein the omega terminus of the polyethyleneimine fragment is connected to the first terminal end of the polyethylene glycol fragment by a divalent covalent linking group - Z_{-X1-, wherein -Z-X1- is not a single bond and -Z- is not an amide; and} wherein the second terminal end of the polyethylene glycol fragment is connected to a targeting fragment by a divalent covalent linking moiety X², and wherein said second nucleic acid is a gRNA. _{15. The composition of claim 14, wherein a ratio of the first nucleic acid to the second} nucleic acid is 1:1 (w/w). _{P6797PC00 – 265 –} _{16. The composition of any one of claims 14 to 15, wherein said first polyplex comprises a} third nucleic acid, wherein said third nucleic acid is a template DNA. _{17. The composition of any one of claims 14 to 15, wherein said second polyplex comprises} a third nucleic acid, wherein said third nucleic acid is a template DNA. _{18. The composition of any one of claims 14 to 15, wherein said composition comprises a} third polyplex, wherein said third polyplex comprises a third conjugate and a third nucleic acid, wherein said third conjugate comprises: a linear polyethyleneimine fragment comprising an alpha terminus and an omega terminus; wherein the alpha terminus of said polyethyleneimine fragment is an initiation residue; a polyethylene glycol fragment comprising a first terminal end and a second terminal end; and wherein the omega terminus of the polyethyleneimine fragment is connected to the first terminal end of the polyethylene glycol fragment by a divalent covalent linking group - Z_{-X1-, wherein -Z-X1- is not a single bond and -Z- is not an amide; and} wherein the second terminal end of the polyethylene glycol fragment is connected to a targeting fragment by a divalent covalent linking moiety X², and wherein said third nucleic acid is a template DNA. _{19. The composition of any one of the preceding claims, wherein an N/P ratio of the} composition is 4 or 6. _{20. The composition of any one of the preceding claims, for use in a method of inserting,} _{altering, or modifying a gene and/or altering or modifying its expression in a subject.}