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WO2024263721A1 - Estrogen receptor compositions and methods of use thereof - Google Patents

Estrogen receptor compositions and methods of use thereof Download PDF

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Publication number
WO2024263721A1
WO2024263721A1 PCT/US2024/034742 US2024034742W WO2024263721A1 WO 2024263721 A1 WO2024263721 A1 WO 2024263721A1 US 2024034742 W US2024034742 W US 2024034742W WO 2024263721 A1 WO2024263721 A1 WO 2024263721A1
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Prior art keywords
erβ
nucleic acid
cancer
mrna
composition
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French (fr)
Inventor
Christoforos THOMAS
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Methodist Hospital
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Methodist Hospital
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/177—Receptors; Cell surface antigens; Cell surface determinants
    • A61K38/1796—Receptors; Cell surface antigens; Cell surface determinants for hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • A61K48/005—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'active' part of the composition delivered, i.e. the nucleic acid delivered
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • A61K48/0075—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the delivery route, e.g. oral, subcutaneous
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/72—Receptors; Cell surface antigens; Cell surface determinants for hormones
    • C07K14/721—Steroid/thyroid hormone superfamily, e.g. GR, EcR, androgen receptor, oestrogen receptor
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
    • C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/87—Introduction of foreign genetic material using processes not otherwise provided for, e.g. co-transformation
    • C12N15/88—Introduction of foreign genetic material using processes not otherwise provided for, e.g. co-transformation using microencapsulation, e.g. using amphiphile liposome vesicle
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/5123—Organic compounds, e.g. fats, sugars

Definitions

  • compositions comprising nucleic acid delivery vehicles encoding the estrogen receptor beta (ER ⁇ ), and methods of treating and/or preventing diseases or disorders with ER ⁇ dysregulated function.
  • ER ⁇ estrogen receptor beta
  • BACKGROUND The physiological functions of estrogen and estrogen derived compounds are propagated through the estrogen receptors subtypes alpha (ER ⁇ ) and beta (ER ⁇ ).
  • ER ⁇ is reported to have profound effects on the reproductive, central nervous, and immune systems contributing to differentiation of cells such as the breast, uterus, ovarian and prostate.
  • dysregulation of ER ⁇ expression and/or function has been implicated in various diseases and disorders, including cancer, neuropathies and neurodegenerative disorders, cardiovascular diseases, osteoporosis, obesity, and metabolic disorders.
  • therapies to improve ER ⁇ expression and/or function are limiting.
  • the present disclosure provides a therapeutic composition comprising a nucleic acid encoding ER ⁇ .
  • the present disclosure also provides methods of treating or preventing ER-related disorders, including ER ⁇ -related disorders using a therapeutic composition comprising a nucleic acid encoding ER ⁇ .
  • a therapeutic composition comprising a nucleic acid encoding estrogen receptor beta (ER ⁇ ), wherein the nucleic acid is encapsulated in or conjugated to a nucleic acid delivery vehicle.
  • the nucleic acid delivery vehicle comprises a pharmaceutically acceptable carrier selected from a lipid nanoparticle (LPN), a lipid carrier, an organic polymer, a cell, a virus-like particle, an excipient, a diluent, a salt, a buffer, or a stabilizer.
  • the nucleic acid comprises mRNA.
  • the nucleic acid comprises at least 80% identity to SEQ ID NO: 1 or SEQ ID NO: 2.
  • the nucleic acid comprises at least 90% identity to SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, the nucleic acid comprises SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, the mRNA comprises a full-length mRNA. In some embodiments, the mRNA comprises a functional fragment of the full-length mRNA. In some embodiments, the LPN comprises a solid lipid nanoparticle, a nanostructured lipid carrier, or any variations thereof. In some embodiments, the lipid carrier comprises a liposome, a liposome-like nanoparticle, a lipid-polymer hybrid nanoparticle, a nanoemulsion, an exosome, a lipoprotein particle, or any combinations thereof.
  • the organic polymer comprises a polypeptide or peptide, a nucleic acid , a lipid, a carbohydrate, or any combinations thereof.
  • the cell comprises a dendritic cell.
  • the virus- like particle comprises one or more non-infectious components from a virus selected from Human immunodeficiency virus (HIV), Influenza virus, Hepatitis B virus, Hepatitis E virus, Ebola virus, Severe acute respiratory syndrome coronavirus (SARS-CoV), SARS-CoV-2, Respiratory syncytial virus (RSV), Human papillomavirus (HPVs), and Middle east respiratory syndrome coronavirus (MERS-CoV).
  • HAV Human immunodeficiency virus
  • Influenza virus Hepatitis B virus
  • Hepatitis E virus Ebola virus
  • SARS-CoV Severe acute respiratory syndrome coronavirus
  • SARS-CoV-2 Severe acute respiratory syndrome coronavirus
  • RSV Respiratory sy
  • the composition comprises a naked nucleic acid encoding an ER ⁇ protein.
  • the nucleic acid comprises one or more chemical modifications to increase stability of the nucleic acid encoding ER ⁇ .
  • the one or more chemical modifications are selected from a 5’-7-methylguanosine cap, a 5’ untranslated region 5’ UTR, a 3’ UTR, a modification to the open reading frame (ORF), and a poly-adenylate tail.
  • a method of treating or preventing an ER ⁇ -related disorder in a subject in need thereof comprising administering a pharmaceutically effective amount of a composition comprising a nucleic acid encoding ER ⁇ , wherein the nucleic acid is encapsulated in or conjugated to a nucleic acid delivery vehicle, wherein the method increases expression of a ER ⁇ protein in the subject relative to an untreated subject with cancer.
  • a method of treating or preventing tumor development in a subject with cancer comprising administering a pharmaceutically effective amount of a composition comprising a nucleic acid encoding ER ⁇ , wherein the nucleic acid is encapsulated in or conjugated to a nucleic acid delivery vehicle, wherein the method increases expression of a ER ⁇ protein in the subject relative to an untreated subject with cancer.
  • a method of treating or preventing a metastasis in a subject comprising administering a pharmaceutically effective amount of a composition comprising a nucleic acid encoding ER ⁇ , wherein the nucleic acid is encapsulated in or conjugated to a nucleic acid delivery vehicle, and wherein the method increases expression of a ER ⁇ protein in the subject relative to an untreated subject with a metastasis.
  • the nucleic acid delivery vehicle comprises a pharmaceutically acceptable carrier selected from a lipid nanoparticle (LPN), a lipid carrier, an organic polymer, a cell, a virus-like particle, an excipient, a diluent, a salt, a buffer, or a stabilizer.
  • the nucleic acid comprises mRNA.
  • the mRNA comprises a full-length mRNA.
  • the mRNA comprises a functional fragment of the full-length mRNA.
  • the nucleic acid comprises one or more chemical modifications to increase stability of the nucleic acid encoding ER ⁇ .
  • the one or more chemical modifications are selected from a 5’-7-methylguanosine cap, a 5’ untranslated region 5’ UTR, a 3’ UTR, a modification to the open reading frame (ORF), and a poly-adenylate tail.
  • the composition is administered intratumorally or intravenously.
  • the ER ⁇ -related disorder comprises a cancer selected from a breast cancer, an ovarian cancer, a uterine cancer, vaginal cancer, vulvar cancer, cervical cancer, urethral Docket No.10063-085WO1 cancer, a prostate cancer, colorectal cancer, bladder cancer, thyroid cancer, or cancers affecting a tissue from a reproductive, gastrointestinal, or urinary system.
  • the breast cancer comprises inflammatory breast cancer (IBC), Triple-Negative Breast Cancer (TNBC), HER2-positive breast cancer, or Hormone Receptor-(HR)-positive breast cancer.
  • the LPN comprises a solid lipid nanoparticle, a nanostructured lipid carrier, or any variations thereof.
  • the lipid carrier comprises a liposome, a liposome-like nanoparticle, a lipid-polymer hybrid nanoparticle, a nanoemulsion, an exosome, a lipoprotein particle, or any combinations thereof.
  • the organic polymer comprises a polypeptide or peptide, a nucleic acid, a lipid, a carbohydrate, or any combinations thereof.
  • the cell comprises a dendritic cell.
  • the virus- like particle comprises one or more non-infectious components from a virus selected from Human immunodeficiency virus (HIV), Influenza virus, Hepatitis B virus, Hepatitis E virus, Ebola virus, Severe acute respiratory syndrome coronavirus (SARS-CoV), SARS-CoV-2, Respiratory syncytial virus (RSV), Human papillomavirus (HPVs), and Middle east respiratory syndrome coronavirus (MERS-CoV).
  • the composition comprises a naked nucleic acid encoding an ER ⁇ protein.
  • the ER ⁇ protein targets one or more metastasis- and cancer progression-associated genes selected from CD36, TGFb, TGFbR2, ALDH1A1, ELMO1, ILR1, IL6, IL8, IL1, IL17, CCL2, GPR141, CREB1, TFF1, FN1, NRG1, LCN2, VTCN1, FST1, NRP1, RHOBTB3.
  • the composition is administered at a dose of at least 2 ⁇ g of ER ⁇ nucleic acid.
  • the composition is administered for at least one week.
  • the composition is administered at least once per week.
  • the composition is administered in combination with an adjuvant.
  • the composition is administered in combination with an additional therapeutic composition.
  • the additional therapeutic composition comprises an anti-cancer agent, a chemotherapeutic agent, an anti-inflammatory agent, or a combination thereof.
  • the anti-cancer agent comprises an interferon, a cytokine, a vaccine, a growth factor, an antibody or serotherapy, or an immunomodulatory agent.
  • the chemotherapeutic agent comprises a luteinizing hormone releasing hormone (LHRH), anti- androgens, endocrine therapy, aromatase inhibitors, anti-estrogens, photodynamic therapies, nitrogen mustards, nitrosoureas, metal containing compounds, nucleotide analogs, anti- metabolites, or a cancer suppressing agent.
  • LHRH luteinizing hormone releasing hormone
  • the method decreases the growth of cancer cells, the stemness of cancer cells, or the invasiveness of cancer cells in the subject relative to an untreated subject with an ER ⁇ -related disorder.
  • the method enhances cancer-associated immune response in the subject relative to an untreated subject with an ER ⁇ -related disorder.
  • kits comprising a nucleic acid encoding an estrogen receptor beta (ER ⁇ ), wherein the nucleic acid is encapsulated in or conjugated to a nucleic acid delivery vehicle.
  • the nucleic acid comprises mRNA.
  • the mRNA comprises a full-length mRNA.
  • the mRNA comprises a functional fragment of the full-length mRNA.
  • the nucleic acid comprises one or more chemical modifications to increase stability of the nucleic acid encoding ER ⁇ .
  • the one or more chemical modifications are selected from a 5’-7-methylguanosine cap, a 5’ untranslated region 5’ UTR, a 3’ UTR, a modification to the open reading frame (ORF), and a poly-adenylate tail.
  • the nucleic acid delivery vehicle comprises a pharmaceutically acceptable carrier selected from a lipid nanoparticle (LPN), a lipid carrier, an organic polymer, a virus-like particle, or a stabilizer.
  • the kit further comprises an RNase-free reagent selected from RNase-free water, RNase-free buffered solution, and RNase-free saline.
  • FIGS. 1A, 1B, and 1C show that ER ⁇ inhibits metastasis in inflammatory breast cancer (IBC).
  • FIG.1A shows the Kaplan-Meier estimates of metastasis-free survival and overall survival of patients with IBC.
  • FIG. 1B shows the invasion of cells with different ER ⁇ levels in Transwell chambers. Graph indicates the mean (cell number per field).
  • FIG. 1C shows the whole-body bioluminescence images of NCG mice that were intravenously injected with KPL4 cells with different ER ⁇ levels.
  • FIG. 2 shows the effects of ER ⁇ mRNA in tumor development after intratumoral administration.
  • FIGS. 3A, 3B, 3C, and 3D show the tissue distribution of luciferase mRNA after intratumoral and intravenous administration.
  • FIGS.3A and 3B show the in vivo bioluminescence imaging of mice 2 and 4 days after intratumoral injection of complexes of 5 ⁇ g (left side tumor) and 10 ⁇ g (right side tumor) luciferase mRNA with LNPs.
  • Arrows indicate signal indicative of mRNA expression in sites of orthotopically implanted tumors.
  • FIGS.3C and 3D show the in vivo bioluminescence imaging (C: whole body, D: tumor area) of mice 1 and 3 days after intravenous administration of complexes of increasing concentrations (mouse 1: 5 ⁇ g, mouse 2: 10 ⁇ g, mouse 3: 10 ⁇ g and mouse 4: 15 mg) of luciferase mRNA with LNPs.
  • FIG. 4B shows the kinetics of GFPmRNA-LNPs uptake by breast cancer cells and the duration of its presence inside the cells as this is indicated by the red signal that is produced by rhodamine that is used to label the lipids in LNPs.
  • FIG.4C shows the expression of ER ⁇ protein inside breast cancer cells after incubating these cells with 0.05 ⁇ g/ml or 0.075 ⁇ g/ml concentrations of ER ⁇ mRNA- LNPs.
  • the higher the concentration of ER ⁇ mRNA that is used to treat the cells the higher the protein levels of ER ⁇ protein inside the cells.
  • GFPmRNA-LNPs is used as negative control to demonstrate the specificity of the detection method (immunoblotting) to recognize exclusively ER ⁇ .
  • FIGS.5A, 5B and 5C show that upregulation of ER ⁇ protein in breast cancer cells regulates genes that affect the immune system indicating the ability of ER ⁇ to inhibit breast cancer progression and metastasis by inducing anti-tumor immunity.
  • FIG. 5A, 5B and 5C show that upregulation of ER ⁇ protein in breast cancer cells regulates genes that affect the immune system indicating the ability of ER ⁇ to inhibit breast cancer progression and metastasis by inducing anti-tumor immunity.
  • FIG. 5A depicts the results from a Docket No.10063-085WO1 microarray analysis (gene expression analysis) of breast cancer cells with different levels of ER ⁇ and shows the altered gene expression signatures.
  • FIGS.5B and 5C indicate the different levels of mRNA of immune response-associated genes in cells with different levels of ER ⁇ .
  • FIG.6 shows differences in the development of the mammary gland (size of ductal tree) in female mice that have ER ⁇ (WT) and transgenic mice that engineered to lack ER ⁇ expression (ER ⁇ KO). This figure demonstrates the role of ER ⁇ in regulating processes during development that also play important roles in cancer.
  • FIG.7 shows the gene expression after treatment of breast cancer cells with control (GFP) or varying amounts of ER ⁇ mRNA-LNP for 48 hours. Treatment with increased amounts of ER ⁇ increases gene expression of ER ⁇ and IL6.
  • FIGS. 8A, 8B, 8C, and 8D show the effects of ER ⁇ mRNA on growth of breast cancers.
  • FIG. 8A depicts the treatment scheme of human breast tumor xenografts with ER ⁇ mRNA-LNP in a mouse breast cancer model.
  • IBC Inflammatory breast cancer
  • FIG. 8B shows in vivo bioluminescence imaging (whole body) of mice before treatment (upper panel) and after (lower panel) the completion of the treatment with mCherry mRNA-LNP (Vehicle) and ER ⁇ mRNA-LNP. Luciferase signal was adjusted separately in mice before and after treatment to indicate the differences between control and ER ⁇ mRNA treatments.
  • FIG. 8C shows the immunohistochemical analysis of the resected orthotopic breast tumors showing expression of ER ⁇ protein in tumors that were treated with ER ⁇ mRNA-LNP.
  • FIG.8D is a graph depicting tumor growth in mice with orthotopically implanted tumors during the treatment with mCherry and ER ⁇ mRNA.
  • FIG. 9 shows the analysis of mRNA levels in primary tumors. Tumors treated with ER ⁇ mRNA have increased mRNA levels of ELMO1 and ESR2 (ER ⁇ ).
  • FIGS.10A and 10B show the effects of ER ⁇ mRNA on breast cancer metastasis.
  • FIG.10A shows ex vivo bioluminescence imaging of lungs resected at endpoint, four weeks after the resection of primary tumors that were treated with mCherry mRNA (vehicle) (upper panel) and Docket No.10063-085WO1 ER ⁇ mRNA-LNP (lower panel) for the presence of metastasis.
  • FIG.10B shows a graph depicting luciferase signal indicative of metastatic burden as total flux in the resected lungs of FIG. 10A. Treatment with ER ⁇ mRNA substantially decreases lung metastasis of orthotopically grown breast tumors.
  • FIGS. 11A and 11B show the ER ⁇ expression in breast cancer.
  • FIG. 11A shows ER ⁇ expression in normal and cancer tissues across 24 tumor types from TCGA (BRCA (breast cancer), COAD (colon adenocarcinoma), KIRC (kidney and renal cell carcinoma).
  • FIG. 11B shows ER ⁇ mRNA levels in normal and malignant breast (left) and across different breast cancer subtypes (right).
  • FIG. 11A and 11B demonstrate the downregulation of ER ⁇ in breast and other types of cancer that justifies the importance of our technology with the use of ER ⁇ mRNA to restore its expression and tumor suppressor function in breast cancer.
  • DETAILED DESCRIPTION The following description of the disclosure is provided as an enabling teaching of the disclosure in its best, currently known embodiment(s).
  • data is provided in a number of different formats, and that this data represents endpoints and starting points, and ranges for any combination of the data points. For example, if a particular data point “10” and a particular data point 15 are disclosed, it is understood that greater than, greater than or equal to, less than, less than or equal to, and equal to 10 and 15 are considered disclosed as well as between 10 and 15. It is also understood that each unit between two particular units are also disclosed. For example, if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also disclosed. As used herein, the terms “may,” “optionally,” and “may optionally” are used interchangeably and are meant to include cases in which the condition occurs as well as cases in which the condition does not occur.
  • composition refers to any agent that has a beneficial biological effect.
  • beneficial biological effects include both therapeutic effects, e.g., treatment of a disorder or other undesirable physiological condition, and prophylactic effects, e.g., prevention of a disorder or other Docket No.10063-085WO1 undesirable physiological condition.
  • composition also encompass pharmaceutically acceptable, pharmacologically active derivatives of beneficial agents specifically mentioned herein, including, but not limited to, a vector, polynucleotide, cells, salts, esters, amides, proagents, active metabolites, isomers, fragments, analogs, and the like.
  • composition includes the composition per se as well as pharmaceutically acceptable, pharmacologically active vector, polynucleotide, salts, esters, amides, proagents, conjugates, active metabolites, isomers, fragments, analogs, etc.
  • a “delivery vehicle” refers to a bioactive molecule, cell, or microorganism, including, but not limited to a proteins, lipids, carbohydrates, nucleic acids, cells, bacteria, bacterial plasmids, viral vectors, virus-like particles, or any combinations or variations thereof, used to deliver or administer therapeutic compositions or therapeutic molecules into a cell, a tissue, or a subject in need thereof.
  • a “comprising”, and variations thereof as used herein is used synonymously with the term “including” and variations thereof and are open, non-limiting terms.
  • an "increase” can refer to any change that results in a greater amount of a symptom, disease, composition, condition, or activity.
  • An increase can be any individual, median, or average increase in a condition, symptom, activity, composition in a statistically significant amount.
  • the increase can be a 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100% increase so long as the increase is statistically significant.
  • a “decrease” can refer to any change that results in a smaller amount of a symptom, disease, composition, condition, or activity.
  • a substance is also understood to decrease the genetic output of a gene when the genetic output of the gene product with the substance is less relative to the output of the gene product without the substance. Also, for example, a decrease can be a change in the symptoms of a disorder such that the symptoms are less than previously observed.
  • a decrease can be any individual, median, or average decrease in a condition, symptom, activity, composition in a statistically significant amount.
  • the decrease can be a 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100% decrease so long as the decrease is statistically significant.
  • Docket No.10063-085WO1 By “reduce” or other forms of the word, such as “reducing” or “reduction,” means lowering of an event or characteristic (e.g., tumor growth). It is understood that this is typically in relation to some standard or expected value, in other words it is relative, but that it is not always necessary for the standard or relative value to be referred to.
  • “reduces tumor growth” means reducing the rate of growth of a tumor relative to a standard or a control.
  • prevent or other forms of the word, such as “preventing” or “prevention,” is meant to stop a particular event or characteristic, to stabilize or delay the development or progression of a particular event or characteristic, or to minimize the chances that a particular event or characteristic will occur. Prevent does not require comparison to a control as it is typically more absolute than, for example, reduce.
  • something could be reduced but not prevented, but something that is reduced could also be prevented.
  • something could be prevented but not reduced, but something that is prevented could also be reduced. It is understood that where reduce or prevent are used, unless specifically indicated otherwise, the use of the other word is also expressly disclosed.
  • the term “subject” refers to any individual who is the target of administration or treatment.
  • the subject can be a vertebrate, for example, a mammal.
  • the subject can be human, non-human primate, bovine, equine, porcine, canine, or feline.
  • the subject can also be a guinea pig, rat, hamster, rabbit, mouse, or mole.
  • the subject can be a human or veterinary patient.
  • patient refers to a subject under the treatment of a clinician, e.g., physician.
  • treatment refers to the medical management of a patient with the intent to cure, ameliorate, stabilize, or prevent a disease, pathological condition, or disorder.
  • This term includes active treatment, that is, treatment directed specifically toward the improvement of a disease, pathological condition, or disorder, and also includes causal treatment, that is, treatment directed toward removal of the cause of the associated disease, pathological condition, or disorder.
  • active treatment that is, treatment directed specifically toward the improvement of a disease, pathological condition, or disorder
  • causal treatment that is, treatment directed toward removal of the cause of the associated disease, pathological condition, or disorder.
  • palliative treatment that is, treatment designed for the relief of symptoms rather than the curing of the disease, pathological condition, or disorder
  • preventative treatment that is, treatment directed to minimizing or partially or completely inhibiting the development of the associated disease, pathological condition, or disorder
  • supportive treatment that is, treatment employed to supplement another specific therapy directed toward the improvement of the associated disease, pathological condition, or disorder.
  • “enhance”, “enhanced”, “enhancement”, “enhancing”, and any grammatical variations thereof as used herein refers to an act of intensifying, increasing, or further Docket No.10063-085WO1 improving the quality, value, or extent of a biological function, composition, compound, cell, or tissue.
  • amino acid includes but is not limited to amino acids contained in the group consisting of alanine (Ala or A), cysteine (Cys or C), aspartic acid (Asp or D), glutamic acid (Glu or E), phenylalanine (Phe or F), glycine (Gly or G), histidine (His or H), isoleucine (Ile or I), lysine (Lys or K), leucine (Leu or L), methionine (Met or M), asparagine (Asn or N), proline (Pro or P), glutamine (Gln or Q), arginine (Arg or R), serine (Ser or S), threonine (Thr or T), valine (Val or V), tryptophan (Trp or W), and tyrosine (Tyr or Y) residues.
  • amino acid residue also may include amino acid residues contained in the group consisting of homocysteine, 2- Aminoadipic acid, N-Ethylasparagine, 3-Aminoadipic acid, Hydroxylysine, ⁇ -alanine, ⁇ -Amino- propionic acid, allo-Hydroxylysine acid, 2-Aminobutyric acid, 3-Hydroxyproline, 4- Aminobutyric acid, 4-Hydroxyproline, piperidinic acid, 6-Aminocaproic acid, Isodesmosine, 2- Aminoheptanoic acid, allo-Isoleucine, 2-Aminoisobutyric acid, N-Methylglycine, sarcosine, 3- Aminoisobutyric acid, N-Methylisoleucine, 2-Aminopimelic acid, 6-N-Methyllysine, 2,4- Diaminobutyric acid, N-Met
  • the amide linkages of the peptides are formed from an amino group of the backbone of one amino acid and a carboxyl group of the backbone of another amino acid.
  • a “protein”, “polypeptide”, or “peptide” each refer to a polymer of amino acids and does not imply a specific length of a polymer of amino acids.
  • the terms peptide, oligopeptide, protein, antibody, and enzyme are included within the definition of polypeptide.
  • the peptides, polypeptides, and proteins disclosed herein may be modified to include non- amino acid moieties.
  • Modifications may include but are not limited to carboxylation (e.g., N- terminal carboxylation via addition of a di-carboxylic acid having 4-7 straight-chain or branched carbon atoms, such as glutaric acid, succinic acid, adipic acid, and 4,4-dimethylglutaric acid), amidation (e.g., C-terminal amidation via addition of an amide or substituted amide such as alkylamide or dialkylamide), PEGylation (e.g., N-terminal or C-terminal PEGylation via additional of polyethylene glycol), acylation (e.g., O-acylation (esters), N-acylation (amides), S- acylation (thioesters)), acetylation (e.g., the addition of an acetyl group, either at the N-terminus of the protein or at lysine residues), formylation lipoylation (e.g., attachment of a lipoate, a C8 functional
  • glycation Distinct from glycation, which is regarded as a nonenzymatic attachment of sugars, polysialylation (e.g., the addition of polysialic acid), glypiation (e.g., glycosylphosphatidylinositol (GPI) anchor formation, hydroxylation, iodination (e.g., of thyroid hormones), and phosphorylation (e.g., the addition of a phosphate group, usually to serine, tyrosine, threonine, or histidine).
  • polysialylation e.g., the addition of polysialic acid
  • glypiation e.g., glycosylphosphatidylinositol (GPI) anchor formation
  • hydroxylation e.g., iodination
  • phosphorylation e.g., the addition of a phosphate group, usually to serine, tyrosine,
  • the BLAST software suite includes various sequence analysis programs including “blastp,” that is used to align a known amino acid sequence with other amino acids sequences from a variety of databases. Percent identity may be measured over the length of an entire defined polypeptide sequence or may be measured over a shorter length, for example, over the length of a fragment taken from a larger, defined polypeptide sequence, for instance, a fragment of at least 15, at least 20, at least 30, at least 40, at least 50, at least 70 or at least 150 contiguous residues. Such lengths are exemplary only, and it is understood that any fragment length may be used to describe a length over which percentage identity may be measured.
  • “Expression” as used herein refers to the process by which information from a gene is used in the synthesis of a functional gene product that enables it to produce a peptide/protein end product, and ultimately affect a phenotype, as the final effect.
  • variant means a polypeptide derived from a parent estrogen receptor by one or more (several) alteration(s), i.e., a substitution, insertion, and/or deletion, at one or more (several) Docket No.10063-085WO1 positions.
  • a substitution means a replacement of an amino acid occupying a position with a different amino acid; a deletion means removal of an amino acid occupying a position; and an insertion means adding 1 or more, such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, preferably 1-3 amino acids immediately adjacent an amino acid occupying a position.
  • ‘immediately adjacent’ may be to the N-side (‘upstream’) or C-side (‘downstream’) of the amino acid occupying a position (‘the named amino acid’). Therefore, for an amino acid named/numbered ‘X,’ the insertion may be at position ‘X+1’ (‘downstream’) or at position ‘X ⁇ 1’ (‘upstream’).
  • a “variant” of a particular polypeptide sequence may be defined as a polypeptide sequence having at least 50% sequence identity to the particular polypeptide sequence over a certain length of one of the polypeptide sequences using blastp with the “BLAST 2 Sequences” tool available at the National Center for Biotechnology Information's website. (See Tatiana A. Tatusova, Thomas L. Madden (1999), “Blast 2 sequences—a new tool for comparing protein and nucleotide sequences”, FEMS Microbiol Lett.174:247-250).
  • a variant polypeptide may show, for example, at least 60%, at least 70%, at least 80%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% or greater sequence identity over a certain defined length relative to a reference polypeptide.
  • a variant polypeptide may have substantially the same functional activity as a reference polypeptide.
  • a variant polypeptide may exhibit or more biological activities associated with binding a ligand and/or binding DNA at a specific binding site.
  • mRNA refers to messenger ribonucleic acid, or single stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is translated by a ribosome in the process of synthesizing a protein.
  • mRNA is created during the process of transcription, where a gene is converted into a primary transcript mRNA (or pre-mRNA). The primary transcript is further processed through RNA splicing to only contain regions that will encode protein. mRNA can also be targeted for epigenetic modifications, such as methylation, to impact mRNA translation, nuclear retention, nuclear export, processing, and splicing.
  • a “nucleotide” is a compound consisting of a nucleoside, which consists of a nitrogenous base and a 5-carbon sugar, linked to a phosphate group forming the basic structural unit of nucleic acids, such as DNA or RNA.
  • the four types of nucleotides are adenine (A), cytosine (C), guanine (G), and thymine (T), each of which are bound together by a phosphodiester bond to form a nucleic acid molecule.
  • a “nucleic acid” is a chemical compound that serves as the primary information-carrying molecules in cells and make up the cellular genetic material.
  • Nucleic acids comprise nucleotides, which are the monomers made of a 5-carbon sugar (usually ribose or deoxyribose), a phosphate group, and a nitrogenous base.
  • a nucleic acid can also be a deoxyribonucleic acid (DNA) or a ribonucleic acid (RNA).
  • a “naked nucleic acid” refers to a nucleic acid that is not associated with proteins, lipids, or any other molecule to help protect it. Naked nucleic acids are the result of the release or purification of genetic information from their initial source or environment, including, but not limited to a cellular environment.
  • percent identity and “% identity,” as applied to polynucleotide sequences, refer to the percentage of residue matches between at least two polynucleotide sequences aligned using a standardized algorithm. Such an algorithm may insert, in a standardized and reproducible way, gaps in the sequences being compared in order to optimize alignment between two sequences, and therefore achieve a more meaningful comparison of the two sequences. Percent identity for a nucleic acid sequence may be determined as understood in the art. (See, e.g., U.S. Pat. No. 7,396,664, which is incorporated herein by reference in its entirety).
  • NCBI National Center for Biotechnology Information
  • BLAST Basic Local Alignment Search Tool
  • NCBI National Center for Biotechnology Information
  • BLAST 2 Sequences a tool that is used for direct pairwise comparison of two nucleotide sequences.
  • BLAST 2 Sequences can be accessed and used interactively at the NCBI website.
  • the “BLAST 2 Sequences” tool can be used for both blastn and blastp (discussed above).
  • Percent identity may be measured over the length of an entire defined polynucleotide sequence or may be measured over a shorter length, for example, over the length of a fragment taken from a larger, defined sequence, for instance, a fragment of at least 20, at least 30, at least 40, at least 50, at least 70, at least 100, or at least 200 contiguous nucleotides.
  • Such lengths are exemplary only, and it is understood that any fragment length may be used to describe a length over which percentage identity may be measured.
  • a “gene” refers to a polynucleotide containing at least one open reading frame that is capable of encoding a particular polypeptide or protein after being transcribed and translated. Any of the polynucleotides sequences described herein may be used to identify larger fragments or full- Docket No.10063-085WO1 length coding sequences of the gene with which they are associated.
  • a “gene product” refers to the amino acid (e.g., peptide or polypeptide) generated when a gene is transcribed and translated.
  • a “full length” polynucleotide sequence is one containing at least a translation initiation codon (e.g., methionine) followed by an open reading frame and a translation termination codon.
  • a “full length” polynucleotide sequence encodes a “full length” polypeptide sequence.
  • a “variant,” “mutant,” or “derivative” of a particular nucleic acid sequence may be defined as a nucleic acid sequence having at least 50% sequence identity to the particular nucleic acid sequence over a certain length of one of the nucleic acid sequences using blastn with the “BLAST 2 Sequences” tool available at the National Center for Biotechnology Information's website. (See Tatiana A. Tatusova, Thomas L. Madden (1999), “Blast 2 sequences—a new tool for comparing protein and nucleotide sequences”, FEMS Microbiol Lett.174:247-250).
  • a variant polynucleotide may show, for example, at least 60%, at least 70%, at least 80%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% or greater sequence identity over a certain defined length relative to a reference polynucleotide.
  • a “mutation” refers to changing the structure of a gene, resulting in a variant form that may be transmitted to later generations. A mutation is caused by the alteration of single nucleotides in DNA, or the deletion, insertion, or rearrangement of larger sections of genes.
  • a mutation can lead to the expression of a protein that has been changed physically or functionally leading to lethality, non-lethal dysfunction effects, or no effects.
  • Variants comprising a fragment of a reference amino acid sequence or nucleotide sequence are contemplated herein.
  • a “fragment” is a portion of an amino acid sequence or a nucleotide sequence which is identical in sequence to but shorter in length than the reference sequence.
  • a fragment may comprise up to the entire length of the reference sequence, minus at least one nucleotide/amino acid residue.
  • a fragment may comprise from 5 to 1000 contiguous nucleotides or contiguous amino acid residues of a reference polynucleotide or reference polypeptide, respectively.
  • a fragment may comprise at least 5, 10, 15, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 40, 50, 60, 70, 80, 90, 100, 150, 250, or 500 contiguous nucleotides or contiguous amino acid residues of a reference polynucleotide or reference polypeptide, respectively. Fragments may be preferentially selected from certain regions of a molecule, for example the N-terminal region and/or the C-terminal region of a polypeptide or the 5′-terminal region and/or the 3′ terminal region of a polynucleotide. The term “at least a fragment” encompasses the full length polynucleotide or full length polypeptide.
  • a “functional fragment” Docket No.10063-085WO1 refers to a portion of an amino acid sequence or a nucleotide sequence which is identical in sequence to but shorter in length than the reference sequence that retains or increases the activity of the reference sequence.
  • the word “vector” refers to any vehicle that carries a polynucleotide into a cell for the expression of the polynucleotide in the cell.
  • the vector may be, for example, a plasmid, a virus, a phage particle, or a nanoparticle. Once transformed into a suitable host, the vector may replicate and function independently of the host genome, or may in some instances, integrate into the genome itself.
  • the vector is a DNA construct containing a DNA sequence which is operably linked to a suitable control sequence capable of affecting the expression of the DNA in a suitable host cell.
  • control sequences can include a promoter to effect transcription, an optional operator sequence to control such transcription, a sequence encoding suitable mRNA ribosome binding sites, and sequences which control the termination of transcription and translation.
  • the vector is a lipid nanoparticle. Lipid nanoparticles can be used to deliver mRNA to a host cell for expression of the mRNA in the host cell.
  • the expression vector comprises a plasmid or a virus or viral vector.
  • a plasmid or a viral vector can be capable of extrachromosomal replication or, optionally, can integrate into the host genome.
  • the term "integrated" used in reference to an expression vector means the expression vector, or a portion thereof, is incorporated (physically inserted or ligated) into the chromosomal DNA of a host cell.
  • a “viral vector” refers to a virus-like particle containing genetic material which can be introduced into a eukaryotic cell without causing substantial pathogenic effects to the eukaryotic cell.
  • viruses or viral vectors can be used for transduction but should be compatible with the cell type the virus or viral vector are transduced into (e.g., low toxicity, capability to enter cells).
  • Suitable viruses and viral vectors include adenovirus, lentivirus, retrovirus, among others.
  • the expression vector encoding a chimeric polypeptide is a naked DNA or is comprised in a nanoparticle (e.g., liposomal vesicle, porous silicon nanoparticle, gold-DNA conjugate particle, polyethyleneimine polymer particle, cationic peptides, etc.).
  • administer refers to delivering a composition, substance, inhibitor, or medication to a subject or object by one or more the following routes: oral, topical, intravenous, subcutaneous, transcutaneous, transdermal, intramuscular, intra- joint, parenteral, intra-arteriole, intradermal, intraventricular, intracranial, intraperitoneal, intralesional, intranasal, rectal, vaginal, by inhalation or via an implanted reservoir.
  • parenteral includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, Docket No.10063-085WO1 intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injections or infusion techniques.
  • encapsulate or “encapsulating” refers to a process in which molecules, such as nucleic acids, proteins, and other macromolecules are surrounded or coated by nanoparticles for delivery to a targeted tissue or cell-type.
  • cancer is used to address any neoplastic disease, and is not limited to epithelial neoplasms (surface and glandular cancers; such a squamous cancers or adenomas)). It is used here to describe both solid tumors and hematologic malignancies, including epithelial (surface and glandular) cancers, soft tissue, and bone sarcomas, angiomas, mesothelioma, melanoma, lymphomas, leukemias and myeloma.
  • a “metastasis”, or variations thereof refer to the development of a secondary neoplastic growth at a distance from a primary site of cancer.
  • cell includes progeny. It is also understood that all progenies may not be precisely identical in DNA content, due to deliberate or inadvertent mutations. Variant progeny that have the same function or biological property, as screened for in the original cell, are included.
  • kit describes a wide variety of bags, containers, carrying cases, and other portable enclosures which may be used to carry and store solid substances, liquid substances, and other accessories necessary to deliver nucleic acid compositions.
  • treat include partially or completely delaying, alleviating, mitigating, or reducing the intensity of one or more attendant symptoms of a disorder or condition and/or alleviating, mitigating, or impeding one or more causes of a disorder or condition.
  • Treatments according to the disclosure may be applied preventively, prophylactically, palliatively, or remedially. Treatments are administered to a subject prior to disease onset, during early disease onset, or after an established development of disease.
  • a “pharmaceutically effective amount” of a drug necessary to achieve a therapeutic effect may vary according to factors such as the age, sex, and weight of the subject. Dosage regimens can be adjusted to provide the optimum therapeutic response.
  • “Pharmaceutically acceptable” component can refer to a component that is not biologically or otherwise undesirable, i.e., the component may be incorporated into a pharmaceutical formulation of the invention and administered to a subject as described herein without causing significant undesirable biological effects or interacting in a deleterious manner with any of the Docket No.10063-085WO1 other components of the formulation in which it is contained.
  • the term When used in reference to administration to a human, the term generally implies the component has met the required standards of toxicological and manufacturing testing or that it is included on the Inactive Ingredient Guide prepared by the U.S. Food and Drug Administration.
  • “Pharmaceutically acceptable carrier” (sometimes referred to as a “carrier”) means a carrier or excipient that is useful in preparing a pharmaceutical or therapeutic composition that is generally safe and non-toxic, and includes a carrier that is acceptable for veterinary and/or human pharmaceutical or therapeutic use.
  • carrier or “pharmaceutically acceptable carrier” can include, but are not limited to, phosphate buffered saline solution, water, emulsions (such as an oil/water or water/oil emulsion) and/or various types of wetting agents.
  • carrier encompasses any excipient, diluent, filler, salt, buffer, stabilizer, solubilizer, lipid, stabilizer, or other material well known in the art for use in pharmaceutical formulations.
  • a carrier for use in a composition will depend upon the intended route of administration for the composition.
  • the preparation of pharmaceutically acceptable carriers and formulations containing these materials is described in, e.g., Remington's Pharmaceutical Sciences, 21st Edition, ed. University of the Sciences in Philadelphia, Lippincott, Williams & Wilkins, Philadelphia, PA, 2005.
  • physiologically acceptable carriers include saline, glycerol, DMSO, buffers such as phosphate buffers, citrate buffer, and buffers with other organic acids; antioxidants including ascorbic acid; low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, arginine or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; salt-forming counterions such as sodium; and/or nonionic surfactants such as TWEEN TM (ICI, Inc.; Bridgewater, New Jersey), polyethylene glycol (PEG), and PLURONICS TM (BASF; Florham Park, NJ).
  • buffers such as phosphat
  • compositions disclosed herein can advantageously comprise between about 0.1% and 99% by weight of the total of one or more of the subject compounds based on the weight of the total composition including carrier or diluent.
  • a “gene therapy” refers to a medical/clinic approach to treat or prevent a disease, condition, or disorder by correcting an underlying genetic issue. This therapeutic technique involves introducing a gene to a subject or patient to replace or alleviate consequences of the dysfunction gene(s) causing the disease, condition, or disorder. Docket No.10063-085WO1
  • a “virus” is a microscopic infectious agent that replicates only inside the living cells of an organism.
  • Viruses can infect all life forms, including mammalian and non-mammalian animals, plants, and other microorganisms.
  • a complete virus also known as a virion, consists of nucleic acid genetic material surrounded by a protective coat of protein called a capsid.
  • Virus can have a lipid envelope derived from the infected host cell membrane. In general, there are five morphological virus types including helical, icosahedral, prolate, enveloped, and complex virus.
  • a virus can either have a DNA or RNA genome, though a vast majority have RNA genomes. Irrespective of the type of nucleic acid genome, a viral genome can be either a single-stranded genome or a double-stranded genome.
  • therapeutic strategies using nucleic acids can also make cells, tissues, organs, and/or organ systems behave in a certain way by activating, suppressing, or supplementing gene expression.
  • Utilizing said strategies to regulate estrogen receptor (ER) gene expression is an approach to treatment and/or prevent ER-related diseases or disorders.
  • ERs estrogen receptors
  • Disregulation of ER ⁇ signaling has been implicated in numerous diseases and disorders, including, but not limited to cancer, neurological diseases (including, but not limited to Alzheimer's diseases, Parkinson’s disease, and multiple sclerosis), gastrointestinal diseases (including, but not limited to inflammatory bowel syndrome, liver diseases, and Crohn’s disease) cardiovascular diseases (including, but not limited to coronary artery disease and atherosclerosis), endometriosis, and fibroids.
  • neurological diseases including, but not limited to Alzheimer's diseases, Parkinson’s disease, and multiple sclerosis
  • gastrointestinal diseases including, but not limited to inflammatory bowel syndrome, liver diseases, and Crohn’s disease
  • cardiovascular diseases including, but not limited to coronary artery disease and atherosclerosis
  • endometriosis and fibroids.
  • the present disclosure provides a therapeutic composition comprising a nucleic acid encoding ER ⁇ and a nucleic acid delivery vehicle.
  • a therapeutic composition comprising a nucleic acid encoding estrogen receptor beta (ER ⁇ ), wherein the nucleic acid is encapsulated in or conjugated to a nucleic acid delivery vehicle.
  • the nucleic acid comprises mRNA.
  • the nucleic acid comprises DNA.
  • the mRNA comprises a full-length mRNA.
  • the mRNA comprises a functional fragment of the full-length mRNA.
  • the nucleic acid comprises at least 50% identity to SEQ ID NO: 1 or SEQ ID NO: 2.
  • the nucleic acid comprises at least 60% identity to SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, the nucleic acid comprises at least 70% identity to SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, the nucleic acid comprises at least 80% identity to SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, the nucleic acid comprises at least 81% identity to SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, the nucleic acid comprises at least 82% identity to SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, the nucleic acid comprises at least 83% identity to SEQ ID NO: 1 or SEQ ID NO: 2.
  • the nucleic acid comprises at least 84% identity to SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, the nucleic acid comprises at least 85% identity to SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, the nucleic acid comprises at least 86% identity to SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, the nucleic acid comprises at least 87% identity to SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, the nucleic acid comprises at least 88% identity to SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, the nucleic acid comprises at least 89% identity to SEQ ID NO: 1 or SEQ ID NO: 2.
  • the nucleic acid comprises at least 90% identity to SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, the nucleic acid comprises at least 91% identity to SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, the nucleic acid comprises at least 92% identity to SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, the nucleic acid comprises at least 93% identity to SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, the nucleic acid comprises at least 94% identity to SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, the nucleic acid comprises at least 95% identity to SEQ ID NO: 1 or SEQ ID NO: 2.
  • the nucleic acid comprises at least Docket No.10063-085WO1 96% identity to SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, the nucleic acid comprises at least 97% identity to SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, the nucleic acid comprises at least 98% identity to SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, the nucleic acid comprises at least 99% identity to SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, the nucleic acid comprises SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, the nucleic acid sequence comprises an ER ⁇ nucleic acid, such as an mRNA sequence.
  • the ER ⁇ mRNA is a full length ER ⁇ mRNA.
  • the Er ⁇ -encoding nucleic acid is a functional fragment of the full-length naturally occurring ER ⁇ mRNA.
  • the ER ⁇ mRNA comprises SEQ ID NO: 1, or fragments thereof.
  • the ER ⁇ mRNA comprises the gene accession no. NM_001437.3, or fragments thereof.
  • a “functional fragment” refers to the gene product of a nucleic acid sequence, wherein the nucleic acid sequence is a smaller sequence within a larger parent nucleic acid sequence, that retains functional activities at or near the level of the gene product expressed by the parent nucleic acid sequence.
  • the ER ⁇ mRNA is a linear mRNA.
  • the ER ⁇ mRNA is a circular mRNA. It should be noted that the circular ER ⁇ mRNA produces the same ER ⁇ protein, however the circular ER ⁇ is more stable than the linear structure. Circular mRNA is protected from ribonuclease-dependent degradation inside the cells and is considered to remain in cells for longer period compared with the linear mRNA.
  • Circular mRNA can be produced by vectors (including, but not limited to plasmids) that incorporate some modifications that do not change the sequence of the protein but facilitate the circulation of mRNA.
  • the nucleic acid sequence comprises an ER ⁇ DNA.
  • the ER ⁇ DNA is a full length ER ⁇ DNA.
  • the ER ⁇ DNA is a functional fragment of the full-length ER ⁇ DNA.
  • the ER ⁇ DNA comprises SEQ ID NO: 2, or fragments thereof.
  • the ER ⁇ DNA comprises the gene accession no. NC_000014.9, or fragments thereof.
  • nucleic acid payloads can have different biochemical mechanisms of action, all of them must avoid clearance of off-target organs, must access the correct tissue, must interact with the targeted cell type in a complex tissue microenvironment, must be taken up by an intracellular mechanism, directed to regulate and/or influence a gene-related mechanism or product, and subsequently removed into the extracellular microenvironment.
  • nucleic acid therapeutics can be modified using stable chemical modifications and Docket No.10063-085WO1 delivered using stable conjugates, most RNA-based and DNA-based therapeutics still require a vehicle for entry into a cell. To facilitate this, several delivery systems have been developed including lipid nanoparticle (LPN) vehicles and polymeric vehicles.
  • LPN lipid nanoparticle
  • the nucleic acid delivery vehicle comprises a pharmaceutically acceptable carrier selected from an LPN, a lipid carrier, an organic polymer, a cell, a virus-like particle, an excipient, a diluent, a salt, a buffer, a stabilizer, or combinations thereof.
  • lipid nanoparticle or “LPN” refers to a lipid-nucleic acid particle or a nucleic acid lipid particle (e.g., a stable lipid particle conjugated to, encapsulating, or interacting with a nucleic acid).
  • a LNP represents a particle made from lipids (including, but not limited to a cationic lipid, a non-cationic lipid, and a conjugated lipid that prevents aggregation of the particle) and a nucleic acid, wherein the nucleic acid (including, but not limited to mRNA, double stranded(ds) DNA, siRNA, miRNA, single stranded (ss) DNA, ssRNA, shRNA, aiRNA, self-amplifying RNA, plasmids, and vectors) is encapsulated within the lipid.
  • the nucleic acid is at least 50% encapsulated in the LPN.
  • the nucleic acid is at least 60% encapsulated in the LPN. In some embodiments, the nucleic acid is at least 70% encapsulated in the LPN. In some embodiments, the nucleic acid is at least 75% encapsulated in the LPN. In some embodiments, the nucleic acid is at least 80% encapsulated in the LPN. In some embodiments, the nucleic acid is at least 90% encapsulated in the LPN. In some embodiments, the nucleic acid is at least 95% encapsulated in the LPN. In some embodiments, the nucleic acid is at least 99% encapsulated in the LPN. In some embodiments, the nucleic acid is at least 100% encapsulated in the LPN.
  • LPN vehicles are extremely useful for systemic applications, as they can exhibit extended circulation lifetimes following intravenous (i.v.) injection(s), they can accumulate at distal sites (e.g., sites physically separated from the administration site), and they can mediate expression of the delivered gene or silence expression of a target gene at distal sites.
  • the LPN of the present disclosure have a diameter from about 30nm to about 200nm, from about 40nm to about 150nm, from about 50nm to about 140nm, from about 60nm to about 130nm, from about 70nm to about 120nm, from about 80nm to about 110nm, from about 90nm to about 100nm, and are substantially non-toxic. LPN and their methods of preparation are disclosed in U.S.
  • the LPN comprises a solid lipid nanoparticle, a nanostructured lipid carrier, or any variations thereof.
  • the LPN is biodegradable and/or biocompatible. Docket No.10063-085WO1
  • a “lipid carrier” or “liposome” refers to enclosed phospholipid bilayer spherical vesicles composed of amphiphilic lipids surrounding an aqueous interior that is optimal for carrying and delivering hydrophilic or hydrophobic payloads.
  • the lipid carrier comprises a liposome, a liposome-like nanoparticle, a lipid-polymer hybrid nanoparticle, a nanoemulsion, an exosome, a lipoprotein particle, or any combinations thereof.
  • the lipid carrier is biodegradable and/or biocompatible.
  • the term “polymer” or “polymer chain” refers to macromolecules comprising repeating structural units of from about 2 monomeric units to about one million or more monomeric units, connected by one or more covalent bonds.
  • Polymer may be organic polymers or inorganic polymers. Polymers may also be synthetic, semi-synthetic, or naturally occurring, and can comprise homopolymers (e.g., comprising the same repeating monomer unit) or copolymers (e.g., comprising at least two different monomeric units). Copolymers can be periodic copolymers (e.g., where monomer residues A and B are arranged in a repeating sequence such as A-B-A-A-B-B-A-A-A-B-B-B), or random copolymers having random sequences of monomers A and B. Generally, the average molecular weight of the polymer ranges from about 1kDa to about 1000 kDa.
  • the average molecular weight of the polymer is about 1, 2, 3, 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, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113,
  • the organic polymer comprises a polypeptide or peptide, a nucleic acid, a lipid, a carbohydrate, or any combinations thereof.
  • the polymer is a linear polymer, or a non-linear or branched polymer.
  • Exemplary non-linear polymers or branched polymers include, but are not limited to brush polymers, star polymers, comb polymers, dendrimer polymers, networked polymers, crosslinked polymers, semi-cross-linked polymers, graft polymers, and combinations thereof.
  • the polymer is a water soluble polymer, including but not limited to polysaccharides, polyesters, polyamides, polyethers, and polycarbonates.
  • the polymer is biodegradable and/or biocompatible.
  • the virus-like particle comprises one or more non-infectious components from a virus selected from Human immunodeficiency virus (HIV), Influenza virus, Hepatitis B virus, Hepatitis E virus, Ebola virus, Severe acute respiratory syndrome coronavirus (SARS-CoV), SARS-CoV-2, Respiratory syncytial virus (RSV), Human papillomavirus (HPVs), Middle east respiratory syndrome coronavirus (MERS-CoV), and swine fever virus.
  • HAV Human immunodeficiency virus
  • Influenza virus Hepatitis B virus
  • Hepatitis E virus Ebola virus
  • SARS-CoV Severe acute respiratory syndrome coronavirus
  • SARS-CoV-2 Severe acute respiratory syndrome coronavirus
  • virus-like particles refers to biomolecules, including but not limited to whole protein and protein fragments, that closely resemble or are derived from viruses, but are non-infectious because they contain no or minimal genetic material.
  • Virus-like particles can resemble or be derived from viruses including, but not limited to Adenoviridae, Birnaviridae, Bunyaviridae, Caliciviridae, Capillovirus group, Carlavirus group, Carmovirus group, Caulimovirus group, Closterovirus group, Commelina yellow mottle virus group, Comovirus virus group, Docket No.10063-085WO1 Coronaviridae, PM2 phage group, Corcicoviridae, Cryptic virus group, Cryptovirus group, Cucumovirus group, ⁇ 6 phage group, Cysioviridae, Carnation ringspot group, Dianthovirus virus group, Broad bean wilt group, Fabavirus virus group, Filoviridae, Flaviviridae,
  • the cell comprises a dendritic cell.
  • the composition comprises a naked nucleic acid encoding an ER ⁇ protein.
  • nucleic acids comprising chemical modifications to improve pharmacokinetic properties, innate immune responses, and/or stability.
  • the nucleic acid comprises one or more chemical modifications to increase stability of the nucleic acid encoding ER ⁇ .
  • the one or more chemical modifications are selected from a 5’-7-methylguanosine cap, a 5’ untranslated region 5’ UTR, a 3’ UTR, a modification to the open reading frame (ORF), a poly-adenylate tail, 2’-O-methyl (2’-OMe), 2’- methoxyethyl (2’-MOE), 2’-fluoro (2’-F), locked nucleic acids, constrained nucleic acids, and tricyclo-DNA oligonucleotides.
  • ORF open reading frame
  • the composition further comprises a nucleic acid sequence encoding a reporter gene.
  • the reporter gene encodes a reporter protein selected from a mCherry, luciferase, green fluorescent protein (GFP), yellow fluorescent protein (YFP), blue fluorescent protein (BFP), cyane fluorescent protein (CFP), monomeric red fluorescent protein (mRFP), Discosoma striata (DsRed), mCherry, mOrange, tdTomato, mSTrawberry, mPlum, photoactivatable GFP (PA-GFP), Venus, Kaede, monomeric kusabira orange (mKO), Dronpa, enhanced CFP (ECFP), Emerald, Cyan fluorescent protein for energy transfer (CyPet), super CFP (SCFP), Cerulean, photoswitchable CFP (PS-CFP2), photoactivatable RFP1 (PA-RFP1), Docket No.10063-085WO1 photoactivatable mCherry (PA-mCherry), monomeric teal fluorescent protein (mTFP1), Eos fluorescent protein (mTFP1)
  • Estrogen is a key regulator of growth and differentiation in a broad range of target tissues, including the reproductive system, mammary glands, central nervous systems, skeletal muscles, and the cardiovascular system. Estrogen and estrogen-derived molecules influence said target tissues by binding to estrogen receptors, such as ER ⁇ , to initiate a signaling cascade impacting gene expression in various organ systems.
  • ER ⁇ is a member of the nuclear receptor superfamily and is classified as a type I nuclear receptor because it originally resides in the cytosol and travels into the nucleus upon binding to estrogen or an estrogen-derived molecule.
  • ER ⁇ can influence gene expression in numerous ways including, but not limited to binding DNA sequences (termed estrogen-responsive elements (EREs)) that attract transcription factors and other coregulator proteins to transcription start sites to enhance or repress gene expression.
  • EpEs estrogen-responsive elements
  • the characteristics and molecular mechanisms of ER ⁇ are disclosed in Leung et al. “Estrogen receptor ER ⁇ isoforms: A key to understanding ER ⁇ signaling” PNAS. 29 Aug 2006. Vol. 103. No. 35. 13162-13167, Zhao et al. “Estrogen receptor ⁇ : an overview and update” Nuclear Receptor Signaling.1 Feb 2008.6, e003, and “Estrogen receptor ⁇ acts as a dominant regulator of estrogen signaling” Oncogene. 12 Oct 2000.
  • ER ⁇ proteins target one or more genes to regulate gene expression, a process that once dysregulated is detrimental leading to diseases or disorders.
  • the present disclosure provides methods of treating or preventing ER-related disorders, including, but not limited to primary tumors and metastatic tumors, using a therapeutic composition comprising a nucleic acid encoding ER ⁇ .
  • a method of treating or preventing an ER ⁇ -related disorder in a subject in need thereof comprising administering a pharmaceutically effective amount of a composition comprising a nucleic acid encoding ER ⁇ , wherein the nucleic acid is encapsulated in or conjugated to a nucleic acid delivery vehicle, wherein the method increases expression of a ER ⁇ protein in the subject relative to an untreated subject with cancer.
  • a method of treating or preventing tumor development in a subject with cancer comprising administering a pharmaceutically effective amount of a composition comprising a nucleic acid encoding ER ⁇ , wherein the nucleic acid is encapsulated in or conjugated to a nucleic acid delivery vehicle, wherein the method increases expression of a ER ⁇ protein in the subject relative to an untreated subject with cancer.
  • a method of treating or preventing a metastasis in a subject comprising administering a pharmaceutically effective amount of a composition comprising a nucleic acid encoding ER ⁇ , wherein the nucleic acid is encapsulated in or conjugated to a nucleic acid delivery vehicle, and wherein the method increases expression of a ER ⁇ protein in the subject relative to an untreated subject with a metastasis.
  • the method comprises the use of an ER ⁇ mRNA.
  • the method comprises the use of a full length ER ⁇ mRNA.
  • the method comprises the use of a functional fragment of the full-length ER ⁇ mRNA.
  • the method comprises the use of SEQ ID NO: 1, or fragments thereof. In some embodiments, the method comprises the use of gene accession no. NM_001437.3, or fragments thereof. In some embodiments, the method comprises the use of an ER ⁇ DNA. In some embodiments, the method comprises the use of a full length ER ⁇ DNA. In some embodiments, the method comprises the use of a functional fragment of the full-length ER ⁇ DNA. In some embodiments, the method comprises SEQ ID NO: 2, or fragments thereof. In some embodiments, the method comprises the use of the gene accession no. NC_000014.9, or fragments thereof.
  • the nucleic acid delivery vehicle comprises a pharmaceutically acceptable carrier selected from a lipid nanoparticle (LPN), a lipid carrier, an organic polymer, a cell, a virus-like particle, an excipient, a diluent, a salt, a buffer, or a stabilizer.
  • LPN lipid nanoparticle
  • the composition may be administered in such amounts, time, and route deemed necessary in order to achieve the desired result.
  • the exact amount of the composition may vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the ER-related disorder or disease, the particular composition, its mode of administration, its mode of activity, and the like.
  • the composition is preferably formulated in dosage unit form for ease of administration and uniformity of dosage.
  • the total daily usage of the composition will be decided by the attending physician within the scope of sound medical judgment.
  • the specific therapeutically effective dose level for any particular subject will depend upon a variety of factors including the ER-related disorder or disease being treated and the severity Docket No.10063-085WO1 of the ER-related disorder or disease; the activity of the composition employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific composition employed; the duration of the treatment; drugs used in combination or coincidental with the specific composition employed; and like factors well known in the medical arts.
  • the composition is administered intratumorally or intravenously.
  • the most appropriate route of administration will depend upon a variety of factors including the nature of the composition (e.g., its stability in the systemic or vascular environment), the condition of the subject (e.g., whether the subject is able to tolerate systemic or local administration), etc.
  • the exact amount of composition required to achieve a therapeutically effective amount will vary from subject to subject, depending on species, age, and general condition of a subject, severity of the side effects, identity of the particular compound(s), mode of administration, and the like.
  • the amount to be administered to, for example, a child or an adolescent can be determined by a medical practitioner or person skilled in the art and can be lower or the same as that administered to an adult.
  • the composition is administered at a dose of at least 2 ⁇ g of ER ⁇ nucleic acid. In some embodiments, the composition is administered at a dose ranging from about 2 ⁇ g to about 20 ⁇ g ER ⁇ nucleic acid. In some embodiments, the composition is administered at a dose of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 ⁇ g of ER ⁇ nucleic acid. In some embodiments, the composition is administered at a dose of at least 2 ⁇ g of ER ⁇ mRNA. In some embodiments, the composition is administered at a dose ranging from about 2 ⁇ g to about 20 ⁇ g ER ⁇ mRNA.
  • the composition is administered at a dose of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 ⁇ g of ER ⁇ mRNA. In some embodiments, the composition is administered at a dose of at least 2 ⁇ g of ER ⁇ DNA. In some embodiments, the composition is administered at a dose ranging from about 2 ⁇ g to about 20 ⁇ g ER ⁇ DNA. In some embodiments, the composition is administered at a dose of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 ⁇ g of ER ⁇ DNA. In some embodiments, the composition is administered for at least one week. In some embodiments, the composition is administered for 1, 2, 3, or 4 weeks.
  • the composition is administered for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 months. In some embodiments, the composition is administered for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more years. Docket No.10063-085WO1 In some embodiments, the composition is administered at least once per week.
  • the composition is administered 1, 2, 3, 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, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116,
  • the method of any preceding aspect treats, prevents, ameliorates, or reduces triple negative breast cancer (TNBC) or invasive breast cancer.
  • the ER ⁇ -related disorder comprises a cancer selected from a breast cancer, an ovarian cancer, a uterine cancer, vaginal cancer, vulvar cancer, cervical cancer, urethral cancer, a prostate cancer, colorectal cancer, bladder cancer, thyroid cancer, or cancers affecting a tissue from a reproductive, gastrointestinal, or urinary system.
  • the breast cancer comprises inflammatory breast cancer (IBC), Triple-Negative Breast Cancer (TNBC), HER2-positive breast cancer, or Hormone Receptor-(HR)-positive breast cancer.
  • the cancer includes, but is not limited to acoustic neuroma, adenocarcinoma, adrenal gland cancer, anal cancer, angiosarcoma (e.g., lymphangiosarcoma, lymphangioendotheliosarcoma, hemangiosarcoma), appendix cancer, benign monoclonal gammopathy, biliary cancer (e.g., cholangiocarcinoma), bladder cancer, breast cancer (e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, mammary cancer, medullary carcinoma of the breast), brain cancer (e.g., meningioma; glioma, e.g., astrocytoma, oligodendroglioma; medulloblastoma), bronchus cancer, carcinoid tumor, cervical cancer (e.g., cervical adenocarcinoma), choriocarcinoma, chord
  • HCC hepatocellular cancer
  • lung cancer e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung
  • the ER ⁇ protein targets one or more metastasis- and cancer progression-associated genes selected from CD36, TGFb, TGFbR2, ALDH1A1, ELMO1, ILR1, IL6, IL8, IL1, IL17, CCL2, GPR141, CREB1, TFF1, FN1, NRG1, LCN2, VTCN1, FST1, NRP1, RHOBTB3.
  • the composition is administered in combination with an adjuvant, including, but not limited to neoadjuvants.
  • Exemplary adjuvants include, but are not limited to aluminum hydroxide, aluminum phosphate, aluminum potassium sulfate, heat shock proteins (HSPs) (including, but not limited to HSP70 and HSP90), Toll-like receptor (TLR) agonists (including, but not limited to TLR1 agonists, TLR2 agonists, TLR1/2 agonists, TLR 3 agonists, TLR 4 agonist, TLR 5 agonist, TLR 7 agonist, TLR 8 agonists, TLR7/8 agonists, and TLR 9 agonists), Freund’s adjuvants (which refers to a water in oil emulsion), MF59, AS01, AS02, AS03, AS04, virus-like particles, virosomes, polylactic acid (PLA), poly(lactic-co-glycolic acid) (PLGA), and mucosal adjuvants (including, but not limited to cholera toxin (CT), heat-labile enterotoxins (LTK3 or LTR72
  • the additional therapeutic composition comprises Docket No.10063-085WO1 an anti-cancer agent, a chemotherapeutic agent, an anti-inflammatory agent, or a combination thereof.
  • the anti-cancer agent comprises an interferon, a cytokine, a vaccine, a growth factor, an antibody or serotherapy, or an immunomodulatory agent.
  • biotherapeutic anti-cancer agents include, but are not limited to, interferons, cytokines (e.g., tumor necrosis factor, interferon ⁇ , interferon ⁇ ), vaccines, hematopoietic growth factors, monoclonal serotherapy, immunostimulants and/or immunodulatory agents (e.g., IL-1, 2, 4, 6, or 12, anti- PDL1, anti-PD1, anti-CTLA-4), immune cell growth factors (e.g., GM-CSF) and antibodies (e.g.
  • the chemotherapeutic agent comprises a luteinizing hormone releasing hormone (LHRH), anti-androgens, endocrine therapy, aromatase inhibitors, anti- estrogens, photodynamic therapies, nitrogen mustards, nitrosoureas, metal containing compounds, nucleotide analogs, anti-metabolites, or a cancer suppressing agent.
  • LHRH luteinizing hormone releasing hormone
  • anti-androgens endocrine therapy
  • aromatase inhibitors anti- estrogens
  • photodynamic therapies nitrogen mustards, nitrosoureas, metal containing compounds, nucleotide analogs, anti-metabolites, or a cancer suppressing agent.
  • chemotherapeutic agents include, but are not limited to, anti-estrogens (e.g. tamoxifen, raloxifene, and megestrol), LHRH agonists (e.g. goscrclin and leuprolide), anti-androgens (e.g. flutamide and bicalutamide), photodynamic therapies (e.g. vertoporfin (BPD-MA), phthalocyanine, photosensitizer Pc4, and demethoxy-hypocrellin A (2BA-2-DMHA)), nitrogen mustards (e.g.
  • anti-estrogens e.g. tamoxifen, raloxifene, and megestrol
  • LHRH agonists e.g. goscrclin and leuprolide
  • anti-androgens e.g. flutamide and bicalutamide
  • photodynamic therapies e.g. vertoporfin (BPD-MA), phthalocyanine
  • cyclophosphamide ifosfamide, trofosfamide, chlorambucil, estramustine, and melphalan
  • nitrosoureas e.g. carmustine (BCNU) and lomustine (CCNU)
  • alkylsulphonates e.g. busulfan and treosulfan
  • triazenes e.g. dacarbazine, temozolomide
  • platinum containing compounds e.g. cisplatin, carboplatin, oxaliplatin
  • vinca alkaloids e.g. vincristine, vinblastine, vindesine, and vinorelbine
  • taxoids e.g.
  • paclitaxel or a paclitaxel equivalent such as nanoparticle albumin-bound paclitaxel (ABRAXANE), docosahexaenoic acid bound-paclitaxel (DHA-paclitaxel, Taxoprexin), polyglutamate bound-paclitaxel (PG-paclitaxel, paclitaxel poliglumex, CT-2103, XYOTAX), the tumor-activated prodrug (TAP) ANG1005 (Angiopep-2 bound to three molecules of paclitaxel), paclitaxel-EC-1 (paclitaxel bound to the erbB2-recognizing peptide EC-1), and glucose- conjugated paclitaxel, e.g., 2′-paclitaxel methyl 2-glucopyranosyl succinate; docetaxel, taxol), epipodophyllins (e.g.
  • ABRAXANE nanoparticle albumin-bound paclitaxel
  • etoposide etoposide phosphate, teniposide, topotecan, 9- aminocamptothecin, camptoirinotecan, irinotecan, crisnatol, mytomycin C
  • anti-metabolites DHFR inhibitors (e.g. methotrexate, dichloromethotrexate, trimetrexate, edatrexate), IMP dehydrogenase inhibitors (e.g. mycophenolic acid, tiazofurin, ribavirin, and EICAR), ribonucleotide reductase inhibitors (e.g. hydroxyurea and deferoxamine), uracil analogs (e.g.
  • 5- fluorouracil 5-FU
  • floxuridine doxifluridine
  • ratitrexed tegafur-uracil
  • capecitabine cytosine Docket No.10063-085WO1 analogs
  • cytarabine ara C
  • cytosine arabinoside e.g. cytarabine (ara C)
  • purine analogs e.g. mercaptopurine and Thioguanine
  • Vitamin D3 analogs e.g. EB 1089, CB 1093, and KH 1060
  • isoprenylation inhibitors e.g. lovastatin
  • dopaminergic neurotoxins e.g.
  • cell cycle inhibitors e.g. staurosporine
  • actinomycin e.g. actinomycin D, dactinomycin
  • bleomycin e.g. bleomycin A2, bleomycin B2, peplomycin
  • anthracycline e.g. daunorubicin, doxorubicin, pegylated liposomal doxorubicin, idarubicin, epirubicin, pirarubicin, zorubicin, mitoxantrone
  • MDR inhibitors e.g. verapamil
  • Ca 2+ ATPase inhibitors e.g.
  • thapsigargin imatinib, thalidomide, lenalidomide, tyrosine kinase inhibitors (e.g., axitinib (AG013736), bosutinib (SKI-606), cediranib (RECENTINTM, AZD2171), dasatinib (SPRYCEL®, BMS-354825), erlotinib (TARCEVA®), gefitinib (IRESSA®), imatinib (Gleevec®, CGP57148B, STI-571), lapatinib (TYKERB®, TYVERB®), lestaurtinib (CEP-701), neratinib (HKI-272), nilotinib (TASIGNA®), semaxanib (semaxinib, SU5416), sunitinib (SUTENT®, SU11248), toceranib (PALLADIA®), vandetanib
  • the method decreases the growth of cancer cells, the stemness of cancer cells, or the invasiveness of cancer cells in the subject relative to an untreated subject with an ER ⁇ -related disorder. In some embodiments, the method decreases the growth of cancer cells, the stemness of cancer cells, or the invasiveness of cancer cells by 10%, 20%, 30%, 40%, 50%, Docket No.10063-085WO1 60%, 70%, 80%, 90%, 95%, 99%, or 100% in the subject relative to an untreated subject with an ER ⁇ -related disorder. In some embodiments, the method enhances cancer-associated immune response in the subject relative to an untreated subject with an ER ⁇ -related disorder.
  • kits containing nucleic acid compositions comprising a nucleic acid encoding an estrogen receptor beta (ER ⁇ ), wherein the nucleic acid is encapsulated in or conjugated to a nucleic acid delivery vehicle.
  • the kit comprises mRNA.
  • the kit comprises DNA.
  • the kit comprises a full-length mRNA.
  • the kit comprises a functional fragment of the full-length mRNA.
  • the kit comprises a full-length DNA. In some embodiments, the kit comprises a functional fragment of the full-length DNA. In some embodiments, the kit comprises a nucleic acid with at least 50% identity to SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, the kit comprises a nucleic acid with at least 60% identity to SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, the kit comprises a nucleic acid with at least 70% identity to SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, the kit comprises a nucleic acid with at least 80% identity to SEQ ID NO: 1 or SEQ ID NO: 2.
  • the kit comprises a nucleic acid with at least 81% identity to SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, the kit comprises a nucleic acid with at least 82% identity to SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, the kit comprises a nucleic acid with at least 83% identity to SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, the kit comprises a nucleic acid with at least 84% identity to SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, the kit comprises a nucleic acid with at least 85% identity to SEQ ID NO: 1 or SEQ ID NO: 2.
  • the kit comprises a nucleic acid with at least 86% identity to SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, the kit comprises a nucleic acid with at least 87% identity to SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, the kit comprises a nucleic acid with at least 88% identity to SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, the kit comprises a nucleic acid with at least 89% identity to SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, Docket No.10063-085WO1 kit comprises a nucleic acid with at least 90% identity to SEQ ID NO: 1 or SEQ ID NO: 2.
  • kit comprises a nucleic acid with at least 91% identity to SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, kit comprises a nucleic acid with at least 92% identity to SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, kit comprises a nucleic acid with at least 93% identity to SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, kit comprises a nucleic acid with at least 94% identity to SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, the kit comprises a nucleic acid with at least 95% identity to SEQ ID NO: 1 or SEQ ID NO: 2.
  • kit comprises a nucleic acid with at least 96% identity to SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, kit comprises a nucleic acid with at least 97% identity to SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, kit comprises a nucleic acid with at least 98% identity to SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, the kit comprises a nucleic acid with at least 99% identity to SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, the kit comprises a nucleic acid comprising SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, the kit comprises an ER ⁇ mRNA.
  • the ER ⁇ mRNA is a full length ER ⁇ mRNA. In some embodiments, the ER ⁇ mRNA is a functional fragment of the full-length ER ⁇ mRNA. In some embodiments, the ER ⁇ mRNA comprises SEQ ID NO: 1, or fragments thereof. In some embodiments, the ER ⁇ mRNA comprises the gene accession no. NM_001437.3, or fragments thereof. In some embodiments, the kit comprises an ER ⁇ DNA. In some embodiments, the ER ⁇ DNA is a full length ER ⁇ DNA. In some embodiments, the ER ⁇ DNA is a functional fragment of the full-length ER ⁇ DNA. In some embodiments, the ER ⁇ DNA comprises SEQ ID NO: 2, or fragments thereof.
  • the ER ⁇ DNA comprises the gene accession no. NC_000014.9, or fragments thereof.
  • the kit comprises a nucleic acid comprising one or more chemical modifications selected from a 5’-7-methylguanosine cap, a 5’ untranslated region 5’ UTR, a 3’ UTR, a modification to the open reading frame (ORF), a poly-adenylate tail, 2’-O-methyl (2’- OMe), 2’-methoxyethyl (2’-MOE), 2’-fluoro (2’-F), locked nucleic acids, constrained nucleic acids, and tricyclo-DNA oligonucleotides.
  • the kit further comprises a nucleic acid sequence encoding a reporter gene.
  • the reporter gene encodes a reporter protein selected from a Docket No.10063-085WO1 mCherry, luciferase, green fluorescent protein (GFP), yellow fluorescent protein (YFP), blue fluorescent protein (BFP), cyane fluorescent protein (CFP), monomeric red fluorescent protein (mRFP), Discosoma striata (DsRed), mCherry, mOrange, tdTomato, mSTrawberry, mPlum, photoactivatable GFP (PA-GFP), Venus, Kaede, monomeric kusabira orange (mKO), Dronpa, enhanced CFP (ECFP), Emerald, Cyan fluorescent protein for energy transfer (CyPet), super CFP (SCFP), Cerulean, photoswitchable CFP (PS-CFP2), photoactivatable RFP1 (PA-RFP1), photoactivatable mCherry (PA-mCherry), monomeric teal fluorescent protein (mTFP1), Eos fluorescent protein (
  • the nucleic acid delivery vehicle comprises a pharmaceutically acceptable carrier selected from a lipid nanoparticle (LPN), a lipid carrier, an organic polymer, a virus-like particle, or a stabilizer.
  • the kit further comprises an RNase-free reagent selected from RNase-free water, RNase-free buffered solution, and RNase-free saline.
  • Example 1 Targeting Estrogen Receptor ⁇ Signaling in Breast Cancer Inflammatory breast cancer (IBC) accounts for about 10% of the breast cancer mortality that occurs annually in the US. It is characterized by rapid progression, distant metastases, younger Docket No.10063-085WO1 age of onset and a median survival of approximately 4 years compared with more than 10 years for non-IBC.
  • IBC Breast Cancer Inflammatory breast cancer
  • the expression frequency combined with function indicate the downregulation of ER ⁇ in tumors of patients with metastasis and that tumor-specific expression of the receptor by mRNA injection can inhibit progression of the disease. It is, therefore, of high importance to evaluate the ER ⁇ mRNA as novel therapeutic to combat progression and metastasis of IBC.
  • This disclosure develops ER ⁇ mRNA as a novel therapeutic for a disease that currently lacks targeted therapy that either alone or in combination with existing therapies will substantially eliminate metastasis and associated mortality, ensuring that these findings will rapidly impact clinical treatment of IBC.
  • treatments can be validated that benefit patients with other forms of aggressive breast cancer.
  • ER ⁇ target genes were previously identified as associated with metastasis. It was recently found that similar gene expression changes in ER ⁇ mRNA-treated cells (FIG.4C). Identifying ER ⁇ target genes that inhibit metastasis. The mechanism of ER ⁇ mRNA action is fully elucidated. The gene expression in ER ⁇ mRNA-treated tumors is analyzed by RNA-Seq to corroborate the antimetastatic activity of ER ⁇ and identify novel target and metastasis- associated genes. This data is associated with previously identified ER ⁇ targets in IBC cells.
  • ER ⁇ mRNA-treated IBC cells are also analyzed by ChIP- Seq to determine which of the altered genes Docket No.10063-085WO1 in ER ⁇ mRNA-treated tumors are direct ER ⁇ targets and define the ER ⁇ cistrome in IBC.
  • the importance of identified genes as therapy targets is evaluated in functional in vitro and in vivo studies after genetic and pharmacological alteration of their expression and activity.
  • Clinical Relevance Decreased levels of ER ⁇ were observed in IBC tumors and tumor-specific upregulation by using complexes of ER ⁇ mRNA with lipid nanoparticles is an effective therapy intervention to restore expression and anti-metastatic activity to prevent progression of the disease.
  • Example 2 Tumor repressive effects of ER ⁇ mRNA-based therapy in aggressive breast cancers
  • IBC Inflammatory breast cancer
  • TNBC triple-negative breast cancer
  • Er ⁇ estrogen receptor ⁇
  • ER ⁇ second ER
  • ER ⁇ mRNA-based approach was employed to induce tumor-specific upregulation of the receptor and restore its anti-metastatic activity.
  • Treatment with ER ⁇ mRNA induces the expression of the ER ⁇ receptor and decreases the invasiveness of breast cancer cells.
  • Cancerous cells were treated with complexes of mRNA (Control (GFP) or ER ⁇ ) with lipid nanoparticles (LNP) for 48 hours. Increased GFP expression within the first 20 hours is observed in a dose-dependent response (FIG.4A) as well as increased lipid uptake (FIG. 4B).
  • Treatment with ER ⁇ mRNA reduced cell invasion (FIG. 4D).
  • ER ⁇ mRNA Treatment of cancer cells with ER ⁇ mRNA not only increased levels of ER ⁇ mRNA transcript, but also altered the mRNA transcripts of genes that are regulated by ER ⁇ including CCL5, TNF, and IL6 (FIG.4E and FIG.7).
  • ER ⁇ treatment reduces tumor progression.
  • treatment with ER ⁇ mRNA-LNP resulted in smaller tumors than control treated mice (FIG. 8B).
  • ER ⁇ mRNA treatment resultsed in increased transcript levels of ELMO1 and ESR2 (ER ⁇ ) when compared to control in primary tumors (FIG.9).
  • ER ⁇ mRNA treatment has anti-metastatic effects. IBC frequently metastasizes to lungs and other organs. In a mouse breast cancer model, mice treated with ER ⁇ exhibited less metastasis in their lungs when compared to control treatment alone (FIGS. 10A-10B). Treatment with ER ⁇ mRNA substantially decreases lung metastasis of orthotopically grown breast tumors. Thus, treatment of IBC with ER ⁇ mRNA-LPN is a viable therapeutic.
  • Example 3 ER ⁇ as an anti-cancer therapeutic Despite advances in diagnosis and therapy, breast cancer remains the second leading cause of cancer-related deaths in women. Among the most aggressive forms that account for the high mortality are the triple negative (TNBC) and inflammatory (IBC) breast cancer. The five-year survival rate for patients with TNBC that has spread to distant sites is 12% and the median overall survival (OS) for patients with stage IV disease is ⁇ 12 months compared with 36 months for hormone receptor-positive breast cancer. Similarly, the median OS of patients with stage III IBC is 4.75 years versus 13.40 years for patients with the same stage non-IBC. Besides, both subtypes disproportionately affect younger and black women.
  • TNBC triple negative
  • IBC inflammatory breast cancer
  • TNBC is characterized by the absence of estrogen receptor alpha (ER ⁇ ) and IBC by high frequency of ER ⁇ negativity.
  • ER ⁇ inhibits the migration of IBC cells and ER ⁇ -proficient cells are less metastatic than ER ⁇ knockout cells in xenograft models of the disease. Based on these findings, ER ⁇ is downregulated in tumors of patients with TNBC and IBC that eventually relapse with metastasis and tumor-specific re-expression of the receptor through the administration of ER ⁇ mRNA will likely leverage its anti-metastatic activity and prevent progression of the disease. This hypothesis is empowered by recent investigations that employed mRNA to upregulate tumor suppressor proteins (p53, PTEN), promoting the implementation of this strategy for cancer treatment.
  • p53 tumor suppressor proteins
  • This innovative approach establishes the foundation for clinical translation of ER ⁇ mRNA in treatment of TNBC and IBC. Notably, due to downregulation of ER ⁇ in other breast cancers and cancer types, these findings benefit patients with other malignancies. b) the optimization of methods of exploiting mRNA technology to enhance signaling by a tumor suppressor. Various lipid formulations for mRNA delivery are options to achieve maximum uptake by tumor cells and intracellular expression of a functional protein. Further, the present disclosure explores novel approaches of in vivo treatment to define optimal doses and duration, ensuring that a clinically relevant administration of mRNA can result in prolonged tumor specific expression of the receptor with desired anti-tumor activity.
  • ER ⁇ is a molecule Docket No.10063-085WO1 with targeting potential because it is downregulated in TNBC and IBC and its positivity correlates with better prognosis, yet the use of ER ⁇ agonists alone was deemed to be fairly ineffective due to the lack of the receptor in many of these tumors.
  • the present disclosure describes upregulation of ER ⁇ in tumors by using ER ⁇ mRNA-LNPs, yet the efficacy of this complex to produce an active receptor in cells has not previously been assessed.
  • Preliminary findings point to a strong induction of functional ER ⁇ in breast cancer cells following treatment with mRNA. They also indicate the advantage of the method of in vivo mRNA administration in facilitating tumor specific protein expression.
  • ER ⁇ mRNA the capacity of ER ⁇ mRNA to produce a potent tumor suppressor across breast cancer cells with diverse molecular and biological properties and an active receptor in tumors that represses breast cancer in models that accurately reflect the clinical pattern of disease progression is evaluated.
  • the present disclosure provides the following conceptual and technical innovations: a) There is no published work on the effects of ER ⁇ mRNA-LNPs in preclinical cancer models. These results are the first to show that ER ⁇ mRNA produces a functional protein that decreases the invasiveness of breast cancer cells and points toward inhibition of metastasis. The present disclosure is, therefore, unique since demonstrating the importance of ER ⁇ mRNA for prevention and treatment of breast cancer metastasis represents an entirely new direction for both nuclear receptor and breast cancer research.
  • the present disclosure also identifies a clinically Docket No.10063-085WO1 relevant approach to restore expression of ER ⁇ in IBC and TNBC tumors through the administration of complexes of ER ⁇ mRNA with LNPs to leverage its anti-metastatic activity.
  • Design of ER ⁇ mRNA-LNPs Recent advances in RNA therapeutics and mRNA vaccines have drawn significant attention due to their ability to tackle unmet clinical needs.
  • mRNA promises to transform clinical applications such as immunizations, genetic disorders and protein replacement therapies. Efficient delivery of mRNA and its targeted cellular expression are key factors to optimize mRNA therapeutic applications. Despite the advances in mRNA synthesis and regulation, its therapeutic use is limited due to high sensitivity to nucleases and the need for a protective delivery system that enables long half-life and a slow body clearance. Furthermore, the negative charge, high molecular weight and hydrophilicity of mRNA may also prevent it from crossing the cell membrane, leading to low cellular uptake. LNP is the most frequently used non- viral vector for RNA delivery due to an efficient binding and condensing RNA, protecting from enzymatic and chemical degradation in extracellular milieu, and efficient intracellular delivery.
  • a key feature of using LNP for mRNA delivery is the presence of positively charged lipid that enables complexation and encapsulation of negatively charged RNA.
  • a permanently cationic or ionizable lipid also facilitates through membrane disruption the endosomal escape of the LNP.
  • Research has demonstrated the ability to make reproducible mRNA-LNP using a microfluidic Nanoassemblr technology that is cGMP compatible and scalable to manufacture homogeneous mRNA-LNP for clinical application.
  • PDI polydispersity index
  • ER ⁇ mRNA-LNP ER ⁇ mRNA-LNP systems with cationic (e.g., DOTAP, DODMA) or ionizable lipid (e.g., SM-102, Dlin-MC3-DMA) are designed. Besides the charged lipid, the systems contain dioleoylphosphatidylcholine (DOPC), cholesterol, 1,2-Dimyristoyl-rac- glycerol-3-methoxy polyethylene glycol-2000 (DMG-PEG 2000), and phosphatidylethanolamine (PE).
  • DOPC dioleoylphosphatidylcholine
  • DOPC 1,2-Dimyristoyl-rac- glycerol-3-methoxy polyethylene glycol-2000
  • PE phosphatidylethanolamine
  • ER ⁇ mRNA (capped) is synthetically produced using established protocols suitable for clinical-grade mRNA.
  • Several lipids and lipid/nucleic acid ratios are used to optimize the mRNA loading and LNP characteristics using Nanoassemblr technology. Briefly, lipids and mRNA are Docket No.10063-085WO1 dissolved in ethanolic and aqueous phases, respectively. The phases are combined in a microfluidic chip at the ratio of 1:3 with a flow rate of 4-10 ml/min and the mixture is dialyzed in PBS to remove ethanol and unbound mRNA/siRNA.
  • Characterization of ER ⁇ mRNA-LNP Physico-chemical properties of LNP including diameter (size) and zeta potential (charge) are assessed in phosphate buffer by Dynamic Light Scattering (DLS) in a Malvern nano-ZS Zetasizer. The efficiency of mRNA encapsulation in LNP is quantified using RiboGreen® RNA assay and the integrity of mRNA in LNP is determined by High-Res Electrophoresis. Evaluate the functionality of ER ⁇ mRNA Preliminary findings demonstrate the efficacy of mRNA carrier (LNPs) to accumulate in breast cancer cells and efficiently deliver the encapsulated mRNA ensuring that non-toxic doses of ER ⁇ mRNA produce a functional receptor.
  • LDS Dynamic Light Scattering
  • FIG. 4B A strong induction of ER ⁇ protein with evident anti-migratory activity after incubation of KPL4 and TNBC SUM159 cells with lower amounts of ER ⁇ mRNA-LNPs (0.05-0.1 ⁇ g/ml) was observed (FIGS. 4C-4D). Delivery of ER ⁇ mRNA in breast cancer cells translates into a functional protein with tumor suppressor activity.
  • Experimental design and methods In vitro assessment of intracellular delivery and expression of ER ⁇ mRNA.
  • IBC and TNBC cell lines were screened for their ability to rapidly uptake complexes of mRNA-LNPs to evaluate their efficacy to penetrate tumor cells of different molecular subtypes.
  • additional IBC SUM149, SUM190, FC-IBC02
  • TNBC cell lines MDA-MB-231, MDA-MB-468, HCC-1395
  • concentrations 0.05-2 ⁇ g/ml
  • Optimal concentrations for each cell line were applied to test the expression of ER ⁇ mRNA by immunoblotting.
  • the functionality of the produced ER ⁇ protein was evaluated in luciferase reporter assays with an ERE-containing reporter plasmid and by assessing target gene expression by qPCR. Docket No.10063-085WO1
  • In vitro validation of the anti-tumor activity of ER ⁇ mRNA was evaluated by measuring cell invasion and migration in different molecular subtypes of aggressive breast cancer.
  • IBC SUM149, SUM190, FC-IBC02
  • TNBC cell lines MDA-MB-231, MDA-MB-468, HCC-1395
  • ER ⁇ mRNA- LNPs concentrations of ER ⁇ mRNA- LNPs that induce expression of the receptor using mCherry mRNA as control treatment.
  • Transwell invasion was monitored along with wound healing as well as cell motility on collagen-coated surfaces by recording single cell position in IncuCyte imaging system. Cell viability in real time was then assessed following incubation of cells with the same concentrations of ER ⁇ mRNA-LNPs using luminescent and clonogenic survival assays.
  • the effects on ER ⁇ mRNA-treated and ER ⁇ -transfected cells were compared.
  • ER ⁇ mRNA-treated normal breast (MCF-10A) and cancer cells were assessed and selected to use concentrations that do not stress the normal cells.
  • Two-way ANOVA was used to assess significant differences in cell velocity and Student’s t-test for those in cell viability, migration, invasion and gene expression. Evaluating the anti-tumor activity of ER ⁇ mRNA and elucidate the mechanism of action and Examining the effects of ER ⁇ mRNA on tumor development and metastasis Research has shown the association of ER ⁇ with favorable prognosis in patients with IBC and TNBC (Fig.1A).
  • the present disclosure investigated whether in vivo administration of the same mRNA could restore the protein in tumors and its tumor repressive activity.
  • the mRNA was administered directly in tumors to achieve maximal accumulation and expression in target tissue and the efficacy of administration was assessed through intratumoral injection of luciferase mRNA at same dose (5 ⁇ g) with that of ER ⁇ . Prolonged tumor specific protein expression lasting for more than half a week was observed (FIG. 3A), ensuring that the treatment scheme with biweekly injections will sustain high levels of ER ⁇ for duration of treatment.
  • ER ⁇ Complexes of ER ⁇ (2.5, 5, 10 ⁇ g) and mCherry (10 ⁇ g, vehicle) mRNA with LNPs were intratumorally injected (twice a week) for up to 4 weeks starting in 100 mm3 tumors.
  • Transplants were grown up to 400 mm3 and following resection in a survival surgery, metastasis was assessed weekly by whole body bioluminescence imaging (BLI, FIG.1C) and after mouse was sacrificed by histological, GFP immunofluorescence and immunohistochemical (IHC) assessment with the assistance of pathologist. Differences in early primary tumor growth were also determined by monitoring biweekly tumor volume through caliper measurements and by whole body bioluminescence imaging. Assessment of ER ⁇ expression in tumors.
  • ER ⁇ ER ⁇ -induced tumor expression of ER ⁇ occurs in mRNA- treated IBC xenograft (FIG. 8C).
  • the optimal dose of ER ⁇ mRNA that sustains expression of functional protein for the entire time of treatment across different models of IBC and TNBC was determined by assessing the levels of ER ⁇ and its target genes in resected tumors by IHC, qPCR and immunoblot. Finally, IHC staining was utilized to determine the intratumoral distribution of expression and identity the cells that uptake and synthesize the protein.
  • Toxicity To determine whether the ER ⁇ mRNA-based therapy has any deleterious effect on animal health after a single or multiple intratumoral administrations in four cohorts of animals (four doses) mouse weights and identifiers of animal stress (hunched posture, lethargy, ruffled fur) were monitored during dosing until the experimental end point. As a second measure of toxicity, complete blood cell counts (CBCs) and chemistry readings were defined. After initial and last dosing, blood samples were drawn and analyzed by Flow Cytometry for CBCs and Pathology for blood chemistry readings on 26-whole blood parameters.
  • CBCs complete blood cell counts
  • ER ⁇ target genes that are associated with metastasis were identified. Similar gene expression changes in ER ⁇ mRNA-treated cells were detected (FIG. 7). Indicating that ER ⁇ mRNA inhibits breast cancer progression and metastasis by regulating a complex network of associated pathways. Experimental design and methods: Identify ER ⁇ -associated genes and pathways with tumor repressive function. The present disclosure elucidates the mechanism by which ER ⁇ mRNA inhibits progression and metastasis of IBC and TNBC tumors to corroborate the antimetastatic activity of treatment and identify novel associated genes that regulate metastasis.
  • RNA-Seq Gene expression in vehicle and ER ⁇ mRNA-treated tumors was assessed by RNA-Seq and data was associated with previously identified ER ⁇ targets in IBC and TNBC cells.
  • ER ⁇ mRNA-treated IBC and TNBC cells were analyzed by ChIP-Seq to map the DNA binding of the receptor that mediates transcriptional effects.
  • the DNA binding and gene expression data was combined to define distinct mechanisms of gene regulation and direct targets of ER ⁇ upon mRNA treatment.
  • changes in gene expression were corroborated bt qPCR and IHC analysis of tumors to evaluate the therapeutic relevance of identified factors in functional in vitro and in vivo studies after their genetic and pharmacological inhibition.
  • mice 10 mice/group X 24 groups (6 tumor models X 4 treatments) were analyzed including 12 for the toxicity studies.
  • Kaplan-Meier plots illustrated differences in survival and significant differences were assessed by log-rank test. Differentially expressed genes were determined using SAM with a less than 0.01 FDR and an absolute fold change of greater than 1.5 between different groups. Significant differences in tumor volume, metastasis and mRNA levels were assessed by Student’s t and Fisher's exact tests and for multi- group comparisons by Kruskal-Wallis tests.
  • the present disclosure demonstrates the beneficial use of ER ⁇ mRNA as a therapy approach to prevent progression of breast cancer.

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Abstract

The present disclosure relates to compositions comprising nucleic acid delivery vehicles encoding the estrogen receptor beta (ERβ), and methods of treating and/or preventing diseases or disorders with ERβ dysregulated function.

Description

Docket No.10063-085WO1 ESTROGEN RECEPTOR COMPOSITIONS AND METHODS OF USE THEREOF CROSS-REFERENCE TO RELATED APPLICATION This PCT application claims priority to, and the benefit of, U.S. Provisional Patent Application No. 63/509,188, filed June 20, 2023, entitled “ESTROGEN RECEPTOR COMPOSITIONS AND METHODS OF USE THEREOF,” which is incorporated by reference herein in its entirety. REFERENCE TO SEQUENCE LISTING The sequence listing submitted on June 20th, 2024, as an .XML file entitled “10063- 085WO1_ST26” created on June 12th, 2024, and having a file size of 43,048 bytes is hereby incorporated by reference pursuant to 37 C.F.R. § 1.52(e)(5). FIELD The present disclosure relates to compositions comprising nucleic acid delivery vehicles encoding the estrogen receptor beta (ERβ), and methods of treating and/or preventing diseases or disorders with ERβ dysregulated function. BACKGROUND The physiological functions of estrogen and estrogen derived compounds are propagated through the estrogen receptors subtypes alpha (ERα) and beta (ERβ). These receptors have actions in the cell nucleus that regulate transcription of specific target genes in various organ systems, such as the reproductive, skeletal, cardiovascular, and central nervous systems. ERβ is reported to have profound effects on the reproductive, central nervous, and immune systems contributing to differentiation of cells such as the breast, uterus, ovarian and prostate. Thus, dysregulation of ERβ expression and/or function has been implicated in various diseases and disorders, including cancer, neuropathies and neurodegenerative disorders, cardiovascular diseases, osteoporosis, obesity, and metabolic disorders. However, therapies to improve ERβ expression and/or function are limiting. Given the widespread pathological effects of ERβ decline and minimal effective treatments to alleviate these effects, there is need to address the aforementioned problems mentioned above by developing and delivering nucleic acid compositions to increase the expression of active ERβ Docket No.10063-085WO1 proteins. The compounds, compositions, and methods disclosed herein address these and other needs. SUMMARY The present disclosure provides a therapeutic composition comprising a nucleic acid encoding ERβ. The present disclosure also provides methods of treating or preventing ER-related disorders, including ERβ-related disorders using a therapeutic composition comprising a nucleic acid encoding ERβ. In one aspect, disclosed herein is a therapeutic composition comprising a nucleic acid encoding estrogen receptor beta (ERβ), wherein the nucleic acid is encapsulated in or conjugated to a nucleic acid delivery vehicle. In some embodiments, the nucleic acid delivery vehicle comprises a pharmaceutically acceptable carrier selected from a lipid nanoparticle (LPN), a lipid carrier, an organic polymer, a cell, a virus-like particle, an excipient, a diluent, a salt, a buffer, or a stabilizer. In some embodiments, the nucleic acid comprises mRNA. In some embodiments, the nucleic acid comprises at least 80% identity to SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, the nucleic acid comprises at least 90% identity to SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, the nucleic acid comprises SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, the mRNA comprises a full-length mRNA. In some embodiments, the mRNA comprises a functional fragment of the full-length mRNA. In some embodiments, the LPN comprises a solid lipid nanoparticle, a nanostructured lipid carrier, or any variations thereof. In some embodiments, the lipid carrier comprises a liposome, a liposome-like nanoparticle, a lipid-polymer hybrid nanoparticle, a nanoemulsion, an exosome, a lipoprotein particle, or any combinations thereof. In some embodiments, the organic polymer comprises a polypeptide or peptide, a nucleic acid , a lipid, a carbohydrate, or any combinations thereof. In some embodiments, the cell comprises a dendritic cell. In some embodiments, the virus- like particle comprises one or more non-infectious components from a virus selected from Human immunodeficiency virus (HIV), Influenza virus, Hepatitis B virus, Hepatitis E virus, Ebola virus, Severe acute respiratory syndrome coronavirus (SARS-CoV), SARS-CoV-2, Respiratory syncytial virus (RSV), Human papillomavirus (HPVs), and Middle east respiratory syndrome coronavirus (MERS-CoV). Docket No.10063-085WO1 In some embodiments, the composition comprises a naked nucleic acid encoding an ERβ protein. In some embodiments, the nucleic acid comprises one or more chemical modifications to increase stability of the nucleic acid encoding ERβ. In some embodiments, the one or more chemical modifications are selected from a 5’-7-methylguanosine cap, a 5’ untranslated region 5’ UTR, a 3’ UTR, a modification to the open reading frame (ORF), and a poly-adenylate tail. In one aspect, disclosed herein is a method of treating or preventing an ERβ-related disorder in a subject in need thereof, the method comprising administering a pharmaceutically effective amount of a composition comprising a nucleic acid encoding ERβ, wherein the nucleic acid is encapsulated in or conjugated to a nucleic acid delivery vehicle, wherein the method increases expression of a ERβ protein in the subject relative to an untreated subject with cancer. In one aspect, disclosed herein is a method of treating or preventing tumor development in a subject with cancer, the method comprising administering a pharmaceutically effective amount of a composition comprising a nucleic acid encoding ERβ, wherein the nucleic acid is encapsulated in or conjugated to a nucleic acid delivery vehicle, wherein the method increases expression of a ERβ protein in the subject relative to an untreated subject with cancer. In one aspect, disclosed herein is a method of treating or preventing a metastasis in a subject, the method comprising administering a pharmaceutically effective amount of a composition comprising a nucleic acid encoding ERβ, wherein the nucleic acid is encapsulated in or conjugated to a nucleic acid delivery vehicle, and wherein the method increases expression of a ERβ protein in the subject relative to an untreated subject with a metastasis. In some embodiments, the nucleic acid delivery vehicle comprises a pharmaceutically acceptable carrier selected from a lipid nanoparticle (LPN), a lipid carrier, an organic polymer, a cell, a virus-like particle, an excipient, a diluent, a salt, a buffer, or a stabilizer. In some embodiments, the nucleic acid comprises mRNA. In some embodiments, the mRNA comprises a full-length mRNA. In some embodiments, the mRNA comprises a functional fragment of the full-length mRNA. In some embodiments, the nucleic acid comprises one or more chemical modifications to increase stability of the nucleic acid encoding ERβ. In some embodiments, the one or more chemical modifications are selected from a 5’-7-methylguanosine cap, a 5’ untranslated region 5’ UTR, a 3’ UTR, a modification to the open reading frame (ORF), and a poly-adenylate tail. In some embodiments, the composition is administered intratumorally or intravenously. In some embodiments, the ERβ-related disorder comprises a cancer selected from a breast cancer, an ovarian cancer, a uterine cancer, vaginal cancer, vulvar cancer, cervical cancer, urethral Docket No.10063-085WO1 cancer, a prostate cancer, colorectal cancer, bladder cancer, thyroid cancer, or cancers affecting a tissue from a reproductive, gastrointestinal, or urinary system. In some embodiments, the breast cancer comprises inflammatory breast cancer (IBC), Triple-Negative Breast Cancer (TNBC), HER2-positive breast cancer, or Hormone Receptor-(HR)-positive breast cancer. In some embodiments, the LPN comprises a solid lipid nanoparticle, a nanostructured lipid carrier, or any variations thereof. In some embodiments, the lipid carrier comprises a liposome, a liposome-like nanoparticle, a lipid-polymer hybrid nanoparticle, a nanoemulsion, an exosome, a lipoprotein particle, or any combinations thereof. In some embodiments, the organic polymer comprises a polypeptide or peptide, a nucleic acid, a lipid, a carbohydrate, or any combinations thereof. In some embodiments, the cell comprises a dendritic cell. In some embodiments, the virus- like particle comprises one or more non-infectious components from a virus selected from Human immunodeficiency virus (HIV), Influenza virus, Hepatitis B virus, Hepatitis E virus, Ebola virus, Severe acute respiratory syndrome coronavirus (SARS-CoV), SARS-CoV-2, Respiratory syncytial virus (RSV), Human papillomavirus (HPVs), and Middle east respiratory syndrome coronavirus (MERS-CoV). In some embodiments, the composition comprises a naked nucleic acid encoding an ERβ protein. In some embodiments, the ERβ protein targets one or more metastasis- and cancer progression-associated genes selected from CD36, TGFb, TGFbR2, ALDH1A1, ELMO1, ILR1, IL6, IL8, IL1, IL17, CCL2, GPR141, CREB1, TFF1, FN1, NRG1, LCN2, VTCN1, FST1, NRP1, RHOBTB3. In some embodiments, the composition is administered at a dose of at least 2μg of ERβ nucleic acid. In some embodiments, the composition is administered for at least one week. In some embodiments, the composition is administered at least once per week. In some embodiments, the composition is administered in combination with an adjuvant. In some embodiments, the composition is administered in combination with an additional therapeutic composition. In some embodiments, the additional therapeutic composition comprises an anti-cancer agent, a chemotherapeutic agent, an anti-inflammatory agent, or a combination thereof. In some embodiments, the anti-cancer agent comprises an interferon, a cytokine, a vaccine, a growth factor, an antibody or serotherapy, or an immunomodulatory agent. In some embodiments, the chemotherapeutic agent comprises a luteinizing hormone releasing hormone (LHRH), anti- androgens, endocrine therapy, aromatase inhibitors, anti-estrogens, photodynamic therapies, nitrogen mustards, nitrosoureas, metal containing compounds, nucleotide analogs, anti- metabolites, or a cancer suppressing agent. Docket No.10063-085WO1 In some embodiments, the method decreases the growth of cancer cells, the stemness of cancer cells, or the invasiveness of cancer cells in the subject relative to an untreated subject with an ERβ-related disorder. In some embodiments, the method enhances cancer-associated immune response in the subject relative to an untreated subject with an ERβ-related disorder. In one aspect, disclosed herein is a kit comprising a nucleic acid encoding an estrogen receptor beta (ERβ), wherein the nucleic acid is encapsulated in or conjugated to a nucleic acid delivery vehicle. In some embodiments, the nucleic acid comprises mRNA. In some embodiments, the mRNA comprises a full-length mRNA. In some embodiments, the mRNA comprises a functional fragment of the full-length mRNA. In some embodiments, the nucleic acid comprises one or more chemical modifications to increase stability of the nucleic acid encoding ERβ. In some embodiments, the one or more chemical modifications are selected from a 5’-7-methylguanosine cap, a 5’ untranslated region 5’ UTR, a 3’ UTR, a modification to the open reading frame (ORF), and a poly-adenylate tail. In some embodiments, the nucleic acid delivery vehicle comprises a pharmaceutically acceptable carrier selected from a lipid nanoparticle (LPN), a lipid carrier, an organic polymer, a virus-like particle, or a stabilizer. In some embodiments, the kit further comprises an RNase-free reagent selected from RNase-free water, RNase-free buffered solution, and RNase-free saline. BRIEF DESCRIPTION OF FIGURES The accompanying figures, which are incorporated in and constitute a part of this specification, illustrate several aspects described below. FIGS. 1A, 1B, and 1C show that ERβ inhibits metastasis in inflammatory breast cancer (IBC). FIG.1A shows the Kaplan-Meier estimates of metastasis-free survival and overall survival of patients with IBC. FIG. 1B shows the invasion of cells with different ERβ levels in Transwell chambers. Graph indicates the mean (cell number per field). FIG. 1C shows the whole-body bioluminescence images of NCG mice that were intravenously injected with KPL4 cells with different ERβ levels. FIG. 2 shows the effects of ERβ mRNA in tumor development after intratumoral administration. Volume of orthotopically implanted KPL4 inflammatory breast cancer tumors after intratumoral injection of complexes of 10 μg mCherry or ERβ mRNA with LNPs. mRNA +LNPs were first injected when tumors reached size of 100 mm3 and the administration was repeated twice a week for 3 weeks. Docket No.10063-085WO1 FIGS. 3A, 3B, 3C, and 3D show the tissue distribution of luciferase mRNA after intratumoral and intravenous administration. FIGS.3A and 3B show the in vivo bioluminescence imaging of mice 2 and 4 days after intratumoral injection of complexes of 5 μg (left side tumor) and 10 μg (right side tumor) luciferase mRNA with LNPs. (Arrows indicate signal indicative of mRNA expression in sites of orthotopically implanted tumors). FIGS.3C and 3D show the in vivo bioluminescence imaging (C: whole body, D: tumor area) of mice 1 and 3 days after intravenous administration of complexes of increasing concentrations (mouse 1: 5μg, mouse 2: 10 μg, mouse 3: 10 μg and mouse 4: 15 mg) of luciferase mRNA with LNPs. Arrows indicate tumor area. FIGS. 4A, 4B, 4C, 4D, and 4E show that the mRNA-LNP produce a functional ERβ in IBC cells. FIG.4A shows the duration and magnitude of expression of a fluorescent protein (GFP) into breast cancer cells after treating the cells with various concentrations of GFP mRNA encapsulated in LNPs to indicate the capacity of the complex to enter cancer cells and for the mRNA to be expressed inside the cells. The same delivery method is used for ERβ mRNA. FIG. 4B shows the kinetics of GFPmRNA-LNPs uptake by breast cancer cells and the duration of its presence inside the cells as this is indicated by the red signal that is produced by rhodamine that is used to label the lipids in LNPs. FIG.4C shows the expression of ERβ protein inside breast cancer cells after incubating these cells with 0.05 μg/ml or 0.075 μg/ml concentrations of ERβ mRNA- LNPs. Of note, the higher the concentration of ERβ mRNA that is used to treat the cells, the higher the protein levels of ERβ protein inside the cells. GFPmRNA-LNPs is used as negative control to demonstrate the specificity of the detection method (immunoblotting) to recognize exclusively ERβ. These data indicate that low non-toxic concentrations of ERβmRNA-LNPs are able to produce high levels of ERβ protein demonstrating the efficacy of the approach using ERβmRNA- LNPs. FIG. 4D shows that breast cancer cells that are treated with ERβmRNA-LNPs are less invasive and metastatic than the cells that are treated with another mRNA (GFPmRNA-LNPs). The analysis of the cells for invasion has been performed with the transwell invasion assay. FIG. 4E shows that the ERβ protein that is produced inside breast cancer cells (see FIG. 4C) after the treatment with 0.05 μg/ml or 0.075 μg/ml concentrations of ERβmRNA-LNPs is functional because it can alter the expression (mRNA levels) of genes that are known to be regulated by ERβ. The expression of these genes is altered dramatically even at very low dose of ERβmRNA-LNPs indicating the efficacy of the treatment. FIGS.5A, 5B and 5C show that upregulation of ERβ protein in breast cancer cells regulates genes that affect the immune system indicating the ability of ERβ to inhibit breast cancer progression and metastasis by inducing anti-tumor immunity. FIG. 5A depicts the results from a Docket No.10063-085WO1 microarray analysis (gene expression analysis) of breast cancer cells with different levels of ERβ and shows the altered gene expression signatures. FIGS.5B and 5C indicate the different levels of mRNA of immune response-associated genes in cells with different levels of ERβ. FIG.6 shows differences in the development of the mammary gland (size of ductal tree) in female mice that have ERβ (WT) and transgenic mice that engineered to lack ERβ expression (ERβKO). This figure demonstrates the role of ERβ in regulating processes during development that also play important roles in cancer. FIG.7 shows the gene expression after treatment of breast cancer cells with control (GFP) or varying amounts of ERβ mRNA-LNP for 48 hours. Treatment with increased amounts of ERβ increases gene expression of ERβ and IL6. FIGS. 8A, 8B, 8C, and 8D show the effects of ERβ mRNA on growth of breast cancers. FIG. 8A depicts the treatment scheme of human breast tumor xenografts with ERβ mRNA-LNP in a mouse breast cancer model. Inflammatory breast cancer (IBC) KPL4 cells expressing luciferase were orthotopically injected bilateral into the inguinal mammary glands. Upon reaching a size of 50 – 100 mm3 they were injected with 10 µg of either mCherry mRNA-LNP (Vehicle) or ERβ mRNA-LNP. Treatment with ERβ mRNA-LNPs was repeated twice a week for three weeks. At the end of the treatment period tumors were resected in a survival surgery and tumor progression and lung metastasis were monitored for another four weeks. Lungs were resected at this time (endpoint) and analyzed ex vivo by bioluminescence imaging for the presence of metastasis. FIG. 8B shows in vivo bioluminescence imaging (whole body) of mice before treatment (upper panel) and after (lower panel) the completion of the treatment with mCherry mRNA-LNP (Vehicle) and ERβ mRNA-LNP. Luciferase signal was adjusted separately in mice before and after treatment to indicate the differences between control and ERβ mRNA treatments. FIG. 8C shows the immunohistochemical analysis of the resected orthotopic breast tumors showing expression of ERβ protein in tumors that were treated with ERβ mRNA-LNP. FIG.8D is a graph depicting tumor growth in mice with orthotopically implanted tumors during the treatment with mCherry and ERβ mRNA. Growth curves show that tumors that were injected with ERβ mRNA appear to grow slightly but significantly slower than those treated with vehicle mRNA. FIG. 9 shows the analysis of mRNA levels in primary tumors. Tumors treated with ERβ mRNA have increased mRNA levels of ELMO1 and ESR2 (ERβ). FIGS.10A and 10B show the effects of ERβ mRNA on breast cancer metastasis. FIG.10A shows ex vivo bioluminescence imaging of lungs resected at endpoint, four weeks after the resection of primary tumors that were treated with mCherry mRNA (vehicle) (upper panel) and Docket No.10063-085WO1 ERβ mRNA-LNP (lower panel) for the presence of metastasis. FIG.10B shows a graph depicting luciferase signal indicative of metastatic burden as total flux in the resected lungs of FIG. 10A. Treatment with ERβ mRNA substantially decreases lung metastasis of orthotopically grown breast tumors. FIGS. 11A and 11B show the ERβ expression in breast cancer. FIG. 11A shows ERβ expression in normal and cancer tissues across 24 tumor types from TCGA (BRCA (breast cancer), COAD (colon adenocarcinoma), KIRC (kidney and renal cell carcinoma). FIG. 11B shows ERβ mRNA levels in normal and malignant breast (left) and across different breast cancer subtypes (right). FIG. 11A and 11B demonstrate the downregulation of ERβ in breast and other types of cancer that justifies the importance of our technology with the use of ERβ mRNA to restore its expression and tumor suppressor function in breast cancer. DETAILED DESCRIPTION The following description of the disclosure is provided as an enabling teaching of the disclosure in its best, currently known embodiment(s). To this end, those skilled in the relevant art will recognize and appreciate that many changes can be made to the various embodiments of the invention described herein, while still obtaining the beneficial results of the present disclosure. It will also be apparent that some of the desired benefits of the present disclosure can be obtained by selecting some of the features of the present disclosure without utilizing other features. Accordingly, those who work in the art will recognize that many modifications and adaptations to the present disclosure are possible and can even be desirable in certain circumstances and are a part of the present disclosure. Thus, the following description is provided as illustrative of the principles of the present disclosure and not in limitation thereof. Reference will now be made in detail to the embodiments of the invention, examples of which are illustrated in the drawings and the examples. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Terminology Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which this disclosure belongs. The term “comprising” and variations thereof as used herein is used synonymously with the term “including” and variations thereof and are open, non-limiting terms. Although the terms “comprising” and “including” have been used herein to describe various embodiments, the terms Docket No.10063-085WO1 “consisting essentially of” and “consisting of” can be used in place of “comprising” and “including” to provide for more specific embodiments and are also disclosed. As used in this disclosure and in the appended claims, the singular forms “a”, “an”, “the”, include plural referents unless the context clearly dictates otherwise. The following definitions are provided for the full understanding of terms used in this specification. Ranges can be expressed herein as from “about” one particular value, and/or to “about” another particular value. When such a range is expressed, another embodiment includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms another embodiment. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. It is also understood that there are a number of values disclosed herein, and that each value is also herein disclosed as “about” that particular value in addition to the value itself. For example, if the value “10” is disclosed, then “about 10” is also disclosed. It is also understood that when a value is disclosed that “less than or equal to” the value, “greater than or equal to the value” and possible ranges between values are also disclosed, as appropriately understood by the skilled artisan. For example, if the value “10” is disclosed the “less than or equal to 10”as well as “greater than or equal to 10” is also disclosed. It is also understood that the throughout the application, data is provided in a number of different formats, and that this data represents endpoints and starting points, and ranges for any combination of the data points. For example, if a particular data point “10” and a particular data point 15 are disclosed, it is understood that greater than, greater than or equal to, less than, less than or equal to, and equal to 10 and 15 are considered disclosed as well as between 10 and 15. It is also understood that each unit between two particular units are also disclosed. For example, if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also disclosed. As used herein, the terms "may," "optionally," and "may optionally" are used interchangeably and are meant to include cases in which the condition occurs as well as cases in which the condition does not occur. Thus, for example, the statement that a formulation "may include an excipient" is meant to include cases in which the formulation includes an excipient as well as cases in which the formulation does not include an excipient. “Composition” refers to any agent that has a beneficial biological effect. Beneficial biological effects include both therapeutic effects, e.g., treatment of a disorder or other undesirable physiological condition, and prophylactic effects, e.g., prevention of a disorder or other Docket No.10063-085WO1 undesirable physiological condition. The terms also encompass pharmaceutically acceptable, pharmacologically active derivatives of beneficial agents specifically mentioned herein, including, but not limited to, a vector, polynucleotide, cells, salts, esters, amides, proagents, active metabolites, isomers, fragments, analogs, and the like. When the term “composition” is used, then, or when a particular composition is specifically identified, it is to be understood that the term includes the composition per se as well as pharmaceutically acceptable, pharmacologically active vector, polynucleotide, salts, esters, amides, proagents, conjugates, active metabolites, isomers, fragments, analogs, etc. As used herein, a “delivery vehicle” refers to a bioactive molecule, cell, or microorganism, including, but not limited to a proteins, lipids, carbohydrates, nucleic acids, cells, bacteria, bacterial plasmids, viral vectors, virus-like particles, or any combinations or variations thereof, used to deliver or administer therapeutic compositions or therapeutic molecules into a cell, a tissue, or a subject in need thereof. The term “comprising”, and variations thereof as used herein is used synonymously with the term “including” and variations thereof and are open, non-limiting terms. Although the terms “comprising” and “including” have been used herein to describe various embodiments, the terms “consisting essentially of” and “consisting of” can be used in place of “comprising” and “including” to provide for more specific embodiments and are also disclosed. An "increase" can refer to any change that results in a greater amount of a symptom, disease, composition, condition, or activity. An increase can be any individual, median, or average increase in a condition, symptom, activity, composition in a statistically significant amount. Thus, the increase can be a 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100% increase so long as the increase is statistically significant. A "decrease" can refer to any change that results in a smaller amount of a symptom, disease, composition, condition, or activity. A substance is also understood to decrease the genetic output of a gene when the genetic output of the gene product with the substance is less relative to the output of the gene product without the substance. Also, for example, a decrease can be a change in the symptoms of a disorder such that the symptoms are less than previously observed. A decrease can be any individual, median, or average decrease in a condition, symptom, activity, composition in a statistically significant amount. Thus, the decrease can be a 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100% decrease so long as the decrease is statistically significant. Docket No.10063-085WO1 By “reduce” or other forms of the word, such as “reducing” or “reduction,” means lowering of an event or characteristic (e.g., tumor growth). It is understood that this is typically in relation to some standard or expected value, in other words it is relative, but that it is not always necessary for the standard or relative value to be referred to. For example, “reduces tumor growth” means reducing the rate of growth of a tumor relative to a standard or a control. By “prevent” or other forms of the word, such as “preventing” or “prevention,” is meant to stop a particular event or characteristic, to stabilize or delay the development or progression of a particular event or characteristic, or to minimize the chances that a particular event or characteristic will occur. Prevent does not require comparison to a control as it is typically more absolute than, for example, reduce. As used herein, something could be reduced but not prevented, but something that is reduced could also be prevented. Likewise, something could be prevented but not reduced, but something that is prevented could also be reduced. It is understood that where reduce or prevent are used, unless specifically indicated otherwise, the use of the other word is also expressly disclosed. The term “subject” refers to any individual who is the target of administration or treatment. The subject can be a vertebrate, for example, a mammal. In one aspect, the subject can be human, non-human primate, bovine, equine, porcine, canine, or feline. The subject can also be a guinea pig, rat, hamster, rabbit, mouse, or mole. Thus, the subject can be a human or veterinary patient. The term “patient” refers to a subject under the treatment of a clinician, e.g., physician. The term “treatment” refers to the medical management of a patient with the intent to cure, ameliorate, stabilize, or prevent a disease, pathological condition, or disorder. This term includes active treatment, that is, treatment directed specifically toward the improvement of a disease, pathological condition, or disorder, and also includes causal treatment, that is, treatment directed toward removal of the cause of the associated disease, pathological condition, or disorder. In addition, this term includes palliative treatment, that is, treatment designed for the relief of symptoms rather than the curing of the disease, pathological condition, or disorder; preventative treatment, that is, treatment directed to minimizing or partially or completely inhibiting the development of the associated disease, pathological condition, or disorder; and supportive treatment, that is, treatment employed to supplement another specific therapy directed toward the improvement of the associated disease, pathological condition, or disorder. As used herein, “enhance”, “enhanced”, “enhancement”, “enhancing”, and any grammatical variations thereof as used herein, refers to an act of intensifying, increasing, or further Docket No.10063-085WO1 improving the quality, value, or extent of a biological function, composition, compound, cell, or tissue. The term “amino acid,” includes but is not limited to amino acids contained in the group consisting of alanine (Ala or A), cysteine (Cys or C), aspartic acid (Asp or D), glutamic acid (Glu or E), phenylalanine (Phe or F), glycine (Gly or G), histidine (His or H), isoleucine (Ile or I), lysine (Lys or K), leucine (Leu or L), methionine (Met or M), asparagine (Asn or N), proline (Pro or P), glutamine (Gln or Q), arginine (Arg or R), serine (Ser or S), threonine (Thr or T), valine (Val or V), tryptophan (Trp or W), and tyrosine (Tyr or Y) residues. The term “amino acid residue” also may include amino acid residues contained in the group consisting of homocysteine, 2- Aminoadipic acid, N-Ethylasparagine, 3-Aminoadipic acid, Hydroxylysine, β-alanine, β-Amino- propionic acid, allo-Hydroxylysine acid, 2-Aminobutyric acid, 3-Hydroxyproline, 4- Aminobutyric acid, 4-Hydroxyproline, piperidinic acid, 6-Aminocaproic acid, Isodesmosine, 2- Aminoheptanoic acid, allo-Isoleucine, 2-Aminoisobutyric acid, N-Methylglycine, sarcosine, 3- Aminoisobutyric acid, N-Methylisoleucine, 2-Aminopimelic acid, 6-N-Methyllysine, 2,4- Diaminobutyric acid, N-Methylvaline, Desmosine, Norvaline, 2,2′-Diaminopimelic acid, Norleucine, 2,3-Diaminopropionic acid, Ornithine, and N-Ethylglycine. Typically, the amide linkages of the peptides are formed from an amino group of the backbone of one amino acid and a carboxyl group of the backbone of another amino acid. A “protein”, "polypeptide", or “peptide” each refer to a polymer of amino acids and does not imply a specific length of a polymer of amino acids. Thus, for example, the terms peptide, oligopeptide, protein, antibody, and enzyme are included within the definition of polypeptide. The peptides, polypeptides, and proteins disclosed herein may be modified to include non- amino acid moieties. Modifications may include but are not limited to carboxylation (e.g., N- terminal carboxylation via addition of a di-carboxylic acid having 4-7 straight-chain or branched carbon atoms, such as glutaric acid, succinic acid, adipic acid, and 4,4-dimethylglutaric acid), amidation (e.g., C-terminal amidation via addition of an amide or substituted amide such as alkylamide or dialkylamide), PEGylation (e.g., N-terminal or C-terminal PEGylation via additional of polyethylene glycol), acylation (e.g., O-acylation (esters), N-acylation (amides), S- acylation (thioesters)), acetylation (e.g., the addition of an acetyl group, either at the N-terminus of the protein or at lysine residues), formylation lipoylation (e.g., attachment of a lipoate, a C8 functional group), myristoylation (e.g., attachment of myristate, a C14 saturated acid), palmitoylation (e.g., attachment of palmitate, a C16 saturated acid), alkylation (e.g., the addition Docket No.10063-085WO1 of an alkyl group, such as an methyl at a lysine or arginine residue), isoprenylation or prenylation (e.g., the addition of an isoprenoid group such as farnesol or geranylgeraniol), amidation at C- terminus, glycosylation (e.g., the addition of a glycosyl group to either asparagine, hydroxylysine, serine, or threonine, resulting in a glycoprotein). Distinct from glycation, which is regarded as a nonenzymatic attachment of sugars, polysialylation (e.g., the addition of polysialic acid), glypiation (e.g., glycosylphosphatidylinositol (GPI) anchor formation, hydroxylation, iodination (e.g., of thyroid hormones), and phosphorylation (e.g., the addition of a phosphate group, usually to serine, tyrosine, threonine, or histidine). The phrases “percent identity” and “% identity,” as applied to polypeptide sequences, refer to the percentage of residue matches between at least two polypeptide sequences aligned using a standardized algorithm. Methods of polypeptide sequence alignment are well-known. Some alignment methods consider conservative amino acid substitutions. Such conservative substitutions, explained in more detail above, generally preserve the charge and hydrophobicity at the site of substitution, thus preserving the structure (and therefore function) of the polypeptide. Percent identity for amino acid sequences may be determined as understood in the art. (See, e.g., U.S. Pat. No. 7,396,664, which is incorporated herein by reference in its entirety). A suite of commonly used and freely available sequence comparison algorithms is provided by the National Center for Biotechnology Information (NCBI) Basic Local Alignment Search Tool (BLAST) (Altschul, S. F. et al. (1990) J. Mol. Biol. 215:403410), which is available from several sources, including the NCBI, Bethesda, Md., at its website. The BLAST software suite includes various sequence analysis programs including “blastp,” that is used to align a known amino acid sequence with other amino acids sequences from a variety of databases. Percent identity may be measured over the length of an entire defined polypeptide sequence or may be measured over a shorter length, for example, over the length of a fragment taken from a larger, defined polypeptide sequence, for instance, a fragment of at least 15, at least 20, at least 30, at least 40, at least 50, at least 70 or at least 150 contiguous residues. Such lengths are exemplary only, and it is understood that any fragment length may be used to describe a length over which percentage identity may be measured. “Expression” as used herein refers to the process by which information from a gene is used in the synthesis of a functional gene product that enables it to produce a peptide/protein end product, and ultimately affect a phenotype, as the final effect. The term “variant” means a polypeptide derived from a parent estrogen receptor by one or more (several) alteration(s), i.e., a substitution, insertion, and/or deletion, at one or more (several) Docket No.10063-085WO1 positions. A substitution means a replacement of an amino acid occupying a position with a different amino acid; a deletion means removal of an amino acid occupying a position; and an insertion means adding 1 or more, such as 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, preferably 1-3 amino acids immediately adjacent an amino acid occupying a position. In relation to substitutions, ‘immediately adjacent’ may be to the N-side (‘upstream’) or C-side (‘downstream’) of the amino acid occupying a position (‘the named amino acid’). Therefore, for an amino acid named/numbered ‘X,’ the insertion may be at position ‘X+1’ (‘downstream’) or at position ‘X−1’ (‘upstream’). A “variant” of a particular polypeptide sequence may be defined as a polypeptide sequence having at least 50% sequence identity to the particular polypeptide sequence over a certain length of one of the polypeptide sequences using blastp with the “BLAST 2 Sequences” tool available at the National Center for Biotechnology Information's website. (See Tatiana A. Tatusova, Thomas L. Madden (1999), “Blast 2 sequences—a new tool for comparing protein and nucleotide sequences”, FEMS Microbiol Lett.174:247-250). In some embodiments a variant polypeptide may show, for example, at least 60%, at least 70%, at least 80%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% or greater sequence identity over a certain defined length relative to a reference polypeptide. A variant polypeptide may have substantially the same functional activity as a reference polypeptide. For example, a variant polypeptide may exhibit or more biological activities associated with binding a ligand and/or binding DNA at a specific binding site. The term “mRNA” refers to messenger ribonucleic acid, or single stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is translated by a ribosome in the process of synthesizing a protein. mRNA is created during the process of transcription, where a gene is converted into a primary transcript mRNA (or pre-mRNA). The primary transcript is further processed through RNA splicing to only contain regions that will encode protein. mRNA can also be targeted for epigenetic modifications, such as methylation, to impact mRNA translation, nuclear retention, nuclear export, processing, and splicing. A “nucleotide” is a compound consisting of a nucleoside, which consists of a nitrogenous base and a 5-carbon sugar, linked to a phosphate group forming the basic structural unit of nucleic acids, such as DNA or RNA. The four types of nucleotides are adenine (A), cytosine (C), guanine (G), and thymine (T), each of which are bound together by a phosphodiester bond to form a nucleic acid molecule. Docket No.10063-085WO1 A “nucleic acid” is a chemical compound that serves as the primary information-carrying molecules in cells and make up the cellular genetic material. Nucleic acids comprise nucleotides, which are the monomers made of a 5-carbon sugar (usually ribose or deoxyribose), a phosphate group, and a nitrogenous base. A nucleic acid can also be a deoxyribonucleic acid (DNA) or a ribonucleic acid (RNA). A “naked nucleic acid” refers to a nucleic acid that is not associated with proteins, lipids, or any other molecule to help protect it. Naked nucleic acids are the result of the release or purification of genetic information from their initial source or environment, including, but not limited to a cellular environment. The terms “percent identity” and “% identity,” as applied to polynucleotide sequences, refer to the percentage of residue matches between at least two polynucleotide sequences aligned using a standardized algorithm. Such an algorithm may insert, in a standardized and reproducible way, gaps in the sequences being compared in order to optimize alignment between two sequences, and therefore achieve a more meaningful comparison of the two sequences. Percent identity for a nucleic acid sequence may be determined as understood in the art. (See, e.g., U.S. Pat. No. 7,396,664, which is incorporated herein by reference in its entirety). A suite of commonly used and freely available sequence comparison algorithms is provided by the National Center for Biotechnology Information (NCBI) Basic Local Alignment Search Tool (BLAST) (Altschul, S. F. et al. (1990) J. Mol. Biol. 215:403410), which is available from several sources, including the NCBI, Bethesda, Md., at its website. The BLAST software suite includes various sequence analysis programs including “blastn,” that is used to align a known polynucleotide sequence with other polynucleotide sequences from a variety of databases. Also available is a tool called “BLAST 2 Sequences” that is used for direct pairwise comparison of two nucleotide sequences. “BLAST 2 Sequences” can be accessed and used interactively at the NCBI website. The “BLAST 2 Sequences” tool can be used for both blastn and blastp (discussed above). Percent identity may be measured over the length of an entire defined polynucleotide sequence or may be measured over a shorter length, for example, over the length of a fragment taken from a larger, defined sequence, for instance, a fragment of at least 20, at least 30, at least 40, at least 50, at least 70, at least 100, or at least 200 contiguous nucleotides. Such lengths are exemplary only, and it is understood that any fragment length may be used to describe a length over which percentage identity may be measured. A "gene" refers to a polynucleotide containing at least one open reading frame that is capable of encoding a particular polypeptide or protein after being transcribed and translated. Any of the polynucleotides sequences described herein may be used to identify larger fragments or full- Docket No.10063-085WO1 length coding sequences of the gene with which they are associated. A "gene product" refers to the amino acid (e.g., peptide or polypeptide) generated when a gene is transcribed and translated. A “full length” polynucleotide sequence is one containing at least a translation initiation codon (e.g., methionine) followed by an open reading frame and a translation termination codon. A “full length” polynucleotide sequence encodes a “full length” polypeptide sequence. A “variant,” “mutant,” or “derivative” of a particular nucleic acid sequence may be defined as a nucleic acid sequence having at least 50% sequence identity to the particular nucleic acid sequence over a certain length of one of the nucleic acid sequences using blastn with the “BLAST 2 Sequences” tool available at the National Center for Biotechnology Information's website. (See Tatiana A. Tatusova, Thomas L. Madden (1999), “Blast 2 sequences—a new tool for comparing protein and nucleotide sequences”, FEMS Microbiol Lett.174:247-250). In some embodiments a variant polynucleotide may show, for example, at least 60%, at least 70%, at least 80%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% or greater sequence identity over a certain defined length relative to a reference polynucleotide. As used herein, a “mutation” refers to changing the structure of a gene, resulting in a variant form that may be transmitted to later generations. A mutation is caused by the alteration of single nucleotides in DNA, or the deletion, insertion, or rearrangement of larger sections of genes. A mutation can lead to the expression of a protein that has been changed physically or functionally leading to lethality, non-lethal dysfunction effects, or no effects. Variants comprising a fragment of a reference amino acid sequence or nucleotide sequence are contemplated herein. A “fragment” is a portion of an amino acid sequence or a nucleotide sequence which is identical in sequence to but shorter in length than the reference sequence. A fragment may comprise up to the entire length of the reference sequence, minus at least one nucleotide/amino acid residue. For example, a fragment may comprise from 5 to 1000 contiguous nucleotides or contiguous amino acid residues of a reference polynucleotide or reference polypeptide, respectively. In some embodiments, a fragment may comprise at least 5, 10, 15, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 40, 50, 60, 70, 80, 90, 100, 150, 250, or 500 contiguous nucleotides or contiguous amino acid residues of a reference polynucleotide or reference polypeptide, respectively. Fragments may be preferentially selected from certain regions of a molecule, for example the N-terminal region and/or the C-terminal region of a polypeptide or the 5′-terminal region and/or the 3′ terminal region of a polynucleotide. The term “at least a fragment” encompasses the full length polynucleotide or full length polypeptide. A “functional fragment” Docket No.10063-085WO1 refers to a portion of an amino acid sequence or a nucleotide sequence which is identical in sequence to but shorter in length than the reference sequence that retains or increases the activity of the reference sequence. The word “vector” refers to any vehicle that carries a polynucleotide into a cell for the expression of the polynucleotide in the cell. The vector may be, for example, a plasmid, a virus, a phage particle, or a nanoparticle. Once transformed into a suitable host, the vector may replicate and function independently of the host genome, or may in some instances, integrate into the genome itself. In some embodiments, the vector is a DNA construct containing a DNA sequence which is operably linked to a suitable control sequence capable of affecting the expression of the DNA in a suitable host cell. Such control sequences can include a promoter to effect transcription, an optional operator sequence to control such transcription, a sequence encoding suitable mRNA ribosome binding sites, and sequences which control the termination of transcription and translation. In other embodiments, the vector is a lipid nanoparticle. Lipid nanoparticles can be used to deliver mRNA to a host cell for expression of the mRNA in the host cell. In some embodiments, the expression vector comprises a plasmid or a virus or viral vector. A plasmid or a viral vector can be capable of extrachromosomal replication or, optionally, can integrate into the host genome. As used herein, the term "integrated" used in reference to an expression vector (e.g., a plasmid or viral vector) means the expression vector, or a portion thereof, is incorporated (physically inserted or ligated) into the chromosomal DNA of a host cell. As used herein, a “viral vector” refers to a virus-like particle containing genetic material which can be introduced into a eukaryotic cell without causing substantial pathogenic effects to the eukaryotic cell. A wide range of viruses or viral vectors can be used for transduction but should be compatible with the cell type the virus or viral vector are transduced into (e.g., low toxicity, capability to enter cells). Suitable viruses and viral vectors include adenovirus, lentivirus, retrovirus, among others. In some embodiments, the expression vector encoding a chimeric polypeptide is a naked DNA or is comprised in a nanoparticle (e.g., liposomal vesicle, porous silicon nanoparticle, gold-DNA conjugate particle, polyethyleneimine polymer particle, cationic peptides, etc.). The term “administer,” “administering”, or derivatives thereof refer to delivering a composition, substance, inhibitor, or medication to a subject or object by one or more the following routes: oral, topical, intravenous, subcutaneous, transcutaneous, transdermal, intramuscular, intra- joint, parenteral, intra-arteriole, intradermal, intraventricular, intracranial, intraperitoneal, intralesional, intranasal, rectal, vaginal, by inhalation or via an implanted reservoir. The term “parenteral” includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, Docket No.10063-085WO1 intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injections or infusion techniques. As used herein, the term “encapsulate” or “encapsulating” refers to a process in which molecules, such as nucleic acids, proteins, and other macromolecules are surrounded or coated by nanoparticles for delivery to a targeted tissue or cell-type. The term “cancer” is used to address any neoplastic disease, and is not limited to epithelial neoplasms (surface and glandular cancers; such a squamous cancers or adenomas)). It is used here to describe both solid tumors and hematologic malignancies, including epithelial (surface and glandular) cancers, soft tissue, and bone sarcomas, angiomas, mesothelioma, melanoma, lymphomas, leukemias and myeloma. A “metastasis”, or variations thereof refer to the development of a secondary neoplastic growth at a distance from a primary site of cancer. The terms "cell," "cell line" and "cell culture" include progeny. It is also understood that all progenies may not be precisely identical in DNA content, due to deliberate or inadvertent mutations. Variant progeny that have the same function or biological property, as screened for in the original cell, are included. The term “kit” describes a wide variety of bags, containers, carrying cases, and other portable enclosures which may be used to carry and store solid substances, liquid substances, and other accessories necessary to deliver nucleic acid compositions. The terms “treat,” “treating,” and grammatical variations thereof as used herein, include partially or completely delaying, alleviating, mitigating, or reducing the intensity of one or more attendant symptoms of a disorder or condition and/or alleviating, mitigating, or impeding one or more causes of a disorder or condition. Treatments according to the disclosure may be applied preventively, prophylactically, palliatively, or remedially. Treatments are administered to a subject prior to disease onset, during early disease onset, or after an established development of disease. A “pharmaceutically effective amount” of a drug necessary to achieve a therapeutic effect may vary according to factors such as the age, sex, and weight of the subject. Dosage regimens can be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily, or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation. "Pharmaceutically acceptable" component can refer to a component that is not biologically or otherwise undesirable, i.e., the component may be incorporated into a pharmaceutical formulation of the invention and administered to a subject as described herein without causing significant undesirable biological effects or interacting in a deleterious manner with any of the Docket No.10063-085WO1 other components of the formulation in which it is contained. When used in reference to administration to a human, the term generally implies the component has met the required standards of toxicological and manufacturing testing or that it is included on the Inactive Ingredient Guide prepared by the U.S. Food and Drug Administration. "Pharmaceutically acceptable carrier" (sometimes referred to as a “carrier”) means a carrier or excipient that is useful in preparing a pharmaceutical or therapeutic composition that is generally safe and non-toxic, and includes a carrier that is acceptable for veterinary and/or human pharmaceutical or therapeutic use. The terms "carrier" or "pharmaceutically acceptable carrier" can include, but are not limited to, phosphate buffered saline solution, water, emulsions (such as an oil/water or water/oil emulsion) and/or various types of wetting agents. As used herein, the term “carrier” encompasses any excipient, diluent, filler, salt, buffer, stabilizer, solubilizer, lipid, stabilizer, or other material well known in the art for use in pharmaceutical formulations. The choice of a carrier for use in a composition will depend upon the intended route of administration for the composition. The preparation of pharmaceutically acceptable carriers and formulations containing these materials is described in, e.g., Remington's Pharmaceutical Sciences, 21st Edition, ed. University of the Sciences in Philadelphia, Lippincott, Williams & Wilkins, Philadelphia, PA, 2005. Examples of physiologically acceptable carriers include saline, glycerol, DMSO, buffers such as phosphate buffers, citrate buffer, and buffers with other organic acids; antioxidants including ascorbic acid; low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, arginine or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; salt-forming counterions such as sodium; and/or nonionic surfactants such as TWEENTM (ICI, Inc.; Bridgewater, New Jersey), polyethylene glycol (PEG), and PLURONICSTM (BASF; Florham Park, NJ). To provide for the administration of such dosages for the desired therapeutic treatment, compositions disclosed herein can advantageously comprise between about 0.1% and 99% by weight of the total of one or more of the subject compounds based on the weight of the total composition including carrier or diluent. A “gene therapy” refers to a medical/clinic approach to treat or prevent a disease, condition, or disorder by correcting an underlying genetic issue. This therapeutic technique involves introducing a gene to a subject or patient to replace or alleviate consequences of the dysfunction gene(s) causing the disease, condition, or disorder. Docket No.10063-085WO1 A “virus” is a microscopic infectious agent that replicates only inside the living cells of an organism. Viruses can infect all life forms, including mammalian and non-mammalian animals, plants, and other microorganisms. A complete virus, also known as a virion, consists of nucleic acid genetic material surrounded by a protective coat of protein called a capsid. Virus can have a lipid envelope derived from the infected host cell membrane. In general, there are five morphological virus types including helical, icosahedral, prolate, enveloped, and complex virus. A virus can either have a DNA or RNA genome, though a vast majority have RNA genomes. Irrespective of the type of nucleic acid genome, a viral genome can be either a single-stranded genome or a double-stranded genome. An “adjuvant” refers to a drug, biomolecule, macromolecule, composition, or combinations thereof used to increase the efficacy or potency of a drug or therapeutic composition. Adjuvants can also possess the characteristic of increasing the immune response to an antigen within a subject. Therapeutic compositions Delivery vehicles are versatile tools for therapeutic gene delivery, or delivery of nucleic acids to targeted tissues, cells, and/or organelles. Nucleic acids are also powerful therapeutic molecules to exogenously regulate cellular processes that can have an impact on a whole organism. Strategic delivery of nucleic acids can make changes to the expression of one or more genes in an organism either permanent or transient. For therapeutic purposes, nucleic acids can be used to correct a disease-related gene dysregulation by adding, removing, or replacing genetic material. Further, therapeutic strategies using nucleic acids can also make cells, tissues, organs, and/or organ systems behave in a certain way by activating, suppressing, or supplementing gene expression. Utilizing said strategies to regulate estrogen receptor (ER) gene expression is an approach to treatment and/or prevent ER-related diseases or disorders. A myriad of physiological processes in mammals are regulated by estrogen receptors (ERs). There are two main forms of ERs, ERα and ERβ, where are separately encoded by Esr1 and Esr2 genes, respectively. Disregulation of ERβ signaling has been implicated in numerous diseases and disorders, including, but not limited to cancer, neurological diseases (including, but not limited to Alzheimer's diseases, Parkinson’s disease, and multiple sclerosis), gastrointestinal diseases (including, but not limited to inflammatory bowel syndrome, liver diseases, and Crohn’s disease) cardiovascular diseases (including, but not limited to coronary artery disease and atherosclerosis), endometriosis, and fibroids. Because of the widespread regulation of ERβ on mammalian organ systems, there Docket No.10063-085WO1 remains a need to develop gene delivery compositions to alter or restore ERβ expression in ER- related diseases or disorders. The present disclosure provides a therapeutic composition comprising a nucleic acid encoding ERβ and a nucleic acid delivery vehicle. In one aspect, disclosed herein is a therapeutic composition comprising a nucleic acid encoding estrogen receptor beta (ERβ), wherein the nucleic acid is encapsulated in or conjugated to a nucleic acid delivery vehicle. In some embodiments, the nucleic acid comprises mRNA. In some embodiments, the nucleic acid comprises DNA. In some embodiments, the mRNA comprises a full-length mRNA. In some embodiments, the mRNA comprises a functional fragment of the full-length mRNA. In some embodiments, the nucleic acid comprises at least 50% identity to SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, the nucleic acid comprises at least 60% identity to SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, the nucleic acid comprises at least 70% identity to SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, the nucleic acid comprises at least 80% identity to SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, the nucleic acid comprises at least 81% identity to SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, the nucleic acid comprises at least 82% identity to SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, the nucleic acid comprises at least 83% identity to SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, the nucleic acid comprises at least 84% identity to SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, the nucleic acid comprises at least 85% identity to SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, the nucleic acid comprises at least 86% identity to SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, the nucleic acid comprises at least 87% identity to SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, the nucleic acid comprises at least 88% identity to SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, the nucleic acid comprises at least 89% identity to SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, the nucleic acid comprises at least 90% identity to SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, the nucleic acid comprises at least 91% identity to SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, the nucleic acid comprises at least 92% identity to SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, the nucleic acid comprises at least 93% identity to SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, the nucleic acid comprises at least 94% identity to SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, the nucleic acid comprises at least 95% identity to SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, the nucleic acid comprises at least Docket No.10063-085WO1 96% identity to SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, the nucleic acid comprises at least 97% identity to SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, the nucleic acid comprises at least 98% identity to SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, the nucleic acid comprises at least 99% identity to SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, the nucleic acid comprises SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, the nucleic acid sequence comprises an ERβ nucleic acid, such as an mRNA sequence. This nucleic acid sequence can be naturally occurring or synthetically derived. In a specific embodiment, the ERβ mRNA is a full length ERβ mRNA. In some embodiments, the Erβ-encoding nucleic acid is a functional fragment of the full-length naturally occurring ERβ mRNA. In some embodiments, the ERβ mRNA comprises SEQ ID NO: 1, or fragments thereof. In some embodiments, the ERβ mRNA comprises the gene accession no. NM_001437.3, or fragments thereof. As used herein, a “functional fragment” refers to the gene product of a nucleic acid sequence, wherein the nucleic acid sequence is a smaller sequence within a larger parent nucleic acid sequence, that retains functional activities at or near the level of the gene product expressed by the parent nucleic acid sequence. In some embodiments, the ERβ mRNA is a linear mRNA. In some embodiments, the ERβ mRNA is a circular mRNA. It should be noted that the circular ERβ mRNA produces the same ERβ protein, however the circular ERβ is more stable than the linear structure. Circular mRNA is protected from ribonuclease-dependent degradation inside the cells and is considered to remain in cells for longer period compared with the linear mRNA. Circular mRNA can be produced by vectors (including, but not limited to plasmids) that incorporate some modifications that do not change the sequence of the protein but facilitate the circulation of mRNA. In some embodiments, the nucleic acid sequence comprises an ERβ DNA. In some embodiments, the ERβ DNA is a full length ERβ DNA. In some embodiments, the ERβ DNA is a functional fragment of the full-length ERβ DNA. In some embodiments, the ERβ DNA comprises SEQ ID NO: 2, or fragments thereof. In some embodiments, the ERβ DNA comprises the gene accession no. NC_000014.9, or fragments thereof. Although different nucleic acid payloads can have different biochemical mechanisms of action, all of them must avoid clearance of off-target organs, must access the correct tissue, must interact with the targeted cell type in a complex tissue microenvironment, must be taken up by an intracellular mechanism, directed to regulate and/or influence a gene-related mechanism or product, and subsequently removed into the extracellular microenvironment. Furthermore, even though various nucleic acid therapeutics can be modified using stable chemical modifications and Docket No.10063-085WO1 delivered using stable conjugates, most RNA-based and DNA-based therapeutics still require a vehicle for entry into a cell. To facilitate this, several delivery systems have been developed including lipid nanoparticle (LPN) vehicles and polymeric vehicles. In some embodiments, the nucleic acid delivery vehicle comprises a pharmaceutically acceptable carrier selected from an LPN, a lipid carrier, an organic polymer, a cell, a virus-like particle, an excipient, a diluent, a salt, a buffer, a stabilizer, or combinations thereof. As used herein, the term “lipid nanoparticle” or “LPN” refers to a lipid-nucleic acid particle or a nucleic acid lipid particle (e.g., a stable lipid particle conjugated to, encapsulating, or interacting with a nucleic acid). A LNP represents a particle made from lipids (including, but not limited to a cationic lipid, a non-cationic lipid, and a conjugated lipid that prevents aggregation of the particle) and a nucleic acid, wherein the nucleic acid (including, but not limited to mRNA, double stranded(ds) DNA, siRNA, miRNA, single stranded (ss) DNA, ssRNA, shRNA, aiRNA, self-amplifying RNA, plasmids, and vectors) is encapsulated within the lipid. In some embodiments, the nucleic acid is at least 50% encapsulated in the LPN. In some embodiments, the nucleic acid is at least 60% encapsulated in the LPN. In some embodiments, the nucleic acid is at least 70% encapsulated in the LPN. In some embodiments, the nucleic acid is at least 75% encapsulated in the LPN. In some embodiments, the nucleic acid is at least 80% encapsulated in the LPN. In some embodiments, the nucleic acid is at least 90% encapsulated in the LPN. In some embodiments, the nucleic acid is at least 95% encapsulated in the LPN. In some embodiments, the nucleic acid is at least 99% encapsulated in the LPN. In some embodiments, the nucleic acid is at least 100% encapsulated in the LPN. LPN vehicles are extremely useful for systemic applications, as they can exhibit extended circulation lifetimes following intravenous (i.v.) injection(s), they can accumulate at distal sites (e.g., sites physically separated from the administration site), and they can mediate expression of the delivered gene or silence expression of a target gene at distal sites. The LPN of the present disclosure have a diameter from about 30nm to about 200nm, from about 40nm to about 150nm, from about 50nm to about 140nm, from about 60nm to about 130nm, from about 70nm to about 120nm, from about 80nm to about 110nm, from about 90nm to about 100nm, and are substantially non-toxic. LPN and their methods of preparation are disclosed in U.S. Patent Publication Nos.20040142025 and 20070042031, the disclosures of which are herein incorporated by reference in their entirety. In some embodiments, the LPN comprises a solid lipid nanoparticle, a nanostructured lipid carrier, or any variations thereof. In some embodiments, the LPN is biodegradable and/or biocompatible. Docket No.10063-085WO1 As used herein, a “lipid carrier” or “liposome” refers to enclosed phospholipid bilayer spherical vesicles composed of amphiphilic lipids surrounding an aqueous interior that is optimal for carrying and delivering hydrophilic or hydrophobic payloads. Similar to LPN vehicles, liposomes are extremely used for systemic applications, but primarily carry payloads to targeted destinations internally rather than payloads being conjugated to the external surface. In some embodiments, the lipid carrier comprises a liposome, a liposome-like nanoparticle, a lipid-polymer hybrid nanoparticle, a nanoemulsion, an exosome, a lipoprotein particle, or any combinations thereof. In some embodiments, the lipid carrier is biodegradable and/or biocompatible. As used herein, the term “polymer” or “polymer chain” refers to macromolecules comprising repeating structural units of from about 2 monomeric units to about one million or more monomeric units, connected by one or more covalent bonds. Polymer may be organic polymers or inorganic polymers. Polymers may also be synthetic, semi-synthetic, or naturally occurring, and can comprise homopolymers (e.g., comprising the same repeating monomer unit) or copolymers (e.g., comprising at least two different monomeric units). Copolymers can be periodic copolymers (e.g., where monomer residues A and B are arranged in a repeating sequence such as A-B-A-A-B-B-A-A-A-B-B-B), or random copolymers having random sequences of monomers A and B. Generally, the average molecular weight of the polymer ranges from about 1kDa to about 1000 kDa. In some embodiments, the average molecular weight of the polymer is about 1, 2, 3, 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, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, Docket No.10063-085WO1 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, 383, 384, 385, 386, 387, 388, 389, 390, 391, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 408, 409, 410, 411, 412, 413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 432, 433, 434, 435, 436, 437, 438, 439, 440, 441, 442, 443, 444, 445, 446, 447, 448, 449, 450, 451, 452, 453, 454, 455, 456, 457, 458, 459, 460, 461, 462, 463, 464, 465, 466, 467, 468, 469, 470, 471, 472, 473, 474, 475, 476, 477, 478, 479, 480, 481, 482, 483, 484, 485, 486, 487, 488, 489, 490, 491, 492, 493, 494, 495, 496, 497, 498, 499, 500, 501, 502, 503, 504, 505, 506, 507, 508, 509, 510, 511, 512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, 524, 525, 526, 527, 528, 529, 530, 531, 532, 533, 534, 535, 536, 537, 538, 539, 540, 541, 542, 543, 544, 545, 546, 547, 548, 549, 550, 551, 552, 553, 554, 555, 556, 557, 558, 559, 560, 561, 562, 563, 564, 565, 566, 567, 568, 569, 570, 571, 572, 573, 574, 575, 576, 577, 578, 579, 580, 581, 582, 583, 584, 585, 586, 587, 588, 589, 590, 591, 592, 593, 594, 595, 596, 597, 598, 599, 600, 601, 602, 603, 604, 605, 606, 607, 608, 609, 610, 611, 612, 613, 614, 615, 616, 617, 618, 619, 620, 621, 622, 623, 624, 625, 626, 627, 628, 629, 630, 631, 632, 633, 634, 635, 636, 637, 638, 639, 640, 641, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 653, 654, 655, 656, 657, 658, 659, 660, 661, 662, 663, 664, 665, 666, 667, 668, 669, 670, 671, 672, 673, 674, 675, 676, 677, 678, 679, 680, 681, 682, 683, 684, 685, 686, 687, 688, 689, 690, 691, 692, 693, 694, 695, 696, 697, 698, 699, 700, 701, 702, 703, 704, 705, 706, 707, 708, 709, 710, 711, 712, 713, 714, 715, 716, 717, 718, 719, 720, 721, 722, 723, 724, 725, 726, 727, 728, 729, 730, 731, 732, 733, 734, 735, 736, 737, 738, 739, 740, 741, 742, 743, 744, 745, 746, 747, 748, 749, 750, 751, 752, 753, 754, 755, 756, 757, 758, 759, 760, 761, 762, 763, 764, 765, 766, 767, 768, 769, 770, 771, 772, 773, 774, 775, 776, 777, 778, 779, 780, 781, 782, 783, 784, 785, 786, 787, 788, 789, 790, 791, 792, 793, 794, 795, 796, 797, 798, 799, 800, 801, 802, 803, 804, 805, 806, 807, 808, 809, 810, 811, 812, 813, 814, 815, 816, 817, 818, 819, 820, 821, 822, 823, 824, 825, 826, 827, 828, 829, 830, 831, 832, 833, 834, 835, 836, 837, 838, 839, 840, 841, 842, 843, 844, 845, 846, 847, 848, 849, 850, 851, 852, 853, 854, 855, 856, 857, 858, 859, 860, 861, 862, 863, 864, 865, 866, 867, 868, 869, 870, 871, 872, 873, 874, 875, 876, 877, 878, 879, 880, 881, 882, 883, 884, 885, 886, 887, 888, 889, 890, 891, 892, 893, 894, 895, 896, 897, 898, 899, 900, 901, 902, 903, 904, 905, 906, 907, 908, 909, 910, 911, 912, 913, 914, 915, 916, 917, 918, 919, 920, 921, 922, 923, 924, 925, 926, 927, 928, 929, 930, 931, 932, 933, 934, 935, 936, 937, 938, 939, Docket No.10063-085WO1 940, 941, 942, 943, 944, 945, 946, 947, 948, 949, 950, 951, 952, 953, 954, 955, 956, 957, 958, 959, 960, 961, 962, 963, 964, 965, 966, 967, 968, 969, 970, 971, 972, 973, 974, 975, 976, 977, 978, 979, 980, 981, 982, 983, 984, 985, 986, 987, 988, 989, 990, 991, 992, 993, 994, 995, 996, 997, 998, 999, 1000kDa or more. In some embodiments, the organic polymer comprises a polypeptide or peptide, a nucleic acid, a lipid, a carbohydrate, or any combinations thereof. In some embodiments, the polymer is a linear polymer, or a non-linear or branched polymer. Exemplary non-linear polymers or branched polymers include, but are not limited to brush polymers, star polymers, comb polymers, dendrimer polymers, networked polymers, crosslinked polymers, semi-cross-linked polymers, graft polymers, and combinations thereof. In some embodiments, the polymer comprises polyamides, polypeptides, proteins, polynucleotides, polyesters, polystyrenes, polyether, polyketones, polysulfones, polyurethanes, polysiloxanes, polysilanes, chitosan, cellulose, amylase, polyacetals, polyethylene, glycols, poly(acrylate)s, poly(methylacrylate)s, poly(vinyl alcohol), poly(vinyl pyrrolidone), poly(vinylidene chloride), poly(vinyl acetate), poly(alkylene glycol)s, including but not limited to poly(ethylene glycol) and poly(propylene glycol), polystyrene, polyisoprene, polyisobutylenes, poly(vinyl chloride), poly(propylene), poly(lactic acid), polyisocyanates, polycarbonates, alkyds, phenolics, epoxy resins, polysulf[iota]des, polyimides, liquid crystal polymers, heterocyclic polymers, polyacetylene, polyquinoline, polyaniline, polypyrrole, polythiophene, poly(p-phenylene), poly-lysine, fluoropolymers, or combinations thereof. In some embodiments, the polymer is a water soluble polymer, including but not limited to polysaccharides, polyesters, polyamides, polyethers, and polycarbonates. In some embodiments, the polymer is biodegradable and/or biocompatible. In some embodiments, the virus-like particle comprises one or more non-infectious components from a virus selected from Human immunodeficiency virus (HIV), Influenza virus, Hepatitis B virus, Hepatitis E virus, Ebola virus, Severe acute respiratory syndrome coronavirus (SARS-CoV), SARS-CoV-2, Respiratory syncytial virus (RSV), Human papillomavirus (HPVs), Middle east respiratory syndrome coronavirus (MERS-CoV), and swine fever virus. As used herein, “virus-like particles” refers to biomolecules, including but not limited to whole protein and protein fragments, that closely resemble or are derived from viruses, but are non-infectious because they contain no or minimal genetic material. Virus-like particles can resemble or be derived from viruses including, but not limited to Adenoviridae, Birnaviridae, Bunyaviridae, Caliciviridae, Capillovirus group, Carlavirus group, Carmovirus group, Caulimovirus group, Closterovirus group, Commelina yellow mottle virus group, Comovirus virus group, Docket No.10063-085WO1 Coronaviridae, PM2 phage group, Corcicoviridae, Cryptic virus group, Cryptovirus group, Cucumovirus group, Φ6 phage group, Cysioviridae, Carnation ringspot group, Dianthovirus virus group, Broad bean wilt group, Fabavirus virus group, Filoviridae, Flaviviridae, Furovirus group, Germinivirus group, Giardiavirus, Hepadnaviridae, Herpesviridae, Hordeiviridae virus group, Ilarvirus virus group, Inoviridae, Iridoviridae, Leviviridae, Lipothrixviridae, Luteovirus group, Marafivirus virus group, Maize chlorotic dwarf virus group, icroviridae, Myoviridae, Necorvirus group, Nepovirus virus group, Nodaviridae, Orthomyxoviridae, Papovaviridae, Paramyxoviridae, Parsnip yellow fleck virus group, Partitiviridae, Parvoviridae, Pea enation mosaic virus group, Phycodnaviridae, Picomaviridae, Plasmaviridae, Prodoviridae, Polydnaviridae, Potexvirus group, Potyvirus, Poxviridae, Reoviridae, Retroviridae, Rhabdoviridae, Group Rhizidiovirus, Sipoviridae, Sobemovirus group, SSV 1-Type Phages, Tectiviridae, Tenuvirus, Togaviridae, Tombusvirus group, Torovirus group, Totiviridae, Tymovirus group, and plant virus satellites. In some embodiments, the cell comprises a dendritic cell. In some embodiments, the composition comprises a naked nucleic acid encoding an ERβ protein. Herein, it is contemplated to develop nucleic acids comprising chemical modifications to improve pharmacokinetic properties, innate immune responses, and/or stability. In some embodiments, the nucleic acid comprises one or more chemical modifications to increase stability of the nucleic acid encoding ERβ. In some embodiments, the one or more chemical modifications are selected from a 5’-7-methylguanosine cap, a 5’ untranslated region 5’ UTR, a 3’ UTR, a modification to the open reading frame (ORF), a poly-adenylate tail, 2’-O-methyl (2’-OMe), 2’- methoxyethyl (2’-MOE), 2’-fluoro (2’-F), locked nucleic acids, constrained nucleic acids, and tricyclo-DNA oligonucleotides. Complementing the modifications are phosphate backbone modifications including phosphorothioates, phosphorodiamidate morpholino oligonucleotides (PMO), peptide nucleic acid oligonucleotides (PNA), and nucleobase modifications, including, but not limited to 5-methylcytosine (m5C). In some embodiments, the composition further comprises a nucleic acid sequence encoding a reporter gene. In some embodiments, the reporter gene encodes a reporter protein selected from a mCherry, luciferase, green fluorescent protein (GFP), yellow fluorescent protein (YFP), blue fluorescent protein (BFP), cyane fluorescent protein (CFP), monomeric red fluorescent protein (mRFP), Discosoma striata (DsRed), mCherry, mOrange, tdTomato, mSTrawberry, mPlum, photoactivatable GFP (PA-GFP), Venus, Kaede, monomeric kusabira orange (mKO), Dronpa, enhanced CFP (ECFP), Emerald, Cyan fluorescent protein for energy transfer (CyPet), super CFP (SCFP), Cerulean, photoswitchable CFP (PS-CFP2), photoactivatable RFP1 (PA-RFP1), Docket No.10063-085WO1 photoactivatable mCherry (PA-mCherry), monomeric teal fluorescent protein (mTFP1), Eos fluorescent protein (EosFP), Dendra, TagBFP, TagRFP, enhanced YFP (EYFP), Topaz, Citrine, yellow fluorescent protein for energy transfer (YPet), super YFP (SYFP), enhanced GFP (EGFP), Superfolder GFP, T-Sapphire, Fucci, mKO2, mOrange2, mApple, Sirius, Azurite, EBFP, and/or EBFP2. Methods of treating and/or preventing ER-related diseases and disorders Estrogen is a key regulator of growth and differentiation in a broad range of target tissues, including the reproductive system, mammary glands, central nervous systems, skeletal muscles, and the cardiovascular system. Estrogen and estrogen-derived molecules influence said target tissues by binding to estrogen receptors, such as ERβ, to initiate a signaling cascade impacting gene expression in various organ systems. ERβ is a member of the nuclear receptor superfamily and is classified as a type I nuclear receptor because it originally resides in the cytosol and travels into the nucleus upon binding to estrogen or an estrogen-derived molecule. Once in the nucleus ERβ can influence gene expression in numerous ways including, but not limited to binding DNA sequences (termed estrogen-responsive elements (EREs)) that attract transcription factors and other coregulator proteins to transcription start sites to enhance or repress gene expression. The characteristics and molecular mechanisms of ERβ are disclosed in Leung et al. “Estrogen receptor ERβ isoforms: A key to understanding ERβ signaling” PNAS. 29 Aug 2006. Vol. 103. No. 35. 13162-13167, Zhao et al. “Estrogen receptor β: an overview and update” Nuclear Receptor Signaling.1 Feb 2008.6, e003, and “Estrogen receptor β acts as a dominant regulator of estrogen signaling” Oncogene. 12 Oct 2000. 19, 4970-4978, the disclosures of which are herein incorporated by reference in their entirety. In general, ERβ proteins target one or more genes to regulate gene expression, a process that once dysregulated is detrimental leading to diseases or disorders. Thus, the present disclosure provides methods of treating or preventing ER-related disorders, including, but not limited to primary tumors and metastatic tumors, using a therapeutic composition comprising a nucleic acid encoding ERβ. In one aspect, disclosed herein is a method of treating or preventing an ERβ-related disorder in a subject in need thereof, the method comprising administering a pharmaceutically effective amount of a composition comprising a nucleic acid encoding ERβ, wherein the nucleic acid is encapsulated in or conjugated to a nucleic acid delivery vehicle, wherein the method increases expression of a ERβ protein in the subject relative to an untreated subject with cancer. Docket No.10063-085WO1 In one aspect, disclosed herein is a method of treating or preventing tumor development in a subject with cancer, the method comprising administering a pharmaceutically effective amount of a composition comprising a nucleic acid encoding ERβ, wherein the nucleic acid is encapsulated in or conjugated to a nucleic acid delivery vehicle, wherein the method increases expression of a ERβ protein in the subject relative to an untreated subject with cancer. In one aspect, disclosed herein is a method of treating or preventing a metastasis in a subject, the method comprising administering a pharmaceutically effective amount of a composition comprising a nucleic acid encoding ERβ, wherein the nucleic acid is encapsulated in or conjugated to a nucleic acid delivery vehicle, and wherein the method increases expression of a ERβ protein in the subject relative to an untreated subject with a metastasis. In some embodiments, the method comprises the use of an ERβ mRNA. In some embodiments, the method comprises the use of a full length ERβ mRNA. In some embodiments, the method comprises the use of a functional fragment of the full-length ERβ mRNA. In some embodiments, the method comprises the use of SEQ ID NO: 1, or fragments thereof. In some embodiments, the method comprises the use of gene accession no. NM_001437.3, or fragments thereof. In some embodiments, the method comprises the use of an ERβ DNA. In some embodiments, the method comprises the use of a full length ERβ DNA. In some embodiments, the method comprises the use of a functional fragment of the full-length ERβ DNA. In some embodiments, the method comprises SEQ ID NO: 2, or fragments thereof. In some embodiments, the method comprises the use of the gene accession no. NC_000014.9, or fragments thereof. In some embodiments, the nucleic acid delivery vehicle comprises a pharmaceutically acceptable carrier selected from a lipid nanoparticle (LPN), a lipid carrier, an organic polymer, a cell, a virus-like particle, an excipient, a diluent, a salt, a buffer, or a stabilizer. The composition may be administered in such amounts, time, and route deemed necessary in order to achieve the desired result. The exact amount of the composition may vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the ER-related disorder or disease, the particular composition, its mode of administration, its mode of activity, and the like. The composition is preferably formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the composition will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject will depend upon a variety of factors including the ER-related disorder or disease being treated and the severity Docket No.10063-085WO1 of the ER-related disorder or disease; the activity of the composition employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific composition employed; the duration of the treatment; drugs used in combination or coincidental with the specific composition employed; and like factors well known in the medical arts. In some embodiments, the composition is administered intratumorally or intravenously. In general, the most appropriate route of administration will depend upon a variety of factors including the nature of the composition (e.g., its stability in the systemic or vascular environment), the condition of the subject (e.g., whether the subject is able to tolerate systemic or local administration), etc. The exact amount of composition required to achieve a therapeutically effective amount will vary from subject to subject, depending on species, age, and general condition of a subject, severity of the side effects, identity of the particular compound(s), mode of administration, and the like. The amount to be administered to, for example, a child or an adolescent can be determined by a medical practitioner or person skilled in the art and can be lower or the same as that administered to an adult. In some embodiments, the composition is administered at a dose of at least 2μg of ERβ nucleic acid. In some embodiments, the composition is administered at a dose ranging from about 2 μg to about 20 μg ERβ nucleic acid. In some embodiments, the composition is administered at a dose of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 μg of ERβ nucleic acid. In some embodiments, the composition is administered at a dose of at least 2μg of ERβ mRNA. In some embodiments, the composition is administered at a dose ranging from about 2 μg to about 20 μg ERβ mRNA. In some embodiments, the composition is administered at a dose of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 μg of ERβ mRNA. In some embodiments, the composition is administered at a dose of at least 2μg of ERβ DNA. In some embodiments, the composition is administered at a dose ranging from about 2 μg to about 20 μg ERβ DNA. In some embodiments, the composition is administered at a dose of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 μg of ERβ DNA. In some embodiments, the composition is administered for at least one week. In some embodiments, the composition is administered for 1, 2, 3, or 4 weeks. In some embodiments, the composition is administered for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 months. In some embodiments, the composition is administered for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more years. Docket No.10063-085WO1 In some embodiments, the composition is administered at least once per week. In some embodiments, the composition is administered 1, 2, 3, 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, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, or 168 times per week. In some embodiments, the method of any preceding aspect treats, prevents, ameliorates, or reduces triple negative breast cancer (TNBC) or invasive breast cancer. In some embodiments, the ERβ-related disorder comprises a cancer selected from a breast cancer, an ovarian cancer, a uterine cancer, vaginal cancer, vulvar cancer, cervical cancer, urethral cancer, a prostate cancer, colorectal cancer, bladder cancer, thyroid cancer, or cancers affecting a tissue from a reproductive, gastrointestinal, or urinary system. In some embodiments, the breast cancer comprises inflammatory breast cancer (IBC), Triple-Negative Breast Cancer (TNBC), HER2-positive breast cancer, or Hormone Receptor-(HR)-positive breast cancer. In some embodiments, the cancer includes, but is not limited to acoustic neuroma, adenocarcinoma, adrenal gland cancer, anal cancer, angiosarcoma (e.g., lymphangiosarcoma, lymphangioendotheliosarcoma, hemangiosarcoma), appendix cancer, benign monoclonal gammopathy, biliary cancer (e.g., cholangiocarcinoma), bladder cancer, breast cancer (e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, mammary cancer, medullary carcinoma of the breast), brain cancer (e.g., meningioma; glioma, e.g., astrocytoma, oligodendroglioma; medulloblastoma), bronchus cancer, carcinoid tumor, cervical cancer (e.g., cervical adenocarcinoma), choriocarcinoma, chordoma, craniopharyngioma, colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma), epithelial carcinoma, ependymoma, endotheliosarcoma (e.g., Kaposi's sarcoma, multiple idiopathic hemorrhagic sarcoma), endometrial cancer (e.g., uterine cancer, uterine sarcoma), esophageal cancer (e.g., adenocarcinoma of the esophagus, Barrett's adenocarinoma), Ewing's sarcoma, eye cancer (e.g., intraocular melanoma, retinoblastoma), familiar hypereosinophilia, gall bladder cancer, gastric cancer (e.g., stomach adenocarcinoma), gastrointestinal stromal tumor (GIST), head and neck cancer (e.g., head and neck squamous cell carcinoma, oral cancer (e.g., oral squamous cell carcinoma (OSCC), throat cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer)), hematopoietic cancers Docket No.10063-085WO1 (e.g., leukemia such as acute lymphocytic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), acute myelocytic leukemia (AML) (e.g., B-cell AML, T-cell AML), chronic myelocytic leukemia (CML) (e.g., B-cell CML, T-cell CML), and chronic lymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL); lymphoma such as Hodgkin lymphoma (HL) (e.g., B-cell HL, T-cell HL) and non-Hodgkin lymphoma (NHL) (e.g., B-cell NHL such as diffuse large cell lymphoma (DLCL) (e.g., diffuse large B-cell lymphoma (DLBCL)), follicular lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphomas (e.g., mucosa-associated lymphoid tissue (MALT) lymphomas, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma (i.e., “Waldenstrom's macroglobulinemia”), hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma and primary central nervous system (CNS) lymphoma; and T-cell NHL such as precursor T-lymphoblastic lymphoma/leukemia, peripheral T-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungiodes, Sezary syndrome), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, anaplastic large cell lymphoma); a mixture of one or more leukemia/lymphoma as described above; and multiple myeloma (MM)), heavy chain disease (e.g., alpha chain disease, gamma chain disease, mu chain disease), hemangioblastoma, inflammatory myofibroblastic tumors, immunocytic amyloidosis, kidney cancer (e.g., nephroblastoma a.k.a. Wilms' tumor, renal cell carcinoma), liver cancer (e.g., hepatocellular cancer (HCC), malignant hepatoma), lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung), leiomyosarcoma (LMS), mastocytosis (e.g., systemic mastocytosis), myelodysplastic syndrome (MDS), mesothelioma, myeloproliferative disorder (MPD) (e.g., polycythemia Vera (PV), essential thrombocytosis (ET), agnogenic myeloid metaplasia (AMM) a.k.a. myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myelocytic leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)), neuroblastoma, neurofibroma (e.g., neurofibromatosis (NF) type 1 or type 2, schwannomatosis), neuroendocrine cancer (e.g., gastroenteropancreatic neuroendoctrine tumor (GEP-NET), carcinoid tumor), osteosarcoma, ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma), papillary adenocarcinoma, pancreatic cancer (e.g., pancreatic adenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), Islet cell tumors), penile cancer (e.g., Paget's disease of the penis and scrotum), pinealoma, primitive neuroectodermal tumor (PNT), prostate Docket No.10063-085WO1 cancer (e.g., prostate adenocarcinoma), rectal cancer, rhabdomyosarcoma, salivary gland cancer, skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC)), small bowel cancer (e.g., appendix cancer), soft tissue sarcoma (e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma), sebaceous gland carcinoma, sweat gland carcinoma, synovioma, testicular cancer (e.g., seminoma, testicular embryonal carcinoma), thyroid cancer (e.g., papillary carcinoma of the thyroid, papillary thyroid carcinoma (PTC), medullary thyroid cancer), urethral cancer, vaginal cancer and vulvar cancer (e.g., Paget's disease of the vulva). In some embodiments, the ERβ protein targets one or more metastasis- and cancer progression-associated genes selected from CD36, TGFb, TGFbR2, ALDH1A1, ELMO1, ILR1, IL6, IL8, IL1, IL17, CCL2, GPR141, CREB1, TFF1, FN1, NRG1, LCN2, VTCN1, FST1, NRP1, RHOBTB3. In some embodiments, the composition is administered in combination with an adjuvant, including, but not limited to neoadjuvants. Exemplary adjuvants include, but are not limited to aluminum hydroxide, aluminum phosphate, aluminum potassium sulfate, heat shock proteins (HSPs) (including, but not limited to HSP70 and HSP90), Toll-like receptor (TLR) agonists (including, but not limited to TLR1 agonists, TLR2 agonists, TLR1/2 agonists, TLR 3 agonists, TLR 4 agonist, TLR 5 agonist, TLR 7 agonist, TLR 8 agonists, TLR7/8 agonists, and TLR 9 agonists), Freund’s adjuvants (which refers to a water in oil emulsion), MF59, AS01, AS02, AS03, AS04, virus-like particles, virosomes, polylactic acid (PLA), poly(lactic-co-glycolic acid) (PLGA), and mucosal adjuvants (including, but not limited to cholera toxin (CT), heat-labile enterotoxins (LTK3 or LTR72), and chitosan). In some embodiments, the composition is encapsulated within a lipid nanoparticle (LPN). In some embodiments, the composition and LPN further comprises an antibody to direct the ERβ mRNA to tumor cells. In some embodiments, the antibody targets receptors on the cell membrane of tumor cells. In some embodiments, the antibody targets receptors including, but not limited to human epidermal growth factor receptor 2 (HER2) and epidermal growth factor receptor (EGFR). In some embodiments, the composition and LPN further comprises an anti-HER2 antibody, an anti-EGFR antibody, or combinations thereof. In some embodiments, any combination of the composition, LPN, anti-HER2 antibody, or anti-EGFR antibody are administered intravenously. In some embodiments, the composition is administered in combination with an additional therapeutic composition. In some embodiments, the additional therapeutic composition comprises Docket No.10063-085WO1 an anti-cancer agent, a chemotherapeutic agent, an anti-inflammatory agent, or a combination thereof. In some embodiments, the anti-cancer agent comprises an interferon, a cytokine, a vaccine, a growth factor, an antibody or serotherapy, or an immunomodulatory agent. Exemplary biotherapeutic anti-cancer agents include, but are not limited to, interferons, cytokines (e.g., tumor necrosis factor, interferon α, interferon γ), vaccines, hematopoietic growth factors, monoclonal serotherapy, immunostimulants and/or immunodulatory agents (e.g., IL-1, 2, 4, 6, or 12, anti- PDL1, anti-PD1, anti-CTLA-4), immune cell growth factors (e.g., GM-CSF) and antibodies (e.g. HERCEPTIN (trastuzumab), T-DM1, AVASTIN (bevacizumab), ERBITUX (cetuximab), VECTIBIX (panitumumab), RITUXAN (rituximab), BEXXAR (tositumomab)). In some embodiments, the chemotherapeutic agent comprises a luteinizing hormone releasing hormone (LHRH), anti-androgens, endocrine therapy, aromatase inhibitors, anti- estrogens, photodynamic therapies, nitrogen mustards, nitrosoureas, metal containing compounds, nucleotide analogs, anti-metabolites, or a cancer suppressing agent. Exemplary chemotherapeutic agents include, but are not limited to, anti-estrogens (e.g. tamoxifen, raloxifene, and megestrol), LHRH agonists (e.g. goscrclin and leuprolide), anti-androgens (e.g. flutamide and bicalutamide), photodynamic therapies (e.g. vertoporfin (BPD-MA), phthalocyanine, photosensitizer Pc4, and demethoxy-hypocrellin A (2BA-2-DMHA)), nitrogen mustards (e.g. cyclophosphamide, ifosfamide, trofosfamide, chlorambucil, estramustine, and melphalan), nitrosoureas (e.g. carmustine (BCNU) and lomustine (CCNU)), alkylsulphonates (e.g. busulfan and treosulfan), triazenes (e.g. dacarbazine, temozolomide), platinum containing compounds (e.g. cisplatin, carboplatin, oxaliplatin), vinca alkaloids (e.g. vincristine, vinblastine, vindesine, and vinorelbine), taxoids (e.g. paclitaxel or a paclitaxel equivalent such as nanoparticle albumin-bound paclitaxel (ABRAXANE), docosahexaenoic acid bound-paclitaxel (DHA-paclitaxel, Taxoprexin), polyglutamate bound-paclitaxel (PG-paclitaxel, paclitaxel poliglumex, CT-2103, XYOTAX), the tumor-activated prodrug (TAP) ANG1005 (Angiopep-2 bound to three molecules of paclitaxel), paclitaxel-EC-1 (paclitaxel bound to the erbB2-recognizing peptide EC-1), and glucose- conjugated paclitaxel, e.g., 2′-paclitaxel methyl 2-glucopyranosyl succinate; docetaxel, taxol), epipodophyllins (e.g. etoposide, etoposide phosphate, teniposide, topotecan, 9- aminocamptothecin, camptoirinotecan, irinotecan, crisnatol, mytomycin C), anti-metabolites, DHFR inhibitors (e.g. methotrexate, dichloromethotrexate, trimetrexate, edatrexate), IMP dehydrogenase inhibitors (e.g. mycophenolic acid, tiazofurin, ribavirin, and EICAR), ribonucleotide reductase inhibitors (e.g. hydroxyurea and deferoxamine), uracil analogs (e.g. 5- fluorouracil (5-FU), floxuridine, doxifluridine, ratitrexed, tegafur-uracil, capecitabine), cytosine Docket No.10063-085WO1 analogs (e.g. cytarabine (ara C), cytosine arabinoside, and fludarabine), purine analogs (e.g. mercaptopurine and Thioguanine), Vitamin D3 analogs (e.g. EB 1089, CB 1093, and KH 1060), isoprenylation inhibitors (e.g. lovastatin), dopaminergic neurotoxins (e.g. 1-methyl-4- phenylpyridinium ion), cell cycle inhibitors (e.g. staurosporine), actinomycin (e.g. actinomycin D, dactinomycin), bleomycin (e.g. bleomycin A2, bleomycin B2, peplomycin), anthracycline (e.g. daunorubicin, doxorubicin, pegylated liposomal doxorubicin, idarubicin, epirubicin, pirarubicin, zorubicin, mitoxantrone), MDR inhibitors (e.g. verapamil), Ca2+ ATPase inhibitors (e.g. thapsigargin), imatinib, thalidomide, lenalidomide, tyrosine kinase inhibitors (e.g., axitinib (AG013736), bosutinib (SKI-606), cediranib (RECENTIN™, AZD2171), dasatinib (SPRYCEL®, BMS-354825), erlotinib (TARCEVA®), gefitinib (IRESSA®), imatinib (Gleevec®, CGP57148B, STI-571), lapatinib (TYKERB®, TYVERB®), lestaurtinib (CEP-701), neratinib (HKI-272), nilotinib (TASIGNA®), semaxanib (semaxinib, SU5416), sunitinib (SUTENT®, SU11248), toceranib (PALLADIA®), vandetanib (ZACTIMA®, ZD6474), vatalanib (PTK787, PTK/ZK), trastuzumab (HERCEPTIN®), bevacizumab (AVASTIN®), rituximab (RITUXAN®), cetuximab (ERBITUX®), panitumumab (VECTIBIX®), ranibizumab (Lucentis®), nilotinib (TASIGNA®), sorafenib (NEXAVAR®), everolimus (AFINITOR®), alemtuzumab (CAMPATH®), gemtuzumab ozogamicin (MYLOTARG®), temsirolimus (TORISEL®), ENMD-2076, PCI- 32765, AC220, dovitinib lactate (TKI258, CHIR-258), BIBW 2992 (TOVOK™), SGX523, PF- 04217903, PF-02341066, PF-299804, BMS-777607, ABT-869, MP470, BIBF 1120 (VARGATEF®), AP24534, JNJ-26483327, MGCD265, DCC-2036, BMS-690154, CEP-11981, tivozanib (AV-951), OSI-930, MM-121, XL-184, XL-647, and/or XL228), proteasome inhibitors (e.g., bortezomib (VELCADE)), mTOR inhibitors (e.g., rapamycin, temsirolimus (CCI-779), everolimus (RAD-001), ridaforolimus, AP23573 (Ariad), AZD8055 (AstraZeneca), BEZ235 (Novartis), BGT226 (Norvartis), XL765 (Sanofi Aventis), PF-4691502 (Pfizer), GDC0980 (Genetech), SF1126 (Semafoe) and OSI-027 (OSI)), oblimersen, gemcitabine, caminomycin, leucovorin, pemetrexed, cyclophosphamide, dacarbazine, procarbizine, prednisolone, dexamethasone, campathecin, plicamycin, asparaginase, aminopterin, methopterin, porfiromycin, melphalan, leurosidine, leurosine, chlorambucil, trabectedin, procarbazine, discodermolide, caminomycin, aminopterin, and hexamethyl melamine. In some embodiments, the method decreases the growth of cancer cells, the stemness of cancer cells, or the invasiveness of cancer cells in the subject relative to an untreated subject with an ERβ-related disorder. In some embodiments, the method decreases the growth of cancer cells, the stemness of cancer cells, or the invasiveness of cancer cells by 10%, 20%, 30%, 40%, 50%, Docket No.10063-085WO1 60%, 70%, 80%, 90%, 95%, 99%, or 100% in the subject relative to an untreated subject with an ERβ-related disorder. In some embodiments, the method enhances cancer-associated immune response in the subject relative to an untreated subject with an ERβ-related disorder. In some embodiments, the methods enhances cancer-associated immune response by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, or 100% in the subject relative to an untreated subject with an ERβ- related disorder. Kits containing nucleic acid compositions In one aspect, disclosed herein is a kit comprising a nucleic acid encoding an estrogen receptor beta (ERβ), wherein the nucleic acid is encapsulated in or conjugated to a nucleic acid delivery vehicle. In some embodiments, the kit comprises mRNA. In some embodiments, the kit comprises DNA. In some embodiments, the kit comprises a full-length mRNA. In some embodiments, the kit comprises a functional fragment of the full-length mRNA. In some embodiments, the kit comprises a full-length DNA. In some embodiments, the kit comprises a functional fragment of the full-length DNA. In some embodiments, the kit comprises a nucleic acid with at least 50% identity to SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, the kit comprises a nucleic acid with at least 60% identity to SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, the kit comprises a nucleic acid with at least 70% identity to SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, the kit comprises a nucleic acid with at least 80% identity to SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, the kit comprises a nucleic acid with at least 81% identity to SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, the kit comprises a nucleic acid with at least 82% identity to SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, the kit comprises a nucleic acid with at least 83% identity to SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, the kit comprises a nucleic acid with at least 84% identity to SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, the kit comprises a nucleic acid with at least 85% identity to SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, the kit comprises a nucleic acid with at least 86% identity to SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, the kit comprises a nucleic acid with at least 87% identity to SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, the kit comprises a nucleic acid with at least 88% identity to SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, the kit comprises a nucleic acid with at least 89% identity to SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, Docket No.10063-085WO1 kit comprises a nucleic acid with at least 90% identity to SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, kit comprises a nucleic acid with at least 91% identity to SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, kit comprises a nucleic acid with at least 92% identity to SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, kit comprises a nucleic acid with at least 93% identity to SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, kit comprises a nucleic acid with at least 94% identity to SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, the kit comprises a nucleic acid with at least 95% identity to SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, kit comprises a nucleic acid with at least 96% identity to SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, kit comprises a nucleic acid with at least 97% identity to SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, kit comprises a nucleic acid with at least 98% identity to SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, the kit comprises a nucleic acid with at least 99% identity to SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, the kit comprises a nucleic acid comprising SEQ ID NO: 1 or SEQ ID NO: 2. In some embodiments, the kit comprises an ERβ mRNA. In some embodiments, the ERβ mRNA is a full length ERβ mRNA. In some embodiments, the ERβ mRNA is a functional fragment of the full-length ERβ mRNA. In some embodiments, the ERβ mRNA comprises SEQ ID NO: 1, or fragments thereof. In some embodiments, the ERβ mRNA comprises the gene accession no. NM_001437.3, or fragments thereof. In some embodiments, the kit comprises an ERβ DNA. In some embodiments, the ERβ DNA is a full length ERβ DNA. In some embodiments, the ERβ DNA is a functional fragment of the full-length ERβ DNA. In some embodiments, the ERβ DNA comprises SEQ ID NO: 2, or fragments thereof. In some embodiments, the ERβ DNA comprises the gene accession no. NC_000014.9, or fragments thereof. In some embodiments, the kit comprises a nucleic acid comprising one or more chemical modifications selected from a 5’-7-methylguanosine cap, a 5’ untranslated region 5’ UTR, a 3’ UTR, a modification to the open reading frame (ORF), a poly-adenylate tail, 2’-O-methyl (2’- OMe), 2’-methoxyethyl (2’-MOE), 2’-fluoro (2’-F), locked nucleic acids, constrained nucleic acids, and tricyclo-DNA oligonucleotides. Complementing the modifications are phosphate backbone modifications including phosphorothioates, phosphorodiamidate morpholino oligonucleotides (PMO), peptide nucleic acid oligonucleotides (PNA), and nucleobase modifications, including, but not limited to 5-methylcytosine (m5C). In some embodiments, the kit further comprises a nucleic acid sequence encoding a reporter gene. In some embodiments, the reporter gene encodes a reporter protein selected from a Docket No.10063-085WO1 mCherry, luciferase, green fluorescent protein (GFP), yellow fluorescent protein (YFP), blue fluorescent protein (BFP), cyane fluorescent protein (CFP), monomeric red fluorescent protein (mRFP), Discosoma striata (DsRed), mCherry, mOrange, tdTomato, mSTrawberry, mPlum, photoactivatable GFP (PA-GFP), Venus, Kaede, monomeric kusabira orange (mKO), Dronpa, enhanced CFP (ECFP), Emerald, Cyan fluorescent protein for energy transfer (CyPet), super CFP (SCFP), Cerulean, photoswitchable CFP (PS-CFP2), photoactivatable RFP1 (PA-RFP1), photoactivatable mCherry (PA-mCherry), monomeric teal fluorescent protein (mTFP1), Eos fluorescent protein (EosFP), Dendra, TagBFP, TagRFP, enhanced YFP (EYFP), Topaz, Citrine, yellow fluorescent protein for energy transfer (YPet), super YFP (SYFP), enhanced GFP (EGFP), Superfolder GFP, T-Sapphire, Fucci, mKO2, mOrange2, mApple, Sirius, Azurite, EBFP, and/or EBFP2. In some embodiments, the nucleic acid delivery vehicle comprises a pharmaceutically acceptable carrier selected from a lipid nanoparticle (LPN), a lipid carrier, an organic polymer, a virus-like particle, or a stabilizer. In some embodiments, the kit further comprises an RNase-free reagent selected from RNase-free water, RNase-free buffered solution, and RNase-free saline. A number of embodiments of the disclosure have been described. Nevertheless, it will be understood that various modifications may be made without departing from the spirit and scope of the invention. Accordingly, other embodiments are within the scope of the following claims. By way of non-limiting illustration, examples of certain embodiments of the present disclosure are given below. EXAMPLES The following examples are set forth below to illustrate the compositions, devices, methods, and results according to the disclosed subject matter. These examples are not intended to be inclusive of all aspects of the subject matter disclosed herein, but rather to illustrate representative methods and results. These examples are not intended to exclude equivalents and variations of the present invention which are apparent to one skilled in the art. Example 1: Targeting Estrogen Receptor β Signaling in Breast Cancer Inflammatory breast cancer (IBC) accounts for about 10% of the breast cancer mortality that occurs annually in the US. It is characterized by rapid progression, distant metastases, younger Docket No.10063-085WO1 age of onset and a median survival of approximately 4 years compared with more than 10 years for non-IBC. Despite the improved outcomes by the application of multidisciplinary therapy approach, 5-year survival rates are still much lower compared with other breast cancers. One-third of patients have distant metastases at initial diagnosis indicating the need for developing effective strategies to prevent and treat metastatic disease. However, research failed to identify specific targets and there are currently no FDA-approved targeted therapies that are specific for the disease. Analysis of human tissues and datasets revealed decreased expression of ERβ in 70% of IBC tumors and association with better metastasis-free and overall survival in patients with IBC. Further, ERβ inhibits actin-based cell migration and ERβ -proficient cells are less metastatic than ERβ knockout cells in orthotopic models of IBC. The expression frequency combined with function indicate the downregulation of ERβ in tumors of patients with metastasis and that tumor-specific expression of the receptor by mRNA injection can inhibit progression of the disease. It is, therefore, of high importance to evaluate the ERβ mRNA as novel therapeutic to combat progression and metastasis of IBC. This disclosure develops ERβ mRNA as a novel therapeutic for a disease that currently lacks targeted therapy that either alone or in combination with existing therapies will substantially eliminate metastasis and associated mortality, ensuring that these findings will rapidly impact clinical treatment of IBC. Notably, due to a significant percentage of IBC belonging to clinical HER2-positive and TNBC phenotypes, treatments can be validated that benefit patients with other forms of aggressive breast cancer. These findings can be immediately translated into improvements in clinical outcomes and will serve as the foundation for the innovative use of ERβ mRNA in treatment of IBC. This disclosure describes the following innovations: a) These findings show that ERβ mRNA produces a functional protein that decreases the invasiveness of IBC cells and points toward inhibition of metastasis. The present disclosure demonstrates the importance of ERβ mRNA for the treatment of breast cancer metastasis represents an entirely new direction for both the nuclear receptor and breast cancer research. b) A novel observation was made linking ERβ to regulation of actin organization and immune response. For the first time, the effects of ERβ mRNA in genes and pathways that influence breast cancer metastasis. Evaluation of the efficacy of ERβ mRNA to inhibit metastasis of IBC tumors This disclosure describes the development of a novel targeted therapy for prevention of IBC metastasis. These findings point to the induction of ERβ expression as an effective therapy Docket No.10063-085WO1 intervention because the receptor is downregulated in IBC tumors and its upregulation decreases cell invasion and inhibits metastasis of IBC tumors (FIG.1). ERβ expression is restored in tumors by injecting complexes of ERβ mRNA with lipid nanoparticles (LNPs) to leverage its anti- metastatic activity. These findings indicate that non-toxic doses of ERβ mRNA-LNPs produce a functional receptor with increased anti-invasive activity (FIG.4). In vivo effects of ERβ mRNA on metastasis. To validate the in vitro effects and evaluate the in vivo anti-metastatic activity of ERβ mRNA, it will be examined whether ERβ mRNA inhibits metastasis in murine and PDX models that reflect the clinical pattern of IBC metastasis. An orthotopic injection of 5x105 luciferase/GFP-expressing (KPL4, SUM149, FC-IBC02, 4T1) cells is administered to Rag2-/-;IL2Rγc-/- or BALB/c mice (15 mice/group). Complexes of ERβ and mCherry (vehicle) mRNA (2.5-10 μg) with LNPs are intratumorally injected (twice a week) for 3 weeks starting in 100 mm3 tumors. Transplants are allowed to grow to 300 mm3 and then resected in a survival surgery. After resection, metastasis are assessed weekly by whole body bioluminescence imaging (BLI) (FIG. 1C). Metastasis are also determined after the mouse is sacrificed by histological, GFP immunofluorescence and immunohistochemical assessment with pathologist assistance. Toxicology studies are performed to exclude toxic effects. Statistical Considerations: The number of mice per group was chosen to provide for the potential to see 3-fold difference in BLI at endpoint (3x106 photons/s/cm2 in vehicle-treated tumors vs. 1x106 photons/s/cm2 in ERβ mRNA-treated tumors, alpha = 0.05; power = 0.8). Significant differences are determined by Student’s t and Fisher's exact tests and for multi-group comparisons by Kruskal-Wallis tests. Elucidation of the mechanism of the anti-metastatic activity of ERβ mRNA IBC tumors present with characteristics of poor prognosis (EGFR, HER2, p53 mutations) that are not specific for IBC. It is, therefore, of high significance to identify novel pathways of importance for the biology of IBC and corroborate the specificity of ERβ mRNA treatment. ERβ target genes were previously identified as associated with metastasis. It was recently found that similar gene expression changes in ERβ mRNA-treated cells (FIG.4C). Identifying ERβ target genes that inhibit metastasis. The mechanism of ERβ mRNA action is fully elucidated. The gene expression in ERβ mRNA-treated tumors is analyzed by RNA-Seq to corroborate the antimetastatic activity of ERβ and identify novel target and metastasis- associated genes. This data is associated with previously identified ERβ targets in IBC cells. ERβ mRNA-treated IBC cells are also analyzed by ChIP- Seq to determine which of the altered genes Docket No.10063-085WO1 in ERβ mRNA-treated tumors are direct ERβ targets and define the ERβ cistrome in IBC. The importance of identified genes as therapy targets is evaluated in functional in vitro and in vivo studies after genetic and pharmacological alteration of their expression and activity. Clinical Relevance Decreased levels of ERβ were observed in IBC tumors and tumor-specific upregulation by using complexes of ERβ mRNA with lipid nanoparticles is an effective therapy intervention to restore expression and anti-metastatic activity to prevent progression of the disease. Example 2: Tumor repressive effects of ERβ mRNA-based therapy in aggressive breast cancers Inflammatory breast cancer (IBC) and triple-negative breast cancer (TNBC) are the most aggressive forms of breast cancer due to their high propensity to develop distant metastases and the lack of specific effective targeted therapies. The failure of previous research to produce viable therapeutic targets combined with the absence of estrogen receptor α (Erα) in TNBC and the majority of IBC led to the exploration of the second ER (ERβ) as a molecule with targeting potential. The anti-metastatic effects of ERβ in TNBC and IBC were previously reported. Considering the anti-tumor activity together with the decreased expression of ERβ in IBC and TNBC tumors, an mRNA-based approach was employed to induce tumor-specific upregulation of the receptor and restore its anti-metastatic activity. Treatment with ERβ mRNA induces the expression of the ERβ receptor and decreases the invasiveness of breast cancer cells. Cancerous cells were treated with complexes of mRNA (Control (GFP) or ERβ) with lipid nanoparticles (LNP) for 48 hours. Increased GFP expression within the first 20 hours is observed in a dose-dependent response (FIG.4A) as well as increased lipid uptake (FIG. 4B). Treatment with ERβ mRNA reduced cell invasion (FIG. 4D). Treatment of cancer cells with ERβ mRNA not only increased levels of ERβ mRNA transcript, but also altered the mRNA transcripts of genes that are regulated by ERβ including CCL5, TNF, and IL6 (FIG.4E and FIG.7). In vivo, ERβ treatment reduces tumor progression. In a mouse with xenografts of human breast tumor, treatment with ERβ mRNA-LNP resulted in smaller tumors than control treated mice (FIG. 8B). Treatment yielded significant results at 37 and 41 days (4th and 5th dose) (FIG. 8D). Docket No.10063-085WO1 Furthermore, treatment with ERβ mRNA, resulted in increased transcript levels of ELMO1 and ESR2 (ERβ) when compared to control in primary tumors (FIG.9). ERβ mRNA treatment has anti-metastatic effects. IBC frequently metastasizes to lungs and other organs. In a mouse breast cancer model, mice treated with ERβ exhibited less metastasis in their lungs when compared to control treatment alone (FIGS. 10A-10B). Treatment with ERβ mRNA substantially decreases lung metastasis of orthotopically grown breast tumors. Thus, treatment of IBC with ERβ mRNA-LPN is a viable therapeutic. Example 3: ERβ as an anti-cancer therapeutic Despite advances in diagnosis and therapy, breast cancer remains the second leading cause of cancer-related deaths in women. Among the most aggressive forms that account for the high mortality are the triple negative (TNBC) and inflammatory (IBC) breast cancer. The five-year survival rate for patients with TNBC that has spread to distant sites is 12% and the median overall survival (OS) for patients with stage IV disease is ~12 months compared with 36 months for hormone receptor-positive breast cancer. Similarly, the median OS of patients with stage III IBC is 4.75 years versus 13.40 years for patients with the same stage non-IBC. Besides, both subtypes disproportionately affect younger and black women. Poor prognosis is primarily due to the high propensity of these tumors to develop distant metastases and the lack of effective targeted therapies. Patients with early TNBC are four times more likely to develop distant metastases and one third of those with IBC have disseminated cancer at diagnosis. Despite the aggressive behavior, it is challenging to treat TNBC due to lack of hormone receptors and epidermal growth factor receptor 2 (HER2). Only 20% of TNBCs respond to systemic chemotherapy and targeted therapies including immunotherapy and PARP inhibitors have yet to demonstrate a proven overall survival benefit. Likewise, research has failed to identify specific targets for IBC and there are currently no FDA-approved tailored therapies for the disease. TNBC is characterized by the absence of estrogen receptor alpha (ERα) and IBC by high frequency of ERα negativity. Despite the lack of ERα, estrogen has been reported to signal in these tumors through ERα-independent pathways. With this indication in mind, we have set out to identify alternative hormone signaling with targeting potential by focusing on second estrogen receptor (ERβ) that acts as tumor suppressor in TNBC and IBC and is downregulated in these cancers. We and others previously demonstrated the anti-metastatic activity of ERβ in TNBC. More recently, a study revealed through the analysis of human tissues decreased levels of ERβ in 70% of IBC tumors and associated its presence in tumors with less metastasis in patients. Further, Docket No.10063-085WO1 studies found that ERβ inhibits the migration of IBC cells and ERβ-proficient cells are less metastatic than ERβ knockout cells in xenograft models of the disease. Based on these findings, ERβ is downregulated in tumors of patients with TNBC and IBC that eventually relapse with metastasis and tumor-specific re-expression of the receptor through the administration of ERβ mRNA will likely leverage its anti-metastatic activity and prevent progression of the disease. This hypothesis is empowered by recent investigations that employed mRNA to upregulate tumor suppressor proteins (p53, PTEN), promoting the implementation of this strategy for cancer treatment. Preliminary results further support the hypothesis by indicating the ability of complexes of ERβ mRNA with lipid nanoparticles (LNPs) at non-toxic concentrations to produce a functional receptor with enhanced anti-invasive activity and sustain in vivo tumor specific protein expression with increased anti-metastatic function. It is, therefore, of high importance to evaluate the ERβ mRNA as novel therapeutic to combat progression and metastasis of TNBC and IBC. This disclosure describes: a) the development of ERβ mRNA as novel therapy for aggressive breast cancer with decreased expression of the receptor that currently lacks effective targeted therapy. Based on this solid rational and preliminary results, ERβ mRNA either alone or in combination with existing therapies will substantially prevent metastasis to eliminate associated mortality. This innovative approach establishes the foundation for clinical translation of ERβ mRNA in treatment of TNBC and IBC. Notably, due to downregulation of ERβ in other breast cancers and cancer types, these findings benefit patients with other malignancies. b) the optimization of methods of exploiting mRNA technology to enhance signaling by a tumor suppressor. Various lipid formulations for mRNA delivery are options to achieve maximum uptake by tumor cells and intracellular expression of a functional protein. Further, the present disclosure explores novel approaches of in vivo treatment to define optimal doses and duration, ensuring that a clinically relevant administration of mRNA can result in prolonged tumor specific expression of the receptor with desired anti-tumor activity. c) the identification of novel associated genes and pathways that mediate the tumor repressive effects of ERβ by exploiting direct administration of mRNA to ensure maximal induction in the expression of the receptor and transcription of its target genes. This will lead through the discovery of novel oncogenic drivers to the development of new molecular targets and, therefore, alternate strategies to treat resistant and metastatic disease. The present disclosure has emerged from the urgent need to develop novel treatments for TNBC and IBC that are highly metastatic and lack effective targeted therapy. ERβ is a molecule Docket No.10063-085WO1 with targeting potential because it is downregulated in TNBC and IBC and its positivity correlates with better prognosis, yet the use of ERβ agonists alone was deemed to be fairly ineffective due to the lack of the receptor in many of these tumors. Based on these observations, the present disclosure describes upregulation of ERβ in tumors by using ERβ mRNA-LNPs, yet the efficacy of this complex to produce an active receptor in cells has not previously been assessed. Preliminary findings point to a strong induction of functional ERβ in breast cancer cells following treatment with mRNA. They also indicate the advantage of the method of in vivo mRNA administration in facilitating tumor specific protein expression. In this disclosure, the capacity of ERβ mRNA to produce a potent tumor suppressor across breast cancer cells with diverse molecular and biological properties and an active receptor in tumors that represses breast cancer in models that accurately reflect the clinical pattern of disease progression is evaluated. The present disclosure provides the following conceptual and technical innovations: a) There is no published work on the effects of ERβ mRNA-LNPs in preclinical cancer models. These results are the first to show that ERβ mRNA produces a functional protein that decreases the invasiveness of breast cancer cells and points toward inhibition of metastasis. The present disclosure is, therefore, unique since demonstrating the importance of ERβ mRNA for prevention and treatment of breast cancer metastasis represents an entirely new direction for both nuclear receptor and breast cancer research. b) New observations linking ERβ to regulation of actin organization, metabolism and immune response have been made. For the first time, effects of ERβ mRNA on genes and pathways that influence breast cancer metastasis will be evaluated to validate the specificity of the proposed treatment. c) mRNA technology and lipid nanotechnology to manufacture a harmless reagent with distinct physicochemical and biological properties that does not cause irreversible genome changes and is intended for protein replacement to restore estrogen receptor function, acting as a cancer therapeutic. Determining the capacity of ERβ mRNA to produce a functional receptor The present disclosure has developed a novel targeted therapy for prevention of progression and metastasis of breast cancer. Findings point the induction of ERβ expression as an effective therapy intervention because the receptor is downregulated in aggressive breast tumors and when it is upregulated by conventional transfection in cancer cells decreases their invasiveness and metastatic potential (FIG. 1 and FIG. 11). The present disclosure also identifies a clinically Docket No.10063-085WO1 relevant approach to restore expression of ERβ in IBC and TNBC tumors through the administration of complexes of ERβ mRNA with LNPs to leverage its anti-metastatic activity. Design of ERβ mRNA-LNPs Recent advances in RNA therapeutics and mRNA vaccines have drawn significant attention due to their ability to tackle unmet clinical needs. It is now clear that mRNA promises to transform clinical applications such as immunizations, genetic disorders and protein replacement therapies. Efficient delivery of mRNA and its targeted cellular expression are key factors to optimize mRNA therapeutic applications. Despite the advances in mRNA synthesis and regulation, its therapeutic use is limited due to high sensitivity to nucleases and the need for a protective delivery system that enables long half-life and a slow body clearance. Furthermore, the negative charge, high molecular weight and hydrophilicity of mRNA may also prevent it from crossing the cell membrane, leading to low cellular uptake. LNP is the most frequently used non- viral vector for RNA delivery due to an efficient binding and condensing RNA, protecting from enzymatic and chemical degradation in extracellular milieu, and efficient intracellular delivery. A key feature of using LNP for mRNA delivery is the presence of positively charged lipid that enables complexation and encapsulation of negatively charged RNA. A permanently cationic or ionizable lipid also facilitates through membrane disruption the endosomal escape of the LNP. Research has demonstrated the ability to make reproducible mRNA-LNP using a microfluidic Nanoassemblr technology that is cGMP compatible and scalable to manufacture homogeneous mRNA-LNP for clinical application. During the initial design and characterization of ERβ mRNA containing LNP a narrow size distribution with a polydispersity index (PDI) <0.2 was observed, pointing to a homogenous population of LNP. It is also essential to note that the encapsulation of mRNA in LNP as it was assessed by RiboGreen RNA assay is >94%. Experimental design and methods Design of ERβ mRNA-LNP: ERβ mRNA-LNP systems with cationic (e.g., DOTAP, DODMA) or ionizable lipid (e.g., SM-102, Dlin-MC3-DMA) are designed. Besides the charged lipid, the systems contain dioleoylphosphatidylcholine (DOPC), cholesterol, 1,2-Dimyristoyl-rac- glycerol-3-methoxy polyethylene glycol-2000 (DMG-PEG 2000), and phosphatidylethanolamine (PE). ERβ mRNA (capped) is synthetically produced using established protocols suitable for clinical-grade mRNA. Several lipids and lipid/nucleic acid ratios are used to optimize the mRNA loading and LNP characteristics using Nanoassemblr technology. Briefly, lipids and mRNA are Docket No.10063-085WO1 dissolved in ethanolic and aqueous phases, respectively. The phases are combined in a microfluidic chip at the ratio of 1:3 with a flow rate of 4-10 ml/min and the mixture is dialyzed in PBS to remove ethanol and unbound mRNA/siRNA. Characterization of ERβ mRNA-LNP: Physico-chemical properties of LNP including diameter (size) and zeta potential (charge) are assessed in phosphate buffer by Dynamic Light Scattering (DLS) in a Malvern nano-ZS Zetasizer. The efficiency of mRNA encapsulation in LNP is quantified using RiboGreen® RNA assay and the integrity of mRNA in LNP is determined by High-Res Electrophoresis. Evaluate the functionality of ERβ mRNA Preliminary findings demonstrate the efficacy of mRNA carrier (LNPs) to accumulate in breast cancer cells and efficiently deliver the encapsulated mRNA ensuring that non-toxic doses of ERβ mRNA produce a functional receptor. Specifically, a rapid lipid uptake and high transfection efficiency following treatment of IBC KPL4 cells with reporter GFP mRNA (0.1-2 μg/ml) encapsulated in rhodamine-labelled LNPs was observed (FIG. 4B). A strong induction of ERβ protein with evident anti-migratory activity after incubation of KPL4 and TNBC SUM159 cells with lower amounts of ERβ mRNA-LNPs (0.05-0.1 μg/ml) was observed (FIGS. 4C-4D). Delivery of ERβ mRNA in breast cancer cells translates into a functional protein with tumor suppressor activity. Experimental design and methods: In vitro assessment of intracellular delivery and expression of ERβ mRNA. As breast cancer is heterogeneous disease, multiple IBC and TNBC cell lines were screened for their ability to rapidly uptake complexes of mRNA-LNPs to evaluate their efficacy to penetrate tumor cells of different molecular subtypes. For this, additional IBC (SUM149, SUM190, FC-IBC02) and TNBC cell lines (MDA-MB-231, MDA-MB-468, HCC-1395) were treated with various concentrations (0.05-2μg/ml) of GFP mRNA encapsulated in fluorescently-tagged LNPs. The kinetics of LNP uptake (rhodamine, red signal) and protein expression (GFP, green signal) in our IncuCyte live cell imaging system were assessed. Optimal concentrations for each cell line were applied to test the expression of ERβ mRNA by immunoblotting. The functionality of the produced ERβ protein was evaluated in luciferase reporter assays with an ERE-containing reporter plasmid and by assessing target gene expression by qPCR. Docket No.10063-085WO1 In vitro validation of the anti-tumor activity of ERβ mRNA. The anti-invasive activity of ERβ mRNA was evaluated by measuring cell invasion and migration in different molecular subtypes of aggressive breast cancer. IBC (SUM149, SUM190, FC-IBC02) and TNBC cell lines (MDA-MB-231, MDA-MB-468, HCC-1395) were treated with concentrations of ERβ mRNA- LNPs that induce expression of the receptor using mCherry mRNA as control treatment. Transwell invasion was monitored along with wound healing as well as cell motility on collagen-coated surfaces by recording single cell position in IncuCyte imaging system. Cell viability in real time was then assessed following incubation of cells with the same concentrations of ERβ mRNA-LNPs using luminescent and clonogenic survival assays. To validate the specificity of treatment, the effects on ERβ mRNA-treated and ERβ-transfected cells were compared. To exclude toxicity that is provoked by cell exposure to non-physiological levels of lipids or mRNA, cell viability in ERβ mRNA-treated normal breast (MCF-10A) and cancer cells were assessed and selected to use concentrations that do not stress the normal cells. Two-way ANOVA was used to assess significant differences in cell velocity and Student’s t-test for those in cell viability, migration, invasion and gene expression. Evaluating the anti-tumor activity of ERβ mRNA and elucidate the mechanism of action and Examining the effects of ERβ mRNA on tumor development and metastasis Research has shown the association of ERβ with favorable prognosis in patients with IBC and TNBC (Fig.1A). Due to the decline of the receptor in many of these tumors and the efficacy of synthetic mRNA to express the protein in breast cancer cells, the present disclosure investigated whether in vivo administration of the same mRNA could restore the protein in tumors and its tumor repressive activity. The mRNA was administered directly in tumors to achieve maximal accumulation and expression in target tissue and the efficacy of administration was assessed through intratumoral injection of luciferase mRNA at same dose (5 μg) with that of ERβ. Prolonged tumor specific protein expression lasting for more than half a week was observed (FIG. 3A), ensuring that the treatment scheme with biweekly injections will sustain high levels of ERβ for duration of treatment. Consistent with this expectation, experiments showed high expression of ERβ in orthotopic IBC tumors following intratumoral administration with 5 μg mRNA twice a week for three weeks (FIG.8C). Tumors that were injected with ERβ mRNA appeared to grow a little slower than those treated with vehicle mRNA (FIG. 2). Despite the lack of significant difference in early primary tumor growth, treatment caused a profound inhibition of metastasis Docket No.10063-085WO1 (FIG. 10B) without triggering signs of stress, weight loss and abnormal toxicity markers (ALT, LDH, BUN), ensuring that doses of mRNA that elicit anti-tumor activity did not cause toxicity. Experimental design and methods: In vivo effects of ERβ mRNA on tumor progression and metastasis. To fully define the in vivo tumor repressive activity of the treatment, whether ERβ mRNA inhibits tumor development and metastasis in available xenograft and PDX models that closely reflect the clinical pattern of progression in IBC and TNBC was examined. (2-10)x105 luciferase/GFP-expressing IBC (SUM149, FC-IBC02) and TNBC (MDA-MB-231, SUM159) cells were orthotopically injected and available IBC and TNBC PDX (PDX 2147, BCX010) models in Rag2-/-;IL2Rγc-/- mice (10 mice/group) were used. Complexes of ERβ (2.5, 5, 10 μg) and mCherry (10 μg, vehicle) mRNA with LNPs were intratumorally injected (twice a week) for up to 4 weeks starting in 100 mm3 tumors. Transplants were grown up to 400 mm3 and following resection in a survival surgery, metastasis was assessed weekly by whole body bioluminescence imaging (BLI, FIG.1C) and after mouse was sacrificed by histological, GFP immunofluorescence and immunohistochemical (IHC) assessment with the assistance of pathologist. Differences in early primary tumor growth were also determined by monitoring biweekly tumor volume through caliper measurements and by whole body bioluminescence imaging. Assessment of ERβ expression in tumors. Tumor expression of ERβ occurs in mRNA- treated IBC xenograft (FIG. 8C). The optimal dose of ERβ mRNA that sustains expression of functional protein for the entire time of treatment across different models of IBC and TNBC was determined by assessing the levels of ERβ and its target genes in resected tumors by IHC, qPCR and immunoblot. Finally, IHC staining was utilized to determine the intratumoral distribution of expression and identity the cells that uptake and synthesize the protein. Toxicity: To determine whether the ERβ mRNA-based therapy has any deleterious effect on animal health after a single or multiple intratumoral administrations in four cohorts of animals (four doses) mouse weights and identifiers of animal stress (hunched posture, lethargy, ruffled fur) were monitored during dosing until the experimental end point. As a second measure of toxicity, complete blood cell counts (CBCs) and chemistry readings were defined. After initial and last dosing, blood samples were drawn and analyzed by Flow Cytometry for CBCs and Pathology for blood chemistry readings on 26-whole blood parameters. Docket No.10063-085WO1 Elucidate the mechanism of action of ERβ mRNA Although IBC tumors present with characteristics of poor prognosis (EGFR, HER2, p53 mutations) these are not specific for IBC. Similar, the lack of hormone and HER2 receptors poses challenges in targeted therapy of TNBC and despite the recently approved clinical use of immunotherapies, only 10% of patients are responsive indicating the urgent need to develop new viable molecular targets. The present disclosure employed mRNA technology to achieve full induction in the transcriptional activity of ERβ and, therefore, strong upregulation of target genes that will allow for the identification of downstream mediators with targeting potential that were not previously detected. Besides, studying associated pathways will help to corroborate the functionality of the protein and specificity of treatment. Previously ERβ target genes that are associated with metastasis were identified. Similar gene expression changes in ERβ mRNA-treated cells were detected (FIG. 7). Indicating that ERβ mRNA inhibits breast cancer progression and metastasis by regulating a complex network of associated pathways. Experimental design and methods: Identify ERβ-associated genes and pathways with tumor repressive function. The present disclosure elucidates the mechanism by which ERβ mRNA inhibits progression and metastasis of IBC and TNBC tumors to corroborate the antimetastatic activity of treatment and identify novel associated genes that regulate metastasis. Gene expression in vehicle and ERβ mRNA-treated tumors was assessed by RNA-Seq and data was associated with previously identified ERβ targets in IBC and TNBC cells. ERβ mRNA-treated IBC and TNBC cells were analyzed by ChIP-Seq to map the DNA binding of the receptor that mediates transcriptional effects. The DNA binding and gene expression data was combined to define distinct mechanisms of gene regulation and direct targets of ERβ upon mRNA treatment. Finally, changes in gene expression were corroborated bt qPCR and IHC analysis of tumors to evaluate the therapeutic relevance of identified factors in functional in vitro and in vivo studies after their genetic and pharmacological inhibition. Considering the established association of ERβ with differentiation and inhibition of invasion, mechanistic studies are likely to identify similar biological processes to account for the anti-tumor effects of ERβ mRNA. However, due to strong induction in the transcriptional activity of ERβ by the direct administration of mRNA, new target genes may be enriched that were not previously identified with conventional transfection of DNA. The number of mice per group was chosen for the potential to see 3-fold difference in BLI at endpoint (3x106 p/s/cm2 in vehicle-treated tumors vs. 1x106 p/s/cm2 in ERβ mRNA-treated Docket No.10063-085WO1 tumors, alpha = 0.05; power = 0.8). Thus, 252 mice (10 mice/group X 24 groups (6 tumor models X 4 treatments) were analyzed including 12 for the toxicity studies. Kaplan-Meier plots illustrated differences in survival and significant differences were assessed by log-rank test. Differentially expressed genes were determined using SAM with a less than 0.01 FDR and an absolute fold change of greater than 1.5 between different groups. Significant differences in tumor volume, metastasis and mRNA levels were assessed by Student’s t and Fisher's exact tests and for multi- group comparisons by Kruskal-Wallis tests. The present disclosure demonstrates the beneficial use of ERβ mRNA as a therapy approach to prevent progression of breast cancer. These studies build the foundation to support larger scale preclinical testing and pave the way for clinical investigations to test the ERβ mRNA in patients. Sex of experimental animals: female mice were analyzed because IBC and TNBC almost exclusively affect women. Randomization: Animals were randomly assigned to experimental groups so that handling and treatment was the same across study groups. Blinding: All animal caretakers and investigators performing experiments and assessing outcomes were blinded to the allocation sequence and intervention. Sample-size estimation and data handling: Statistical analysis plans and sample size estimations are described in the proposal and appropriate statistical methods are reported in resulting publications. Criteria for data inclusion or exclusion will be specified prior to data analysis and outliers (points beyond 2xS.D.) will be defined and reported in publications. If data are not normally distributed, appropriate transformation will be applied before normality-based methods are used. Alternatively, robust nonparametric methods for non-Gaussian data or data with outliers will be considered. All missing data because of attrition or exclusion will be reported and experiments will be independently repeated at least three times. It will be apparent to those skilled in the art that various modifications and variations can be made in the present disclosure without departing from the scope or spirit of the invention. Other embodiments of the disclosure will be apparent to those skilled in the art from consideration of the specification and practice of the methods disclosed herein. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the invention being indicated by the following claims.

Claims

Docket No.10063-085WO1 CLAIMS What is claimed is: 1. A therapeutic composition comprising a nucleic acid encoding estrogen receptor beta (ERβ), wherein the nucleic acid is encapsulated in or conjugated to a nucleic acid delivery vehicle. 2. The composition of claim 1, wherein the nucleic acid delivery vehicle comprises a pharmaceutically acceptable carrier selected from a lipid nanoparticle (LPN), a lipid carrier, an organic polymer, a cell, a virus-like particle, an excipient, a diluent, a salt, a buffer, or a stabilizer. 3. The composition of claim 1 or 2, wherein the nucleic acid comprises mRNA. 4. The composition of any one of claims 1-3, wherein the nucleic acid comprises at least 80% identity to SEQ ID NO: 1 or SEQ ID NO: 2. 5. The composition of any one of claims 1-4, wherein the nucleic acid comprises at least 90% identity to SEQ ID NO: 1 or SEQ ID NO: 2. 6. The composition of any one of claims 1-5, wherein the nucleic acid comprises SEQ ID NO: 1 or SEQ ID NO: 2. 7. The composition of any one of claims 3-6, wherein the mRNA comprises a full-length mRNA. 8. The composition of any one of claims 3-7, wherein the mRNA comprises a functional fragment of the full-length ERβ mRNA. 9. The composition of any one of claims 2-8, wherein the LPN comprises a solid lipid nanoparticle, a nanostructured lipid carrier, or any variations thereof. 10. The composition of any one of claims 2-8, wherein the lipid carrier comprises a liposome, a liposome-like nanoparticle, a lipid-polymer hybrid nanoparticle, a nanoemulsion, an exosome, a lipoprotein particle, or any combinations thereof. Docket No.10063-085WO1 11. The composition of any one of claims 2-8, wherein the organic polymer comprises a polypeptide or peptide, a nucleic acid , a lipid, a carbohydrate, or any combinations thereof. 12. The composition of any one of claims 2-8, wherein the cell comprises a dendritic cell. 13. The composition of any one of claims 2-8, wherein the virus-like particle comprises one or more non-infectious components from a virus selected from Human immunodeficiency virus (HIV), Influenza virus, Hepatitis B virus, Hepatitis E virus, Ebola virus, Severe acute respiratory syndrome coronavirus (SARS-CoV), SARS-CoV-2, Respiratory syncytial virus (RSV), Human papillomavirus (HPVs), and Middle east respiratory syndrome coronavirus (MERS-CoV). 14. The composition of any one of claims 1-13, wherein the composition comprises a naked nucleic acid encoding an ERβ protein. 15. The composition of any one of claims 1-14, wherein the nucleic acid comprises one or more chemical modifications to increase stability of the nucleic acid encoding ERβ. 16. The composition of any one of claims 1-15, wherein the one or more chemical modifications are selected from a 5’-7-methylguanosine cap, a 5’ untranslated region 5’ UTR, a 3’ UTR, a modification to the open reading frame (ORF), and a poly-adenylate tail. 17. A method of treating or preventing an ERβ-related disorder in a subject in need thereof, the method comprising administering a pharmaceutically effective amount of a composition comprising a nucleic acid encoding ERβ, wherein the nucleic acid is encapsulated in or conjugated to a nucleic acid delivery vehicle, and wherein the method increases expression of a ERβ protein in the subject relative to an untreated subject with cancer. 18. The method of claim 17, wherein the nucleic acid delivery vehicle comprises a pharmaceutically acceptable carrier selected from a lipid nanoparticle (LPN), a lipid carrier, an organic polymer, a cell, a virus-like particle, an excipient, a diluent, a salt, a buffer, or a stabilizer. 19. The method of claim 17 or 18, wherein the nucleic acid comprises mRNA. 20. The method of claim 19, wherein the mRNA comprises a full-length mRNA. Docket No.10063-085WO1 21. The method of any one of claims 17-20, wherein the mRNA comprises a functional fragment of the full-length mRNA. 22. The method of any one of claims 17-21, wherein the nucleic acid comprises one or more chemical modifications to increase stability of the nucleic acid encoding ERβ. 23. The method of claim 22, wherein the one or more chemical modifications are selected from a 5’-7-methylguanosine cap, a 5’ untranslated region 5’ UTR, a 3’ UTR, a modification to the open reading frame (ORF), and a poly-adenylate tail. 24. The method of any one of claims 17-23, wherein the composition is administered intratumorally or intravenously. 25. The method of any one of claims 17-24, wherein the ERβ-related disorder comprises a cancer selected from a breast cancer, an ovarian cancer, a uterine cancer, vaginal cancer, vulvar cancer, cervical cancer, urethral cancer, a prostate cancer, colorectal cancer, bladder cancer, thyroid cancer, or cancers affecting a tissue from a reproductive, gastrointestinal, or urinary system. 26. The method of claim 25, wherein the breast cancer comprises inflammatory breast cancer (IBC), Triple-Negative Breast Cancer (TNBC), HER2-positive breast cancer, or Hormone Receptor-(HR)-positive breast cancer. 27. The method of any one of claims 18-26, wherein the LPN comprises a solid lipid nanoparticle, a nanostructured lipid carrier, or any variations thereof. 28. The method of any one of claims 18-26, wherein the lipid carrier comprises a liposome, a liposome-like nanoparticle, a lipid-polymer hybrid nanoparticle, a nanoemulsion, an exosome, a lipoprotein particle, or any combinations thereof. 29. The method of any one of claims 18-26, wherein the organic polymer comprises a polypeptide or peptide, a nucleic acid, a lipid, a carbohydrate, or any combinations thereof. Docket No.10063-085WO1 30. The method of any one of claims18-26, wherein the cell comprises a dendritic cell. 31. The method of any one of claims 18-26, wherein the virus-like particle comprises one or more non-infectious components from a virus selected from Human immunodeficiency virus (HIV), Influenza virus, Hepatitis B virus, Hepatitis E virus, Ebola virus, Severe acute respiratory syndrome coronavirus (SARS-CoV), SARS-CoV-2, Respiratory syncytial virus (RSV), Human papillomavirus (HPVs), and Middle east respiratory syndrome coronavirus (MERS-CoV). 32. The method of any one of claims 17-31, wherein the composition comprises a naked nucleic acid encoding an ERβ protein. 33. The method of any one of claims 17-32, wherein the ERβ protein targets one or more metastasis- and cancer progression-associated genes selected from CD36, TGFb, TGFbR2, ALDH1A1, ELMO1, ILR1, IL6, IL8, IL1, IL17, CCL2, GPR141, CREB1, TFF1, FN1, NRG1, LCN2, VTCN1, FST1, NRP1, RHOBTB3. 34. The method of any one of claims 17-33, wherein the composition is administered at a dose of at least 2μg of ERβ nucleic acid. 35. The method of any one of claims 17-34, wherein the composition is administered for at least one week. 36. The method of any one of claims 17-35, wherein the composition is administered at least once per week. 37. The method of any one of claims 17-36, wherein the composition is administered in combination with an adjuvant. 38. The method of any one of claims 17-37, wherein the composition is administered in combination with an additional therapeutic composition. 39. The method of claim 38, wherein the additional therapeutic composition comprises an anti- cancer agent, a chemotherapeutic agent, an anti-inflammatory agent, or a combination thereof. Docket No.10063-085WO1 40. The method of claim 39, wherein the anti-cancer agent comprises an interferon, a cytokine, a vaccine, a growth factor, an antibody or serotherapy, or an immunomodulatory agent. 41. The method of claim 39, wherein the chemotherapeutic agent comprises a luteinizing hormone releasing hormone (LHRH), anti-androgens, endocrine therapy, aromatase inhibitors, anti-estrogens, photodynamic therapies, nitrogen mustards, nitrosoureas, metal containing compounds, nucleotide analogs, anti-metabolites, or a cancer suppressing agent. 42. The method of any one of claims 17-41, wherein the method decreases the growth of cancer cells, the stemness of cancer cells, or the invasiveness of cancer cells in the subject relative to an untreated subject with an ERβ-related disorder. 43. The method of any one of claims 17-42, wherein the method enhances cancer-associated immune response in the subject relative to an untreated subject with an ERβ-related disorder. 44. A method of treating or preventing tumor development in a subject with cancer, the method comprising administering a pharmaceutically effective amount of a composition comprising a nucleic acid encoding ERβ, wherein the nucleic acid is encapsulated in or conjugated to a nucleic acid delivery vehicle, and wherein the method increases expression of a ERβ protein in the subject relative to an untreated subject with cancer. 45. A method of treating or preventing a metastasis in a subject, the method comprising administering a pharmaceutically effective amount of a composition comprising a nucleic acid encoding ERβ, wherein the nucleic acid is encapsulated in or conjugated to a nucleic acid delivery vehicle, and wherein the method increases expression of a ERβ protein in the subject relative to an untreated subject with a metastasis. 46. The method of claim 44 or 45, wherein the nucleic acid delivery vehicle comprises a pharmaceutically acceptable carrier selected a lipid nanoparticle (LPN), a lipid carrier, an organic polymer, a cell, a virus-like particle, an excipient, a diluent, a salt, a buffer, or a stabilizer. 47. The method of any one of claims 44-46, wherein the nucleic acid comprises mRNA. Docket No.10063-085WO1 48. The method of claim 47, wherein the mRNA comprises a full-length mRNA. 49. The method of claim 47 or 48, wherein the mRNA comprises a functional fragment of the full-length mRNA. 50. The method of any one of claims 44-49, wherein the nucleic acid comprises one or more chemical modifications to increase stability of the nucleic acid encoding ERβ. 51. The method of claim 50, wherein the one or more chemical modifications are selected from a 5’-7-methylguanosine cap, a 5’ untranslated region 5’ UTR, a 3’ UTR, a modification to the open reading frame (ORF), and a poly-adenylate tail. 52. The method of any one of claims 44-51, wherein the composition is administered intratumorally or intravenously. 53. The method of any one of claims 44-52, wherein the cancer comprises a breast cancer, an ovarian cancer, a uterine cancer, vaginal cancer, vulvar cancer, cervical cancer, urethral cancer, a prostate cancer, colorectal cancer, bladder cancer, thyroid cancer, or cancers affecting a tissue from a reproductive, gastrointestinal, or urinary system. 54. The method of claim 53, wherein the breast cancer comprises inflammatory breast cancer (IBC) Triple-Negative Breast Cancer (TNBC), HER2-positive breast cancer, or Hormone Receptor-(HR)-positive breast cancer. 55. The method of any one of claims 46-54, wherein the LPN comprises a solid lipid nanoparticle, a nanostructured lipid carrier, or any variations thereof. 56. The method of any one of claims 46-54, wherein the lipid carrier comprises a liposome, a liposome-like nanoparticle, a lipid-polymer hybrid nanoparticle, a nanoemulsion, an exosome, a lipoprotein particle, or any combinations thereof. 57. The method of any one of claims 46-54, wherein the organic polymer comprises a polypeptide or peptide, a nucleic acid , a lipid, a carbohydrate, or any combinations thereof. Docket No.10063-085WO1 58. The method of any one of claims 46-54, wherein the cell comprises a dendritic cell. 59. The method of any one of claims 46-54, wherein the virus-like particle comprises one or more non-infectious components from a virus selected from Human immunodeficiency virus (HIV), Influenza virus, Hepatitis B virus, Hepatitis E virus, Ebola virus, Severe acute respiratory syndrome coronavirus (SARS-CoV), SARS-CoV-2, Respiratory syncytial virus (RSV), Human papillomavirus (HPVs), and Middle east respiratory syndrome coronavirus (MERS-CoV). 60. The method of any one of claims 44-59, wherein the composition comprises a naked nucleic acid encoding an ERβ protein. 61. The method of any one of claims 44-60, wherein the ERβ protein targets one or more metastasis- and cancer progression-associated genes selected from CD36, TGFb, TGFbR2, ALDH1A1, ELMO1, ILR1, IL6, IL8, IL1, IL17, CCL2, GPR141, CREB1, TFF1, FN1, NRG1, LCN2, VTCN1, FST1, NRP1, RHOBTB3. 62. The method of any one of claims 44-61, wherein the composition is administered at a dose of at least 2μg of ERβ nucleic acid. 63. The method of any one of claims 44-62, wherein the composition is administered for at least one week. 64. The method of any one of claims 44-63, wherein the composition is administered at least once per week. 65. The method of any one of claims 44-64, wherein the composition is administered in combination with an adjuvant. 66. The method of any one of claims 44-65, wherein the composition is administered in combination with an additional therapeutic composition. 67. The method of claim 66, wherein the additional therapeutic composition comprises an anti- cancer agent, a chemotherapeutic agent, an anti-inflammatory agent, or a combination thereof. Docket No.10063-085WO1 68. The method of claim 67, wherein the anti-cancer agent comprises an interferon, a cytokine, a vaccine, a growth factor, an antibody or serotherapy, or an immunomodulatory agent. 69. The method of claim 67, wherein the chemotherapeutic agent comprises a luteinizing hormone releasing hormone (LHRH), anti-androgens, endocrine therapy, aromatase inhibitors, anti-estrogens, photodynamic therapies, nitrogen mustards, nitrosoureas, metal containing compounds, nucleotide analogs, anti-metabolites, or a cancer suppressing agent. 70. The method of any one of claims 44-69, wherein the method decreases the growth of cancer cells, the stemness of cancer cells, or the invasiveness of cancer cells in the subject relative to an untreated subject with an ERβ-related disorder. 71. The method of any one of claims 44-70, wherein the method enhances cancer-associated immune response in the subject relative to an untreated subject with an ERβ-related disorder. 72. A kit comprising a nucleic acid encoding an estrogen receptor beta (ERβ), wherein the nucleic acid is encapsulated in or conjugated to a nucleic acid delivery vehicle. 73. The kit of claim 72, wherein the nucleic acid comprises mRNA. 74. The kit of claim 73, wherein the mRNA comprises a full-length mRNA. 75. The kit of claim 73, wherein the mRNA comprises a functional fragment of the full-length mRNA. 76. The method of any one of claims 72-75, wherein the nucleic acid comprises one or more chemical modifications to increase stability of the nucleic acid encoding ERβ. 77. The method of claim 76, wherein the one or more chemical modifications are selected from a 5’-7-methylguanosine cap, a 5’ untranslated region 5’ UTR, a 3’ UTR, a modification to the open reading frame (ORF), and a poly-adenylate tail. Docket No.10063-085WO1 78. The kit of any one of claims 72-77, wherein the nucleic acid delivery vehicle comprises a pharmaceutically acceptable carrier selected from a lipid nanoparticle (LPN), a lipid carrier, an organic polymer, a virus-like particle, or a stabilizer. 79. The kit of any one of claims 72-78, further comprising an RNase-free reagent selected from RNase-free water, RNase-free buffered solution, and RNase-free saline.
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