High density brush shaped polymer lipids reduce Anti-peg antibody binding to enable mRNA lipid nanoparticle repeat administration

Abstract

The present disclosure relates to a compound containing two or more hydrophobic chains and a polyacrylate polymer with one or more PEG side chains attached to the carboxylic acid group of the polyacrylate polymer. The compound is further defined by formula I: wherein the variables are as defined below. These compounds may be used in the preparation of lipid nanoparticles for the treatment or prevention of a disease or disorder.

Description

[0001] DESCRIPTION HIGH DENSITY BRUSH SHAPED POLYMER LIPIDS REDUCE ANTI-PEG ANTIBODY BINDING TO ENABLE MRNA LIPID NANOPARTICLE REPEAT ADMINISTRATION This application claims the benefit of priority to United States Provisional Application No. 63 / 701,428, filed on September 30, 2024, the entire contents of which are hereby incorporated by reference. BACKGROUND This invention was made with government support under grant no. R01 5R01EB025192-06 awarded by the National Institute of Health and grant no. R01 CA269787- 01 awarded by the National Cancer Institute. The government has certain rights in the invention. 1. Field of the Disclosure The present disclosure relates generally to the fields of medicine and therapeutic agents. In some aspects, the present disclosure relates to new compounds for use in lipid nanoparticles to increase the effectiveness of a therapeutic agent such as a nucleic acid therapeutic agent. 2. Background of the Disclosure Messenger RNA (mRNA) therapy holds immense potential to treat various liver conditions caused by genetic mutations, chronic infections, drug and alcohol abuse, and serious injury that lead to more than 2 million deaths worldwide per year. (Rohner et al., 2022; Zabaleta et al., 2022) Genetic metabolic diseases are particularly well suited for mRNA-based protein replacement therapy since the liver functions as an essential metabolism organ by regulating chemical and protein levels in the blood. (Cacicedo et al., 2022; Qin et al., 2022) Various viral and synthetic delivery systems have been developed for protein replacement therapy. (Xiao et al., 2022; Hajj et al., 2017) Viral vectors can accumulate in the liver and transfect cells with high efficacy. (Mendell et al., 2021; Milani et al., 2022; Nguyen et al., 2021; Hakim et al., 2021; Yang et al., 2016; Villiger et al., 2018) However, the wide existence of neutralizing antibodies in humans prevents repeat dose efficacy for viral vectors. (Schulz et al., 2023; Li et al., 2012; Boutin et al., 2010; Colella et al., 2018) Since life-long liver diseases require continuous medication, attention has shifted to non-viral strategies that could potentially overcome immune recognition and antibody production. LNPs represent the most promising synthetic delivery vehicle class due to their clinical use in siRNA liver therapy and two mRNA COVID-19 vaccines. (Dillard & Siegwart, 2023; Liu et al., 2021; Wei et al., 2020; Cheng et al., 2020; Hou et al., 2021) Synthetic LNP carriers are expected to improve safety and redosing feasibility considerations over viral vectors. However, recent reports suggest that the generation and boosting of anti-PEG antibodies after receiving PEGylated therapeutics, including COVID-19 vaccines, limits efficacy when re- administered.22 Anti-PEG IgG was boosted 13.1-fold after Spikevax vaccination where gold standard 1,2-dimyristoyl-rac-glycero-3-methoxypolyethylene glycol-2000 (DMG-PEG2000) was used as a PEG-lipid. (Ju et al., 2022) Meanwhile, specific anti-PEG antibody related phagocytosis was enhanced, leading to accelerated blood clearance (ABC) of re-administrated PEGylated drugs that weakens therapy. Thus, LNP neutralization by existing anti-PEG antibodies in the serum raises concerns for LNP-mediated protein replacement therapy that requires multiple administrations.

[0002] SUMMARY The present disclosure relates to compounds containing two or more hydrophobic tail units and polyacrylate polymer with one or more PEG groups coming off the carboxylic acid of the acrylate group. In some embodiments, the compounds are further defined as: wherein: R1and R1are each independently alkyl(C6-24), alkenyl(C6-24), or a substituted version of either group; R2 and R2 are each independently alkyl(C1-8) or substituted alkyl(C1-8); R3 is alkyl(C1-8) or substituted alkyl(C1-8); X1, X2, and X3are each independently O or NRa, wherein: Rais hydrogen, alkyl(C1-6), or substituted alkyl(C1-6); Y1 is OR4 or NR4′R4′′, wherein: R4, R4′, and R4′′ are each independently selected from a sugar moiety, alkyl(C1-8), substituted alkyl(C1-8), or −Y2−R5, wherein Y2 is alkanediyl(C1-6) or substituted alkanediyl(C1-6); and R5 is alkoxy(C1-8), substituted alkoxy(C1-8), heterocycloalkyl(C1-8), substituted heterocycloalkyl(C1- 8), or NR(R′)(R′′), wherein R, R′, and R′′, are each independently absent, hydrogen, alkyl(C1-6), substituted alkyl(C1-6), or Y1is: −(OCH2CH2)yRb, wherein Rbis hydroxy, alkoxy(C1-6), or substituted alkoxy(C1-6), and y is 1-30; and x is 1-100; or a pharmaceutically acceptable salt thereof. In some embodiments, the compounds are further defined as: wherein: R1 and R1′ are each independently alkyl(C6-24), alkenyl(C6-24), or a substituted version of either group; Y1 is −(OCH2CH2)yRb, wherein Rb is hydroxy, alkoxy(C1-6), or substituted alkoxy(C1-6), and y is 5-30; and x is 1-100; or a pharmaceutically acceptable salt thereof. In some embodiments,X1is O. In some embodiments, X2is O. In some embodiments, X3is O. In some embodiments, R2is alkyl(C1-8)such as methyl. In some embodiments, R2′ is alkyl(C1-8) such as methyl. In some embodiments, R3 is alkyl(C1-8) such as methyl. In some embodiments, R1 is alkyl(C6-24) or substituted alkyl(C6-24). In some embodiments, R1is alkyl(C6-24). In some embodiments, R1is alkyl(C8-20). In some embodiments, R1 is alkyl(C10-20). In some embodiments, R1 is alkyl(C10-18). In some embodiments, R1 is alkyl(C12-16). In some embodiments, R1′ is alkyl(C6-24)or substituted alkyl(C6-24). In some embodiments, R1′ is alkyl(C6-24). In some embodiments, R1′ is alkyl(C8-20). In some embodiments, R1′ is alkyl(C10-20). In some embodiments, R1′ is alkyl(C10-18). In some embodiments, R1′ is alkyl(C12-16). In some embodiments, y is 5-30. In some embodiments, y is 7-30. In some embodiments, y is 10-25. In some embodiments, the compounds are further defined as: wherein: R1and R1′ are each independently alkyl(C6-24), alkenyl(C6-24), or a substituted version of either group; Y1 is −(OCH2CH2)yRb, wherein Rb is methoxy and y is 19; and x is 5-100; or a pharmaceutically acceptable salt thereof. In some embodiments, x is 15-70. In some embodiments, x is 20-60. In some embodiments, x is 30-50. In some embodiments, the compounds are further defined as: wherein: R1 and R1′ are each independently alkyl(C12-16) or substituted alkyl(C12-16); Y1 is −(OCH2CH2)yRb, wherein Rb is methoxy and y is 19; and x is 30-50; or a pharmaceutically acceptable salt thereof. In yet another aspect, the present disclosure provides lipid nanoparticles comprising a compound described herein. In some embodiments, the lipid nanoparticle comprises one or more ionizable cationic lipids. In some embodiments, the ionizable cationic lipid is an ionizable amine lipid. In some embodiments, the lipid nanoparticle further comprises one or more phospholipids. In some embodiments, the phospholipid is a zwitterionic phospholipid. In some embodiments, the lipid nanoparticle further comprises one or more sterol. In some embodiments, the sterol is cholesterol. In some embodiments, the lipid nanoparticle further comprises a payload. In some embodiments, the payload is a nucleic acid. In some embodiments, the nucleic acid is siRNA, a miRNA, a pri-miRNA, a messenger RNA (mRNA), a cluster regularly interspaced short palindromic repeats (CRISPR) related nucleic acid, a single guide RNA (sgRNA), a CRISPR- RNA (crRNA), a trans-activating crRNA (tracrRNA), a plasmid DNA (pDNA), a transfer RNA (tRNA), an antisense oligonucleotide (ASO), a guide RNA, a double stranded DN A (dsDNA), a single stranded DN A (ssDNA), a single stranded RNA (ssRNA), and a double stranded RNA (dsRNA). In some embodiments, the nucleic acid is a therapeutic nucleic acid. In other embodiments, the payload is a peptide or protein. In some embodiments, the payload is a peptide, protein, a nucleic acid, or a combination thereof. In still another aspect, the present disclosure provides pharmaceutical compositions comprising: (A) a lipid nanoparticle described herein; and (B) an excipient. In yet another aspect, the present disclosure provides methods of treating or preventing a disease or disorder in a patient in need thereof comprising administering to the patient a lipid nanoparticle or a pharmaceutical composition described herein to the patient. In some embodiments, the lipid nanoparticle comprises a payload that is useful in treating the disease or disorder. In another aspect, the present disclosure provides methods of increasing the effectiveness of a nucleic acid therapeutic in a patient comprising administering to the patient a lipid nanoparticle or a pharmaceutical composition described herein to the patient. In some embodiments, the lipid nanoparticle or a pharmaceutical results in reduced binding of an antibody against polyethylene glycol (PEG). In yet another aspect, the present disclosure provides methods of decreasing the effects of antibodies against polyethylene glycol (PEG) on a therapeutic agent comprising using a lipid nanoparticle or pharmaceutical composition comprising a compound described herein. Additional aspects and advantages of the present application will become readily apparent to those skilled in this art from the following detailed description, wherein only illustrative embodiments of the present application are shown and described. As will be realized, the present application is capable of other and different embodiments, and its several details are capable of modifications in various obvious respects, all without departing from the disclosure. Accordingly, the drawings and description are to be regarded as illustrative in nature, and not as restrictive. BRIEF DESCRIPTION OF THE DRAWINGS The features of the disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the disclosure are utilized, and the accompanying drawings (also “Figure” and “FIG.” herein), of which: FIGS 1A-1D show synthetic polymer lipid incorporated LNPs mediate efficient mRNA delivery. (a) Scheme illustration of how high-density brush-shaped polymer lipids reduce anti- PEG antibody binding to enable mRNA LNP repeat dose efficacy. (b) Synthetic route of polymer-lipids by ATRP using lipid-Br as initiator. (c) In vivo Luc mRNA delivery by polymer-lipid LNPs (0.1 mg kg−1Luc mRNA, i.v., 6 h). (d) Quantitative data of mean luminescent signal of each organ in (c) after delivery of luciferase mRNA mediated by polymer-lipid LNPs. FIG. 2 shows in vitro Luc mRNA transfection on HepG2 cells. Luc mRNA was encapsulated into different polymer-lipid LNPs and delivered at a dose of 50 ng mRNA per well. FIGS 3A-3O show synthetic chemistry controls polymer architectures and mRNA delivery efficacy. a–e, EG side chain length (x)-dependent mRNA delivery efficacy. a, BPL chemical structure and schematic illustration with different EG side chain lengths. b, Size and polydispersity index (PDI) of BPL LNPs measured using dynamic light scattering. Data are presented as mean ± s.d. (n = 3 biologically independent samples). c, In vivo Luc mRNA delivery (0.1 mg kg−1). d, Quantitative data of Luc activity in livers after Luc mRNA delivery. Data are presented as mean ± s.d. (n = 3 biologically independent samples). e, Serum hEPO level quantified by enzyme-linked immunosorbent assay (ELISA) after hEPO mRNA delivery (0.3 mg kg−1). Data are presented as mean ± s.d. (n = 3 biologically independent samples). f– j, DP (y)-dependent mRNA delivery efficacy. f, BPL chemical structure and schematic illustration with different DP values. g, Size and PDI of BPL LNPs. Data are presented as mean ± s.d. (n = 3 biologically independent samples). h, In vivo Luc mRNA delivery (0.1 mg kg−1). i, Quantitative data of mean Luc activity in livers after Luc mRNA delivery. Data are presented as mean ± s.d. (n = 3 biologically independent samples). j, Serum hEPO level quantified by ELISA after hEPO mRNA delivery (0.3 mg kg−1). Data are presented as mean ± s.d. (n = 3 biologically independent samples). k–o, Alkyl length (n)-dependent mRNA delivery efficacy. k, BPL chemical structure and schematic illustration with different alkyl lengths. l, Size and PDI of BPL LNPs. Data are presented as mean ± s.d. (n = 3 biologically independent samples). m, In vivo Luc mRNA delivery (0.1 mg kg−1). n, Quantitative data of mean Luc activity in livers after Luc mRNA delivery. Data are presented as mean ± s.d. (n = 3 biologically independent samples). o, Serum hEPO level quantified by ELISA after hEPO mRNA delivery (0.3 mg kg−1). Data are presented as mean ± s.d. (n = 3 biologically independent samples). DOG, 1,3-dioctanoyl glycero-; DLG, 1,3-dilauroyl glycero-; DMG, 1,3-dimyristoyl glycero-; DPG, 1,3-dipalmitoyl glycero-; DSG, 1,3-distearoyl glycero-. FIGS.4A-4I show in vitro characterization of BPLs. (a-c) Luc mRNA encapsulation efficiency (a), cell viability against HepG2 cells (b), and Luc mRNA transfection efficacy in HepG2 cells (c) of DMG-PEGxMA BPLs with different side chain length. (d-f) Luc mRNA encapsulation efficiency (d), cell viability against HepG2 cells (e), and Luc mRNA transfection efficacy in HepG2 cells (f) of DMG-PEG19MAy BPLs with different DPs. (g-i) Luc mRNA encapsulation efficiency (g), cell viability against HepG2 cells (h), and Luc mRNA transfection efficacy in HepG2 cells (i) of DNG-PEG19MA BPLs with different alkyl length. FIGS. 5A-5G show DP dependent mRNA delivery efficacy in DMG-PEG9MA polymer-lipid LNPs. (a) Polymer structure and schematic illustration of DMG-PEG9MAywith different DPs. (b) Size and polydispersity of DMG-PEG9MAy LNPs with different DPs measured by DLS. (c) Luc mRNA encapsulation efficiency of DMG-PEG9MAyLNPs with different DPs measured by Ribo green assay. (d) Cell viability against HepG2 cells. (e) In vitro Luc mRNA transfection efficacy in HepG2 cells (50 ng Luc mRNA per well). (f) In vivo Luc mRNA delivery by DMG-PEGxMAy LNPs with different DPs (0.1 mg kg−1 Luc mRNA, i.v., 6 h). (g) Quantitative data of mean luminescent signal of livers delivered by DMG-PEG9MAyLNPs with DPs (0.1 mg kg−1 Luc mRNA, i.v., 6 h, n= 3). FIGS. 6A-6F show alkyl chain length dependent mRNA delivery efficacy in DNG- PEG9MA polymer-lipid LNPs. (a) Polymer structure and schematic illustration of DNG- PEG9MA with different DPs. (b) Size and polydispersity of DNG-PEG9MA LNPs with different alkyl lengths measured by DLS. (c) Luc mRNA encapsulation efficiency of DNG- PEG9MA BPLs with different alkyl lengths measured by Ribo green assay. (d) Cell viability against HepG2 cells. (e) In vitro Luc mRNA transfection efficacy in HepG2 cells (50 ng Luc mRNA per well). (f) In vivo luc mRNA delivery by DNG-PEG9MA BPLs with different alkyl lengths (0.1 mg kg−1 Luc mRNA, i.v., 6 h). (g) Quantitative data of mean luminescent signal of livers delivered by DNG-PEG9MA BPLs with alkyl lengths (0.1 mg kg−1 Luc mRNA, i.v., 6 h, n = 3). FIGS 7A-7P show polymerization parameters and polymer regimes control the pharmacokinetic profile and anti-PEG antibody binding. a, RF values of BPLs and their regimes on the surface of LNPs. b, Representative schematic illustrations of mushroom and brush regimes. c–h, Plasma cholesteryl methyl ether (CME) levels quantified by GC-MS in the mice injected with BPL LNPs with different EG side chain lengths (c and d), DPs (e and f) and alkyl lengths (g and h). PK, pharmacokinetic. The area under curve values were found at 48 h. Data are presented as mean ± s.d. and statistical significance was analysed by one-way analysis of variance (ANOVA) multiple comparisons with DMG-PEG2000: ***P < 0.001; **P < 0.01; *P < 0.05 (n = 3 biologically independent samples). i, Schematic illustration of biolayer interferometry assay for the measurement of binding affinity between LNPs and APA. Left: a typical binding kinetic experiment. Right: association and dissociation between the LNPs and the APA immobilized biosensor. j–o, Equilibrium dissociation constant (KD) values and representative association and dissociation phase curves of APA and BPLs with different EG side chain lengths (j and k), DPs (l and m) and alkyl lengths (n and o), indicating a chemical- structure-dependent association rate behaviour with eligible dissociation. A lower KD value indicates stronger binding. In the biolayer interferometry experiment, the immobilized APA concentration was 100 nM. Data are presented as mean ± s.d. (n = 3 biologically independent samples). FIG.8 shows1H NMR spectra of cholesteryl methyl ether (CME). FIGS 9A-9Q show BPLs improved protein production consistency in repeat dose over DMG-PEG2000 LNPs. (a-j) Mice were first i.v. administered with standard DMG-PEG2000 LNPs or BPLs carrying Luc mRNA (0.1 mg kg-1) or hEPO mRNA (0.3 mg kg-1). After 30 days, mice received same LNPs injection. (b-d) Redosing of BPLs with different EG side chain length (x). (b) In vivo evaluation of Luc mRNA delivery. (c, d) Reduction of luminescent signals by second dose (c) and serum hEPO level (d) compared to that of first dose. (e-g) Redosing of BPLs with different DP (y). (e) In vivo evaluation of Luc mRNA delivery. (f, g) Reduction of luminescent signals by second dose (f) and serum hEPO level (g) compared to that of first dose. (h-j) Redosing of BPLs with different alkyl length (n). (h) In vivo evaluation of Luc mRNA delivery. (i, j) Reduction of luminescent signals by second dose (i) and serum hEPO level (j) compared to that of first dose. (k-q) Mice were first i.v. administrated with BPLs carrying Luc mRNA (0.1 mg kg-1) or hEPO mRNA (0.3 mg kg-1). After 30 days, mice received standard DMG-PEG2000 LNP injection. (l-n) Repeated dosing when first dose is BPLs with different EG side chain length (x). (l) In vivo evaluation of Luc mRNA delivery. (m, n) Reduction of luminescent signals by second dose (m) and serum hEPO level (n) compared to one dose of DMG-PEG2000 LNP. (o-q) Repeated dosing when first dose is BPLs with different DP (y). (o) In vivo evaluation of Luc mRNA delivery. (p, q) Reduction of luminescence signals of second dose (p) and serum hEPO level (q) compared to one dose of DMG- PEG2000 LNP. Statistical significance was analyzed by the two-tailed unpaired t-test: ***P < 0.001; **P < 0.01; *P < 0.05. FIG. 10A-10F show BPLs exhibited less decrement in repeated same dose efficacy than standard DMG-PEG2000 LNPs. (a, b) Comparation of luminescent signals (a) and serum hEPO levels (b) between first dose and second dose. Mice were i.v. injected twice with either DMEPEG2000 LNP or DMG-PEGxMA LNPs with different EG side chain lengths (x) across 30 days. (c, d) Comparation of luminescent signals (c) and serum hEPO levels (d) between first dose and second dose. Mice were i.v. injected twice with either DME-PEG2000 LNP or DMG-PEG19MAyBPLs with different DPs (y) across 30 days. (e, f) Comparation of luminescent signals (e) and serum hEPO levels (f) between first dose and second dose. Mice were i.v. injected twice with either DME-PEG2000 LNP or DNG-PEG19MA BPLs with different alkyl chain lengths (n) across 30 days. FIGS.11A-11D show BPLs exhibited less decrement in repeated dose efficacy than standard DMG-PEG2000 LNPs. Mice were injected with polymer-lipid LNPs at day 1, and DMG-PEG2000 at day 30. (a, b) Comparation of luminescent signals (a) and serum hEPO levels (b) between first dose and second dose. Mice were i.v. injected with DMG-PEGxMA BPLs with different EG side chain lengths (x) at day 1 and standard DMG-PEG2000 LNP at day 30. (c, d) Comparation of luminescent signals (c) and serum hEPO levels (d) between first dose and second dose. Mice were i.v. injected with DMG-PEG19MA BPLs with different DP (y) at day 1 and standard DMGPEG2000 LNP at day 30. FIGS 12A-12E show BPLs could overcome anti-PEG antibody inhibitory effect induced by DMG-PEG2000 LNPs. (a) Schematic illustration of the rechallenge study. Mice were first i.v. administrated with standard DMG-PEG2000 LNPs carrying Luc mRNA (0.1 mg kg-1) or hEPO mRNA (0.3 mg kg-1) to create pre- existing anti-PEG antibodies. After 30 days, mice received BPL injection at a same dose. (b, c) In vivo evaluation of repeated Luc mRNA delivery by BPLs. (d) Plasma CME level at 6 h post injection. (e) Serum hEPO level after by repeated hEPO mRNA delivery by BPLs. Statistical significance was analyzed by the two- tailed unpaired t-test: **P < 0.01; *P < 0.05. FIGS. 13A-13K show BPL LNPs achieve superior therapeutic outcomes in protein replacement and genome editing. a–e, BPL LNPs increase survival in protein replacement therapy. a, Schematic illustration of therapeutic regimen in FAH− / −mice. Mice with pre- existing anti-PEG antibodies (APA)s (off NTBC water) were treated with PBS, DMG- PEG2000 LNPs, DMG-PEG19MA36 BPL LNPs or DPG-PEG19MA36 BPL LNPs every three days (FAH mRNA, 0.3 mg kg−1). b, Body weight was monitored during the treatment. Data are presented as mean ± s.d. (n = 8 at day 0 biologically independent samples; mice with body weight loss over 20% were euthanized (dashed line) and n decreased accordingly). c, Survival analysis of protein replacement therapy. Statistical significance was analyzed by log-rank (Mantel–Cox) test. d,e, Western blot of liver tissues at end-point were measured to evaluate therapeutic efficacy. FAH expression is plotted as fold change relative to PBS. Data are presented as mean ± s.d. and statistical significance was analyzed by one-way ANOVA multiple comparisons: ***P < 0.001; **P < 0.01 (n = 5 biologically independent samples). f– k, BPL LNPs achieve superior CRISPR / Cas9 editing over DMG-PEG2000 LNPs. f, Schematic illustration of genome editing study in C57BL / 6 mice with pre-existing APAs. Cas9 mRNA and sgPCSK9 were co-delivered at a total dose of 1.5 mg kg−1 (2:1, wt / wt). g,h, Indels detected in livers after ten days using Sanger sequencing and next-generation sequencing (NGS). Editing was quantified using TIDE (g) and CRISPResso2 (h) methods. i–k, Western blot of liver tissue (i) and ELISA of liver (j) and serum (k) PCSK9 levels were applied to evaluate the reduction of PCSK9 protein. Data are presented as mean ± s.d. and statistical significance was analysed by one-way ANOVA multiple comparisons: ***P < 0.001; **P < 0.01; *P < 0.05 (n = 3 biologically independent samples). FIG.14 shows a Western blot of FAH protein expression in A549 cells after delivery of FAH mRNA by LNPs at a dose of 300 ng per well. The experiments were repeated three times with similar results. FIGS.15A & 15B show BPL LNPs and DMG-PEG2000 LNPs show comparable FAH mRNA delivery efficacy with FAH protein expression in livers at a dose of 0.3 mg kg-1. FAH expression is plotted as fold change relative to PBS. Data are presented as mean ± s.d. and statistical significance was analyzed by one-way ANOVA multiple comparisons with P >0.05. (n = 3 biologically independent samples) FIGS.16A-16D show body weights of FAH- / -mice in the protein replacement therapy study treated with PBS (a), DMG-PEG2000 LNPs (b), DMG-PEG19MA36 BPL LNPs (c), or DPG-PEG19MA36BPL LNPs (d). FIG. 17 shows FAH- / -mice show low FAH protein expression at the endpoint of treatment with DMG-PEG2000 LNPs. The experiments were repeated three times with similar results. FIG. 18 shows FAH- / -mice stay high FAH protein expression at the endpoint of treatment with DMG-PEG19MA36 BPL LNPs. The experiments were repeated three times with similar results. FIG. 19 shows FAH- / -mice stay high FAH protein expression at the endpoint of treatment with DPG-PEG19MA36BPL LNPs. The experiments were repeated three times with similar results. FIGS. 20A-20E show serum liver damage markers are evaluated at the endpoint of therapeutic study. Data are presented as mean ± s.d. and statistical significance was analyzed by one-way ANOVA multiple comparisons among treatment groups: **P < 0.01; *P < 0.05. (n = 4 biologically independent samples). FIG.21 shows BPL LNPs exhibit higher genome editing efficacy than DMG-PEG2000 LNPs as evidenced by Sanger sequencing data. FIG.22 shows PCSK9 expression is plotted as fold change relative to untreated group from FIG.13I. Data are presented as mean ± s.d. and statistical significance was analyzed by one-way ANOVA multiple comparisons: with ***P <0.001. (n = 3 biologically independent samples). FIGS.23A & 23B shows BPL LNPs reduce serum cholesterol (a) and triglyceride (b) levels after co-delivery of Cas9 / sgPCSK9. Data are presented as mean ± s.d. and statistical significance was analyzed by one-way ANOVA multiple comparisons: ***P < 0.001; **P < 0.01. (n = 3 biologically independent samples). FIG. 24 shows BPL LNPs and DMG-PEG2000 LNPs are well tolerated in vivo at a dose of 1.5 mg kg-1. Mice with pre-existed anti-PEG antibodies were i.v. injected with BPL LNPs or DMG-PEG2000 LNPs. After 10 days, serum was obtained for the evaluation of liver function (AST and ALT) and kidney function (BUN and CREA). Data are presented as mean ± s.d. (n = 3 biologically independent samples). FIG.25 shows H&E staining images of liver tissues. Mice with pre-existed APAs were i.v. injected with BPLs or DMG-PEG2000 LNPs (1.5 mg kg-1). Livers are harvested after 10 days. Scale bar: 500 μm. The experiments were repeated three times with similar results (n = 3 mice). DETAILED DESCRIPTION To address the issue with anti-PEG antibodies, the present disclosure describes a systematic series of new polymer lipids as substitutes for currently used DMG-PEG2000, generating LNPs with reduced anti-PEG antibody reactogenicity and improved repeat dose efficacy (FIG.1A). The present disclosure provides new chemical space for LNP optimization using a polymer lipid component as a handle for LNP optimization. Atom transfer radical polymerization (ATRP) was employed to generate a polymer lipid library with controlled architecture, chemical functionality, and molecular weight using lipid-functionalized initiators and various monomers containing linear, brush, hydrophilic, hydrophobic, positively charged, neutral, and zwitterionic features. From the polymer lipid library, the present disclosures provides compounds that exhibited superior luciferase (Luc) mRNA transfection in vivo. Multiple different factors were examined three chemical design parameters: side chain length, degree of polymerization, and alkyl length. These three factors were modified to increase the mRNA delivery efficacy both in vitro and in vivo. The tested LNPs exhibited reduced anti-PEG antibody binding affinity compared to standard DMG-PEG2000 LNPs owing to the advantage of brushed structure and mushroom polymer regimes that hindered protein absorption and antibody binding. All these features resulted in superior LNPs with slower clearance and higher mRNA delivery efficacy upon repeat dosing compared to DMG-PEG2000 LNPs. Moreover, LNPs can overcome the anti-PEG antibody inhibitory effect induced by DMG-PEG2000 LNPs, demonstrating potential to rescue immunogenicity-stalled protein replacement therapy. Overall, an expanded chemical scope of LNP stabilizing polymer lipids revealed actionable insights into polymer physiochemical properties and architecture that improved repeat dose maintenance of high human protein expression. These compounds. LNPs, and methods resulting therefrom are described in more detail below. A. Definitions The use of the word “a” or “an” when used in conjunction with the term “comprising” in the claims and / or the specification may mean “one,” but it is also consistent with the meaning of “one or more,” “at least one,” and “one or more than one.” The word “about” means plus or minus 5% of the stated number. When used in the context of a chemical group: “hydrogen” means −H; “hydroxy” means −OH; “oxo” means =O; “carbonyl” means −C(=O)−; “carboxy” means −C(=O)OH (also written as −COOH or −CO2H); “halo” means independently −F, −Cl, −Br or −I; “amino” means −NH2; “hydroxyamino” means −NHOH; “nitro” means −NO2; imino means =NH; “cyano” means −CN; “isocyanyl” means −N=C=O; “azido” means −N3; in a monovalent context “phosphate” means −OP(O)(OH)2 or a deprotonated form thereof; in a divalent context “phosphate” means −OP(O)(OH)O− or a deprotonated form thereof; “mercapto” means −SH; and “thio” means =S; “thiocarbonyl” means −C(=S)−; “sulfonyl” means −S(O)2−; and “sulfinyl” means −S(O)−. In the context of chemical formulas, the symbol “−” means a single bond, “=” means adouble bond, and “≡” means triple bond. The symbol “ ” represents an optional bond,which if present is either single or double. The symbol “ ” represents a single bond or adouble bond. Thus, the formula c for example, , , , and And it is understood that no one such ring atom forms part of more than one double bond. Furthermore, it is noted that the covalent bond symbol “−”, when con cting one or two stereogenic atoms, does not indicate any preferred stereochemistry. Instead, it covers allstereoisomers as well as mixtures thereof. The symbol “ ”, when drawn perpendicularlyacross a bond (e.g., for methyl) indicates a point of attachment of the group. It is notedthat the point of attachment is typically only identified in this manner for larger groups in orderto assist the reader in unambiguously identifying a point of attachment. The symbol “ ” means a single bond where the group attached to the thick end of the wedge is “out of the page.”The symbol “ ” means a single bond where the group attached to the thick end of the wedgeis “into the page”. The symbol “ ” means a single bond where the geometry around adouble bond (e.g., either E or Z) is undefined. Both options, as well as combinations thereof are therefore intended. Any undefined valency on an atom of a structure shown in this application implicitly represents a hydrogen atom bonded to that atom. A bold dot on a carbon atom indicates that the hydrogen attached to that carbon is oriented out of the plane of the paper. When a variable is depicted as a “floating group” on a ring system, for example, the group “R” in the formula: R , then the variable may replace any hydrogen atom attached to any of the ring atoms, including a depicted, implied, or expressly defined hydrogen, so long as a stable structure is formed. When a variable is depicted as a “floating group” on a fused ring system, as for example the group “R” in the formula: (R)yN H , then the variable may replace any hydrogen attached to any of the ring atoms of either of the fused rings unless specified otherwise. Replaceable hydrogens include depicted hydrogens (e.g., the hydrogen attached to the nitrogen in the formula above), implied hydrogens (e.g., a hydrogen of the formula above that is not shown but understood to be present), expressly defined hydrogens, and optional hydrogens whose presence depends on the identity of a ring atom (e.g., a hydrogen attached to group X, when X equals −CH−), so long as a stable structure is formed. In the example depicted, R may reside on either the 5-membered or the 6-membered ring of the fused ring system. In the formula above, the subscript letter “y” immediately following the R enclosed in parentheses, represents a numeric variable. Unless specified otherwise, this variable can be 0, 1, 2, or any integer greater than 2, only limited by the maximum number of replaceable hydrogen atoms of the ring or ring system. For the chemical groups and compound classes, the number of carbon atoms in the group or class is as indicated as follows: “Cn” or “C=n” defines the exact number (n) of carbon atoms in the group / class. “C≤n” defines the maximum number (n) of carbon atoms that can be in the group / class, with the minimum number as small as possible for the group / class in question. For example, it is understood that the minimum number of carbon atoms in the groups “alkyl(C≤8)”, “alkanediyl(C≤8)”, “heteroaryl(C≤8)”, and “acyl(C≤8)” is one, the minimum number of carbon atoms in the groups “alkenyl(C≤8)”, “alkynyl(C≤8)”, and “heterocycloalkyl(C≤8)” is two, the minimum number of carbon atoms in the group “cycloalkyl(C≤8)” is three, and the minimum number of carbon atoms in the groups “aryl(C≤8)” and “arenediyl(C≤8)” is six. “Cn-n′” defines both the minimum (n) and maximum number (n′) of carbon atoms in the group. Thus, “alkyl(C2-10)” designates those alkyl groups having from 2 to 10 carbon atoms. These carbon number indicators may precede or follow the chemical groups or class it modifies and it may or may not be enclosed in parenthesis, without signifying any change in meaning. Thus, the terms “C1-4-alkyl”, “C1-4-alkyl”, “alkyl(C1-4)”, and “alkyl(C≤4)” are all synonymous. Except as noted below, every carbon atom is counted to determine whether the group or compound falls with the specified number of carbon atoms. For example, the group dihexylamino is an example of a dialkylamino(C12)group; however, it is not an example of a dialkylamino(C6)group. Likewise, phenylethyl is an example of an aralkyl(C=8) group. When any of the chemical groups or compound classes defined herein is modified by the term “substituted”, any carbon atom in the moiety replacing the hydrogen atom is not counted. Thus methoxyhexyl, which has a total of seven carbon atoms, is an example of a substituted alkyl(C1-6).Unless specified otherwise, any chemical group or compound class listed in a claim set without a carbon atom limit has a carbon atom limit of less than or equal to twelve. The term “saturated” when used to modify a compound or chemical group means the compound or chemical group has no carbon-carbon double and no carbon-carbon triple bonds, except as noted below. When the term is used to modify an atom, it means that the atom is not part of any double or triple bond. In the case of substituted versions of saturated groups, one or more carbon oxygen double bond or a carbon nitrogen double bond may be present. And when such a bond is present, then carbon-carbon double bonds that may occur as part of keto- enol tautomerism or imine / enamine tautomerism are not precluded. When the term “saturated” is used to modify a solution of a substance, it means that no more of that substance can dissolve in that solution. The term “aliphatic” signifies that the compound or chemical group so modified is an acyclic or cyclic, but non-aromatic compound or group. In aliphatic compounds / groups, the carbon atoms can be joined together in straight chains, branched chains, or non-aromatic rings (alicyclic). Aliphatic compounds / groups can be saturated, that is joined by single carbon- carbon bonds (alkanes / alkyl), or unsaturated, with one or more carbon-carbon double bonds (alkenes / alkenyl) or with one or more carbon-carbon triple bonds (alkynes / alkynyl). The term “aromatic” signifies that the compound or chemical group so modified has a planar unsaturated ring of atoms with 4n +2 electrons in a fully conjugated cyclic π system. An aromatic compound or chemical group may be depicted as a single resonance structure; however, depiction of one resonance structure is taken to also refer to any other resonance structure. For example: Aromatic compounds may also be depicted using a circle to represent the delocalized nature of the electrons in the fully conjugated cyclic π system, two non-limiting examples of which are shown below: an The term “alkyl” refers to a monovalent saturated aliphatic group with a carbon atom as the point of attachment, a linear or branched acyclic structure, and no atoms other than carbon and hydrogen. The groups −CH3 (Me), −CH2CH3 (Et), −CH2CH2CH3 (n-Pr or propyl), −CH(CH3)2(i-Pr,iPr or isopropyl), −CH2CH2CH2CH3(n-Bu), −CH(CH3)CH2CH3(sec-butyl), −CH2CH(CH3)2 (isobutyl), −C(CH3)3 (tert-butyl, t-butyl, t-Bu ortBu), and −CH2C(CH3)3 (neo- pentyl) are non-limiting examples of alkyl groups. The term “alkanediyl” refers to a divalent saturated aliphatic group, with one or two saturated carbon atom(s) as the point(s) of attachment, a linear or branched acyclic structure, no carbon-carbon double or triple bonds, and no atoms other than carbon and hydrogen. The groups −CH2− (methylene), −CH2CH2−, −CH2C(CH3)2CH2−, and −CH2CH2CH2− are non-limiting examples of alkanediyl groups. The term “alkylidene” refers to the divalent group =CRR′ in which R and R′ are independently hydrogen or alkyl. Non-limiting examples of alkylidene groups include: =CH2, =CH(CH2CH3), and =C(CH3)2. An “alkane” refers to the class of compounds having the formula H−R, wherein R is alkyl as this term is defined above. The term “alkenyl” refers to a monovalent unsaturated aliphatic group with a carbon atom as the point of attachment, a linear or branched, acyclic structure, at least one nonaromatic carbon-carbon double bond, no carbon-carbon triple bonds, and no atoms other than carbon and hydrogen. Non-limiting examples include: −CH=CH2 (vinyl), −CH=CHCH3, −CH=CHCH2CH3,−CH2CH=CH2(allyl),−CH2CH=CHCH3, and−CH=CHCH=CH2. The term “alkenediyl” refers to a divalent unsaturated aliphatic group, with two carbon atoms as points of attachment, a linear or branched acyclic structure, at least one nonaromatic carbon- carbon double bond, no carbon-carbon triple bonds, and no atoms other than carbon and hydrogen. The groups −CH=CH−, −CH=C(CH3)CH2−, −CH=CHCH2−, and −CH2CH=CHCH2− are non-limiting examples of alkenediyl groups. It is noted that while the alkenediyl group is aliphatic, once connected at both ends, this group is not precluded from forming part of an aromatic structure. The terms “alkene” and “olefin” are synonymous and refer to the class of compounds having the formula H−R, wherein R is alkenyl as this term is defined above. Similarly, the terms “terminal alkene” and “α-olefin” are synonymous and refer to an alkene having just one carbon-carbon double bond, wherein that bond is part of a vinyl group at an end of the molecule. The term “alkoxy” refers to the group −OR, in which R is an alkyl, as that term is defined above. Non-limiting examples include: −OCH3 (methoxy), −OCH2CH3 (ethoxy), −OCH2CH2CH3, −OCH(CH3)2(isopropoxy), or −OC(CH3)3(tert-butoxy). The terms “cycloalkoxy”, “alkenyloxy”, “alkynyloxy”, “aryloxy”, “aralkoxy”, “heteroaryloxy”, “heterocycloalkoxy”, and “acyloxy”, when used without the “substituted” modifier, refers to groups, defined as −OR, in which R is cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heterocycloalkyl, and acyl, respectively. The term “alkylthio” and “acylthio” refers to the group −SR, in which R is an alkyl and acyl, respectively. The term “alcohol” corresponds to an alkane, as defined above, wherein at least one of the hydrogen atoms has been replaced with a hydroxy group. The term “ether” corresponds to an alkane, as defined above, wherein at least one of the hydrogen atoms has been replaced with an alkoxy group. The term “alkylamino” refers to the group −NHR, in which R is an alkyl, as that term is defined above. Non-limiting examples include: −NHCH3and −NHCH2CH3. The term “dialkylamino” refers to the group −NRR′, in which R and R′ can be the same or different alkyl groups. Non-limiting examples of dialkylamino groups include: −N(CH3)2and −N(CH3)(CH2CH3). The term “amido” (acylamino), when used without the “substituted” modifier, refers to the group −NHR, in which R is acyl, as that term is defined above. A non- limiting example of an amido group is −NHC(O)CH3. When a chemical group is used with the “substituted” modifier, one or more hydrogen atom has been replaced, independently at each instance, by −OH, −F, −Cl, −Br, −I, −NH2, −NO2, −CO2H, −CO2CH3, −CO2CH2CH3, −CN, −SH, −OCH3, −OCH2CH3, −C(O)CH3, −NHCH3, −NHCH2CH3, −N(CH3)2, −C(O)NH2, −C(O)NHCH3, −C(O)N(CH3)2, −OC(O)CH3, −NHC(O)CH3, −S(O)2O−, −S(O)2OH, or −S(O)2NH2. For example, the following groups are non-limiting examples of substituted alkyl groups: −CH2OH, −CH2Cl, −CF3, −CH2CN, −CH2C(O)OH, −CH2C(O)OCH3, −CH2C(O)NH2, −CH2C(O)CH3, −CH2OCH3, −CH2OC(O)CH3, −CH2NH2, −CH2N(CH3)2, and −CH2CH2Cl. The term “haloalkyl” is a subset of substituted alkyl, in which the hydrogen atom replacement is limited to halo (i.e. −F, −Cl, −Br, or −I) such that no other atoms aside from carbon, hydrogen and halogen are present. The group, −CH2Cl is a non-limiting example of a haloalkyl. The term “fluoroalkyl” is a subset of substituted alkyl, in which the hydrogen atom replacement is limited to fluoro such that no other atoms aside from carbon, hydrogen and fluorine are present. The groups −CH2F, −CF3, and −CH2CF3are non-limiting examples of fluoroalkyl groups. Non-limiting examples of substituted aralkyls are: (3-chlorophenyl)-methyl, and 2-chloro-2-phenyl-eth-1-yl. The groups, −C(O)CH2CF3, −CO2H (carboxyl), −CO2CH3 (methylcarboxyl), −CO2CH2CH3, −C(O)NH2(carbamoyl), and −CON(CH3)2, are non-limiting examples of substituted acyl groups. The groups −NHC(O)OCH3 and −NHC(O)NHCH3 are non-limiting examples of substituted amido groups. The terms “polypeptide”, “peptide”, and “protein” are used interchangeably herein to generally refer to polymers of amino acids of any length. The polymer may be linear or branched, it may comprise modified amino acids, and it may be interrupted by non-amino acids. The terms also encompass an amino acid polymer that has been modified, for example, by disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation, such as conjugation with a labeling component. As used herein in the context of the structure of a polypeptide, “N-terminus” (or “amino terminus”) and “C-terminus” (or “carboxyl terminus”) generally refer to the extreme amino and carboxyl ends of the polypeptide, respectively. The term “N-terminal end sequence,” as used herein with respect to a polypeptide or polynucleotide sequence of interest, generally means that no other amino acid or nucleotide residues precede the N-terminal end sequence in the polypeptide or polynucleotide sequence of interest at the N-terminal end. The term “C-terminal end sequence,” as used herein with respect to a polypeptide or polynucleotide sequence of interest, generally means that no other amino acid or nucleotide residues follows the C-terminal end sequence in the polypeptide or polynucleotide sequence of interest at the C-terminal end. The terms “non-naturally occurring” and “non-natural” are used interchangeably herein. The term “non-naturally occurring” or “non-natural,” as used herein with respect to a therapeutic agent or prophylactic agent, generally means that the agent is not biologically derived in mammals (including but not limited to human). The term “non-naturally occurring” or “non-natural,” as applied to sequences and as used herein, means polypeptide or polynucleotide sequences that do not have a counterpart to, are not complementary to, or do not have a high degree of homology with a wild-type or naturally-occurring sequence found in a mammal. For example, a non-naturally occurring polypeptide or fragment may share no more than 99%, 98%, 95%, 90%, 80%, 70%, 60%, 50% or even less amino acid sequence identity as compared to a natural sequence when suitably aligned. “Physiological conditions” refers to a set of conditions in a living host as well as in vitro conditions, including temperature, salt concentration, pH, that mimic those conditions of a living subject. A host of physiologically relevant conditions for use in in vitro assays have been established. Generally, a physiological buffer contains a physiological concentration of salt and is adjusted to a neutral pH ranging from about 6.5 to about 7.8, and preferably from about 7.0 to about 7.5. A variety of physiological buffers are listed in Sambrook et al. (2001). Physiologically relevant temperature ranges from about 25°C to about 38°C, and preferably from about 35°C to about 37°C. As used herein, the terms “treatment” or “treating,” or “palliating” or “ameliorating” are used interchangeably herein. These terms generally refer to an approach for obtaining beneficial or desired results including but not limited to a therapeutic benefit and / or a prophylactic benefit. By therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms or improvement in one or more clinical parameters associated with the underlying disorder such that an improvement is observed in the subject, notwithstanding that the subject may still be afflicted with the underlying disorder. For prophylactic benefit, the compositions may be administered to a subject at risk of developing a particular disease, or to a subject reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made. A “therapeutic effect” or “therapeutic benefit,” as used herein, generally refers to a physiologic effect, including but not limited to the mitigation, amelioration, or prevention of disease or an improvement in one or more clinical parameters associated with the underlying disorder in humans or other animals, or to otherwise enhance physical or mental wellbeing of humans or animals, resulting from administration of a polypeptide of the disclosure other than the ability to induce the production of an antibody against an antigenic epitope possessed by the biologically active protein. For prophylactic benefit, the compositions may be administered to a subject at risk of developing a particular disease, a recurrence of a former disease, condition or symptom of the disease, or to a subject reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made. The terms “therapeutically effective amount” and “therapeutically effective dose”, as used herein, generally refer to an amount of a drug or a biologically active protein, either alone or as a part of a polypeptide composition, that is capable of having any detectable, beneficial effect on any symptom, aspect, measured parameter or characteristics of a disease state or condition when administered in one or repeated doses to a subject. Such effect need not be absolute to be beneficial. Determination of a therapeutically effective amount is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein. The term “equivalent molar dose” generally means that the amounts of materials administered to a subject have an equivalent amount of moles, based on the molecular weight of the material used in the dose. The term “therapeutically effective and non-toxic dose,” as used herein, generally refers to a tolerable dose of the compositions as defined herein that is high enough to cause depletion of tumor or cancer cells, tumor elimination, tumor shrinkage or stabilization of disease without or essentially without major toxic effects in the subject. Such therapeutically effective and non- toxic doses may be determined by dose escalation studies described in the art and should be below the dose inducing severe adverse side effects. The terms “cancer” and “cancerous” refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth / proliferation. Throughout this application, the term “about” is used to indicate that a value includes the inherent variation of error for the device, the method being employed to determine the value, or the variation that exists among the study subjects. As used in this application, the term “average molecular weight” refers to the relationship between the number of moles of each polymer species and the molar mass of that species. In particular, each polymer molecule may have different levels of polymerization and thus a different molar mass. The average molecular weight can be used to represent the molecular weight of a plurality of polymer molecules. Average molecular weight is typically synonymous with average molar mass. In particular, there are three major types of average molecular weight: number average molar mass, weight (mass) average molar mass, and Z- average molar mass. In the context of this application, unless otherwise specified, the average molecular weight represents either the number average molar mass or weight average molar mass of the formula. In some embodiments, the average molecular weight is the number average molar mass. In some embodiments, the average molecular weight may be used to describe a PEG component present in a lipid. The terms “comprise,” “have” and “include” are open-ended linking verbs. Any forms or tenses of one or more of these verbs, such as “comprises,” “comprising,” “has,” “having,” “includes” and “including,” are also open-ended. For example, any method that “comprises,” “has” or “includes” one or more steps is not limited to possessing only those one or more steps and also covers other unlisted steps. The term “effective,” as that term is used in the specification and / or claims, means adequate to accomplish a desired, expected, or intended result. “Effective amount,” “Therapeutically effective amount” or “pharmaceutically effective amount” when used in the context of treating a patient or subject with a compound means that amount of the compound which, when administered to a subject or patient for treating a disease, is sufficient to effect such treatment for the disease. As used herein, the term “IC50” refers to an inhibitory dose which is 50% of the maximum response obtained. This quantitative measure indicates how much of a particular drug or other substance (inhibitor) is needed to inhibit a given biological, biochemical or chemical process (or component of a process, i.e. an enzyme, cell, cell receptor or microorganism) by half. An “isomer” of a first compound is a separate compound in which each molecule contains the same constituent atoms as the first compound, but where the configuration of those atoms in three dimensions differs. As used herein, the term “patient” or “subject” refers to a living mammalian organism, such as a human, monkey, cow, sheep, goat, dog, cat, mouse, rat, guinea pig, or transgenic species thereof. In certain embodiments, the patient or subject is a primate (e.g., non-human primate). In certain embodiments, the patient or subject is a human. Non-limiting examples of human subjects are adults, juveniles, infants and fetuses. The term “assemble” or “assembled,” as used herein, in context of delivery of a payload to target cell(s) generally refers to covalent or non-covalent interaction(s) or association(s), for example, such that a therapeutic or prophylactic agent be complexed with or encapsulated in a lipid composition. As used herein, the term “lipid composition” generally refers to a composition comprising lipid compound(s), including but not limited to, a lipoplex, a liposome, a lipid particle. Example of lipid compositions include suspensions, emulsions, and vesicular compositions. As used herein, the term “detectable” refers to an occurrence of, or a change in, a signal that is directly or indirectly detectable either by observation or by instrumentation. Typically, a detectable response is an occurrence of a signal wherein the fluorophore is inherently fluorescent and does not produce a change in signal upon binding to a metal ion or biological compound. Alternatively, the detectable response is an optical response resulting in a change in the wavelength distribution patterns or intensity of absorbance or fluorescence or a change in light scatter, fluorescence lifetime, fluorescence polarization, or a combination of the above parameters. Other detectable responses include, for example, chemiluminescence, phosphorescence, radiation from radioisotopes, magnetic attraction, and electron density The term “potent” or “potency,” as used herein in connection with delivery of therapeutic agent(s), generally refers to a greater ability of a delivery system (e.g., a lipid composition) to achieve or bring about a desired amount, activity, or effect of a therapeutic agent or prophylactic agent (such as a desired level of translation, transcription, production, expression, or activity of a protein or gene) in cells (e.g., targeted cells) to any measurable extent, e.g., relative to a reference delivery system. For example, a lipid composition with a higher potency may achieve a desired therapeutic effect in a greater population of relevant cells, within a shorter response time, or that last a longer period of time. As generally used herein “pharmaceutically acceptable” refers to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues, organs, and / or bodily fluids of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications commensurate with a reasonable benefit / risk ratio. “Pharmaceutically acceptable salts” means salts of compounds of the present application which are pharmaceutically acceptable, as defined above, and which possess the desired pharmacological activity. Such salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or with organic acids such as 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, 2-naphthalenesulfonic acid, 3-phenylpropionic acid, 4,4'-methylenebis(3-hydroxy-2-ene- 1-carboxylic acid), 4-methylbicyclo[2.2.2]oct-2-ene-1-carboxylic acid, acetic acid, aliphatic mono- and dicarboxylic acids, aliphatic sulfuric acids, aromatic sulfuric acids, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, carbonic acid, cinnamic acid, citric acid, cyclopentanepropionic acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, heptanoic acid, hexanoic acid, hydroxynaphthoic acid, lactic acid, laurylsulfuric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, muconic acid, o-(4-hydroxybenzoyl)benzoic acid, oxalic acid, p-chlorobenzenesulfonic acid, phenyl-substituted alkanoic acids, propionic acid, p-toluenesulfonic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, tartaric acid, tertiarybutylacetic acid, trimethylacetic acid, and the like. Pharmaceutically acceptable salts also include base addition salts which may be formed when acidic protons present are capable of reacting with inorganic or organic bases. Acceptable inorganic bases include sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide and calcium hydroxide. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine and the like. It should be recognized that the particular anion or cation forming a part of any salt of this disclosure is not critical, so long as the salt, as a whole, is pharmacologically acceptable. Additional examples of pharmaceutically acceptable salts and their methods of preparation and use are presented in Handbook of Pharmaceutical Salts: Properties, and Use (P. H. Stahl & C. G. Wermuth eds., Verlag Helvetica Chimica Acta, 2002). The term “pharmaceutically acceptable carrier,” as used herein means a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting a chemical agent. “Prevention” or “preventing” includes: (1) inhibiting the onset of a disease in a subject or patient which may be at risk and / or predisposed to the disease but does not yet experience or display any or all of the pathology or symptomatology of the disease, and / or (2) slowing the onset of the pathology or symptomatology of a disease in a subject or patient which may be at risk and / or predisposed to the disease but does not yet experience or display any or all of the pathology or symptomatology of the disease. A “repeat unit” is the simplest structural entity of certain materials, for example, frameworks and / or polymers, whether organic, inorganic or metal-organic. In the case of a polymer chain, repeat units are linked together successively along the chain, like the beads of a necklace. For example, in polyethylene, -[-CH2CH2-]n-, the repeat unit is −CH2CH2−. The subscript “n” denotes the degree of polymerization, that is, the number of repeat units linked together. When the value for “n” is left undefined or where “n” is absent, it simply designates repetition of the formula within the brackets as well as the polymeric nature of the material. The concept of a repeat unit applies equally to where the connectivity between the repeat units extends three dimensionally, such as in metal organic frameworks, modified polymers, thermosetting polymers, etc. Within the context of the dendrimer or dendron, the repeating unit may also be described as the branching unit, interior layers, or generations. Similarly, the terminating group may also be described as the surface group. A “stereoisomer” or “optical isomer” is an isomer of a given compound in which the same atoms are bonded to the same other atoms, but where the configuration of those atoms in three dimensions differs. “Enantiomers” are stereoisomers of a given compound that are mirror images of each other, like left and right hands. “Diastereomers” are stereoisomers of a given compound that are not enantiomers. Chiral molecules contain a chiral center, also referred to as a stereocenter or stereogenic center, which is any point, though not necessarily an atom, in a molecule bearing groups such that an interchanging of any two groups leads to a stereoisomer. In organic compounds, the chiral center is typically a carbon, phosphorus or sulfur atom, though it is also possible for other atoms to be stereocenters in organic and inorganic compounds. A molecule can have multiple stereocenters, giving it many stereoisomers. In compounds whose stereoisomerism is due to tetrahedral stereogenic centers (e.g., tetrahedral carbon), the total number of hypothetically possible stereoisomers will not exceed 2n, where n is the number of tetrahedral stereocenters. Molecules with symmetry frequently have fewer than the maximum possible number of stereoisomers. A 50:50 mixture of enantiomers is referred to as a racemic mixture. Alternatively, a mixture of enantiomers can be enantiomerically enriched so that one enantiomer is present in an amount greater than 50%. Typically, enantiomers and / or diastereomers can be resolved or separated using techniques known in the art. It is contemplated that that for any stereocenter or axis of chirality for which stereochemistry has not been defined, that stereocenter or axis of chirality can be present in its R form, S form, or as a mixture of the R and S forms, including racemic and non-racemic mixtures. As used herein, the phrase “substantially free from other stereoisomers” means that the composition contains ≤ 15%, more preferably ≤ 10%, even more preferably ≤ 5%, or most preferably ≤ 1% of another stereoisomer(s). “Treatment” or “treating” includes (1) inhibiting a disease in a subject or patient experiencing or displaying the pathology or symptomatology of the disease (e.g., arresting further development of the pathology and / or symptomatology), (2) ameliorating a disease in a subject or patient that is experiencing or displaying the pathology or symptomatology of the disease (e.g., reversing the pathology and / or symptomatology), and / or (3) effecting any measurable decrease in a disease in a subject or patient that is experiencing or displaying the pathology or symptomatology of the disease. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. In case of conflict, the patent specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the disclosure. B. Compounds of the Present Disclosure The compounds of the present invention (also referred to as “compounds of the present disclosure”) are shown, for example, above, in the summary of the invention section, and in the claims below. They may be made using the synthetic methods outlined in the Examples section. These methods can be further modified and optimized using the principles and techniques of organic chemistry as applied by a person skilled in the art. Such principles and techniques are taught, for example, in Smith, March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, (2013), which is incorporated by reference herein. In addition, the synthetic methods may be further modified and optimized for preparative, pilot- or large-scale production, either batch or continuous, using the principles and techniques of process chemistry as applied by a person skilled in the art. Such principles and techniques are taught, for example, in Anderson, Practical Process Research & Development – A Guide for Organic Chemists (2012), which is incorporated by reference herein. The compounds include those described by the formula: wherein: R1and R1are each independently alkyl(C6-24), alkenyl(C6-24), or a substituted version of either group; R2 and R2 are each independently alkyl(C1-8) or substituted alkyl(C1-8); R3 is alkyl(C1-8) or substituted alkyl(C1-8); X1, X2, and X3are each independently O or NRa, wherein: Rais hydrogen, alkyl(C1-6), or substituted alkyl(C1-6); Y1 is OR4 or NR4′R4′′, wherein: R4, R4′, and R4′′ are each independently selected from a sugar moiety, alkyl(C1-8), substituted alkyl(C1-8), or −Y2−R5, wherein Y2 is alkanediyl(C1-6) or substituted alkanediyl(C1-6); and R5 is alkoxy(C1-8), substituted alkoxy(C1-8), heterocycloalkyl(C1-8), substituted heterocycloalkyl(C1-8), or NR(R′)(R′′), wherein R, R′, and R′′, are each independently absent, hydrogen, alkyl(C1-6), substituted alkyl(C1-6), or Y1is: −(OCH2CH2)yRb, wherein Rb is hydroxy, alkoxy(C1-6), or substituted alkoxy(C1-6), and y is 1-30; and x is 1-100; or a pharmaceutically acceptable salt thereof. In some embodiments, the compounds of the present disclosure may be present in a lipid nanoparticle in an amount of from about 0.5 mol % to about 5 mol % of the total lipids in the lipid component. In some embodiments, the PEG lipid is present in an amount of from about 1.0 mol % to about 2 mol % of the total lipids in the lipid component. In some embodiments, the PEG lipid is present in an amount of from about 2 mol % to about 3 mol % of the total lipids in the lipid component. In some embodiments, the PEG lipid is present in an amount of from about 2 mol % to about 4 mol % of the total lipids in the lipid component. In some embodiments, the PEG lipid is present in an amount of from about 3 mol % to about 4 mol % of the total lipids in the lipid component. In some embodiments, the PEG lipid is present in an amount of from about 4 mol % to about 5 mol % of the total lipids in the lipid component. In some embodiments of the lipid nanoparticles of the present application, the compounds of the present disclosure are present in the composition at a molar percentage from about 0.5% to about 10%. In some embodiments of the lipid nanoparticles of the present application, the compounds of the present disclosure are present in the composition at a molar percentage about 0.5%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, or about 10%. In some embodiments of the lipid nanoparticles of the present application, the compounds of the present disclosure are present in the composition at a molar percentage from about 0.5% to about 10%, from about 0.5% to about 5%, from about 0.5% to about 4%, from about 0.5% to about 3%, from about 0.5% to about 2%, from about 0.5% to about 1%, from about 1% to about 5%, from about 1% to about 4.5%, from about 1% to about 4%, from about 1% to about 3.5%, from about 1% to about 3%, from about 1% to about 2%, from about 2% to about 5%, from about 2% to about 4.5%, from about 2% to about 4%, from about 2% to about 3.5%, from about 2% to about 3%, from about 3% to about 5%, from about 3% to about 4.5%, from about 3% to about 4%, from about 3% to about 3.5%, from about 4% to about 5%, or from about 4% to about 4.5%. In some embodiments of the lipid nanoparticles of the present application, the compounds of the present disclosure are present at a molar percentage of at least (about) 0.5%, at least (about) 1%, at least (about) 2%, at least (about) 2.5%, at least (about) 3%, or at least (about) 3.5%. In some embodiments of the lipid composition of the present application, the ionizable lipid is present at a molar percentage of at most (about) 10%, at most (about) 9%, at most (about) 8%, at most (about) 7%, at most (about) 6%, or at most (about) 5%. All the compounds of the present disclosure may in some embodiments be used for the prevention and treatment of one or more diseases or disorders discussed herein or otherwise. In some embodiments, one or more of the compounds characterized or exemplified herein as an intermediate, a metabolite, and / or prodrug, may nevertheless also be useful for the prevention and treatment of one or more diseases or disorders. As such unless explicitly stated to the contrary, all the compounds of the present disclosure are deemed “active compounds” and “therapeutic compounds” that are contemplated for use as active pharmaceutical ingredients (APIs). Actual suitability for human or veterinary use is typically determined using a combination of clinical trial protocols and regulatory procedures, such as those administered by the Food and Drug Administration (FDA). In the United States, the FDA is responsible for protecting the public health by assuring the safety, effectiveness, quality, and security of human and veterinary drugs, vaccines and other biological products, and medical devices. In some embodiments, the compounds of the present disclosure have the advantage that they may be more efficacious than, be less toxic than, be longer acting than, be more potent than, produce fewer side effects than, be more easily absorbed than, more metabolically stable than, more lipophilic than, more hydrophilic than, and / or have a better pharmacokinetic profile (e.g., higher oral bioavailability and / or lower clearance) than, and / or have other useful pharmacological, physical, or chemical properties over, compounds known in the prior art, whether for use in the indications stated herein or otherwise. Compounds of the present disclosure may contain one or more asymmetrically- substituted carbon, nitrogen, sulfur, or phosphorus atom and may be isolated in optically active or racemic form. Thus, all chiral, diastereomeric, racemic form, epimeric form, and all geometric isomeric forms of a chemical formula are intended, unless the specific stereochemistry or isomeric form is specifically indicated. Compounds may occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. In some embodiments, a single diastereomer is obtained. The chiral centers of the compounds of the present invention can have the S or the R configuration. In some embodiments, the present compounds may contain two or more atoms which have a defined stereochemical orientation. Chemical formulas used to represent compounds of the present disclosure will typically only show one of possibly several different tautomers. For example, many types of ketone groups are known to exist in equilibrium with corresponding enol groups. Similarly, many types of imine groups exist in equilibrium with enamine groups. Regardless of which tautomer is depicted for a given compound, and regardless of which one is most prevalent, all tautomers of a given chemical formula are intended. In addition, atoms making up the compounds of the present disclosure are intended to include all isotopic forms of such atoms. Isotopes, as used herein, include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include13C and14C. In some embodiments, compounds of the present disclosure exist in salt or non-salt form. With regard to the salt form(s), in some embodiments the particular anion or cation forming a part of any salt form of a compound provided herein is not critical, so long as the salt, as a whole, is pharmacologically acceptable. Additional examples of pharmaceutically acceptable salts and their methods of preparation and use are presented in Handbook of Pharmaceutical Salts: Properties, and Use (2002), which is incorporated herein by reference. It will be appreciated that many organic compounds can form complexes with solvents in which they are reacted or from which they are precipitated or crystallized. These complexes are known as “solvates.” Where the solvent is water, the complex is known as a “hydrate.” It will also be appreciated that many organic compounds can exist in more than one solid form, including crystalline and amorphous forms. All solid forms of the compounds provided herein, including any solvates thereof are within the scope of the present disclosure. C. Pharmaceutical Formulations and Routes of Administration In another aspect, for administration to a patient in need of such treatment, pharmaceutical formulations (also referred to as a pharmaceutical preparations, pharmaceutical compositions, pharmaceutical products, medicinal products, medicines, medications, or medicaments) comprise a therapeutically effective amount of a compound disclosed herein formulated with one or more excipients and / or drug carriers appropriate to the indicated route of administration. In some embodiments, the compounds disclosed herein are formulated in a manner amenable for the treatment of human and / or veterinary patients. In some embodiments, formulation comprises admixing or combining one or more of the compounds disclosed herein with one or more of the following excipients: lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia, sodium alginate, polyvinylpyrrolidone, and / or polyvinyl alcohol. In some embodiments, e.g., for oral administration, the pharmaceutical formulation may be tableted or encapsulated. In some embodiments, the compounds may be dissolved or slurried in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and / or various buffers. In some embodiments, the pharmaceutical formulations may be subjected to pharmaceutical operations, such as sterilization, and / or may contain drug carriers and / or excipients such as preservatives, stabilizers, wetting agents, emulsifiers, encapsulating agents such as lipids, dendrimers, polymers, proteins such as albumin, nucleic acids, and buffers. Pharmaceutical formulations may be administered by a variety of methods, e.g., orally or by injection (e.g. subcutaneous, intravenous, and intraperitoneal). Depending on the route of administration, the compounds disclosed herein may be coated in a material to protect the compound from the action of acids and other natural conditions which may inactivate the compound. To administer the active compound by other than parenteral administration, it may be necessary to coat the compound with, or co-administer the compound with, a material to prevent its inactivation. In some embodiments, the active compound may be administered to a patient in an appropriate carrier, for example, liposomes, or a diluent. Pharmaceutically acceptable diluents include saline and aqueous buffer solutions. Liposomes include water-in- oil-in-water CGF emulsions as well as conventional liposomes. The compounds disclosed herein may also be administered parenterally, intraperitoneally, intraspinally, or intracerebrally. Dispersions can be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations may contain a preservative to prevent the growth of microorganisms. Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (such as, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, sodium chloride, or polyalcohols such as mannitol and sorbitol, in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate or gelatin. The compounds disclosed herein can be administered orally, for example, with an inert diluent or an assimilable edible carrier. The compounds and other ingredients may also be enclosed in a hard or soft-shell gelatin capsule, compressed into tablets, or incorporated directly into the patient’s diet. For oral therapeutic administration, the compounds disclosed herein may be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. The percentage of the therapeutic compound in the compositions and preparations may, of course, be varied. The amount of the therapeutic compound in such pharmaceutical formulations is such that a suitable dosage will be obtained. The therapeutic compound may also be administered topically to the skin, eye, ear, or mucosal membranes. Administration of the therapeutic compound topically may include formulations of the compounds as a topical solution, lotion, cream, ointment, gel, foam, transdermal patch, or tincture. When the therapeutic compound is formulated for topical administration, the compound may be combined with one or more agents that increase the permeability of the compound through the tissue to which it is administered. In other embodiments, it is contemplated that the topical administration is administered to the eye. Such administration may be applied to the surface of the cornea, conjunctiva, or sclera. Without wishing to be bound by any theory, it is believed that administration to the surface of the eye allows the therapeutic compound to reach the posterior portion of the eye. Ophthalmic topical administration can be formulated as a solution, suspension, ointment, gel, or emulsion. Finally, topical administration may also include administration to the mucosa membranes such as the inside of the mouth. Such administration can be directly to a particular location within the mucosal membrane such as a tooth, a sore, or an ulcer. Alternatively, if local delivery to the lungs is desired the therapeutic compound may be administered by inhalation in a dry-powder or aerosol formulation. In some embodiments, it may be advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the patients to be treated; each unit containing a predetermined quantity of therapeutic compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. In some embodiments, the specification for the dosage unit forms of the invention are dictated by and directly dependent on (a) the unique characteristics of the therapeutic compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding such a therapeutic compound for the treatment of a selected condition in a patient. In some embodiments, active compounds are administered at a therapeutically effective dosage sufficient to treat a condition associated with a condition in a patient. For example, the efficacy of a compound can be evaluated in an animal model system that may be predictive of efficacy in treating the disease in a human or another animal. In some embodiments, the effective dose range for the therapeutic compound can be extrapolated from effective doses determined in animal studies for a variety of different animals. In some embodiments, the human equivalent dose (HED) in mg / kg can be calculated in accordance with the following formula (see, e.g., Reagan-Shaw et al., FASEB J., 22(3):659- 661, 2008, which is incorporated herein by reference): HED (mg / kg) = Animal dose (mg / kg) × (Animal Km / Human Km) Use of the Kmfactors in conversion results in HED values based on body surface area (BSA) rather than only on body mass. Kmvalues for humans and various animals are well known. For example, the Kmfor an average 60 kg human (with a BSA of 1.6 m2) is 37, whereas a 20 kg child (BSA 0.8 m2) would have a Kmof 25. Kmfor some relevant animal models are also well known, including: mice Kmof 3 (given a weight of 0.02 kg and BSA of 0.007); hamster Kmof 5 (given a weight of 0.08 kg and BSA of 0.02); rat Kmof 6 (given a weight of 0.15 kg and BSA of 0.025) and monkey Kmof 12 (given a weight of 3 kg and BSA of 0.24). Precise amounts of the therapeutic composition depend on the judgment of the practitioner and are specific to each individual. Nonetheless, a calculated HED dose provides a general guide. Other factors affecting the dose include the physical and clinical state of the patient, the route of administration, the intended goal of treatment and the potency, stability and toxicity of the particular therapeutic formulation. The actual dosage amount of a compound of the present disclosure or composition comprising a compound of the present disclosure administered to a patient may be determined by physical and physiological factors such as type of animal treated, age, sex, body weight, severity of condition, the type of disease being treated, previous or concurrent therapeutic interventions, idiopathy of the patient and on the route of administration. These factors may be determined by a skilled artisan. The practitioner responsible for administration will typically determine the concentration of active ingredient(s) in a composition and appropriate dose(s) for the individual patient. The dosage may be adjusted by the individual physician in the event of any complication. In some embodiments, the therapeutically effective amount typically will vary from about 0.001 mg / kg to about 1000 mg / kg, from about 0.01 mg / kg to about 750 mg / kg, from about 100 mg / kg to about 500 mg / kg, from about 1 mg / kg to about 250 mg / kg, from about 10 mg / kg to about 150 mg / kg in one or more dose administrations daily, for one or several days (depending of course of the mode of administration and the factors discussed above). Other suitable dose ranges include 1 mg to 10,000 mg per day, 100 mg to 10,000 mg per day, 500 mg to 10,000 mg per day, and 500 mg to 1,000 mg per day. In some embodiments, the amount is less than 10,000 mg per day with a range of 750 mg to 9,000 mg per day. In some embodiments, the amount of the active compound in the pharmaceutical formulation is from about 2 to about 75 weight percent. In some of these embodiments, the amount if from about 25 to about 60 weight percent. Single or multiple doses of the agents are contemplated. Desired time intervals for delivery of multiple doses can be determined by one of ordinary skill in the art employing no more than routine experimentation. As an example, patients may be administered two doses daily at approximately 12-hour intervals. In some embodiments, the agent is administered once a day. The agent(s) may be administered on a routine schedule. As used herein a routine schedule refers to a predetermined designated period of time. The routine schedule may encompass periods of time which are identical, or which differ in length, as long as the schedule is predetermined. For instance, the routine schedule may involve administration twice a day, every day, every two days, every three days, every four days, every five days, every six days, a weekly basis, a monthly basis or any set number of days or weeks there-between. Alternatively, the predetermined routine schedule may involve administration on a twice daily basis for the first week, followed by a daily basis for several months, etc. In other embodiments, the invention provides that the agent(s) may be taken orally and that the timing of which is or is not dependent upon food intake. Thus, for example, the agent can be taken every morning and / or every evening, regardless of when the patient has eaten or will eat. D. Lipid Nanoparticles i. Ionizable cationic lipids In some embodiments, the compounds of the present disclosure may be formulated in a lipid nanoparticle comprising an ionizable cationic lipid. In some embodiments, the lipid nanoparticle comprises a first ionizable cationic lipid. In some embodiments, the lipid nanoparticle comprises a first ionizable cationic lipid, and a second ionizable cationic lipid separate from the first ionizable cationic lipid. In some embodiments, the ionizable cationic lipids contain one or more groups which is protonated at physiological pH but may deprotonate and has no charge at a pH above the pKa of the lipid. The ionizable group may contain one or more protonatable amines which are able to form a cationic group at physiological pH. The ionizable cationic lipid compound may also further comprise one or more lipid components such as two or more fatty acids with C6-C24alkyl or alkenyl carbon groups. These lipid groups may be attached through an ester linkage or may be further added through a Michael addition to a sulfur atom. In some embodiments, these compounds may be a dendrimer, a dendron, a polymer, or a combination thereof. A lipid nanoparticle may include one or more ionizable (e.g., ionizable amino) lipids (e.g., lipids that may have a positive or partial positive charge at physiological pH). Ionizable cationic lipids may be selected from the non-limiting group consisting of 3-(didodecylamino)- N1,N1,4-tridodecy1-1-piperazineethanamine (KL10), N1-[2- (didodecylamino)ethyl]N1,N4,N4-tridodecy1-1,4-piperazinediethanamine (KL22), 14,25- ditridecy1-15,18,21,24-tetraaza-octatriacontane (KL25), 1,2-dilinoleyloxy-N,N- dimethylaminopropane (DLin-DMA), 2,2-dilinoley1-4-dimethylaminomethyl-[1,3]-dioxolane (DLin-K-DMA), heptatriaconta-6,9,28,31-tetraen-19-y1-4-(dimethylamino)butanoate (DLin- MC3-DMA), 2,2-dilinoleyl-4-(2 dimethylaminoethyl)-[1,3]-dioxolane (DLin-KC2-DMA), 1,2-dioleyloxy-N,Ndimethylaminopropane (DODMA), 2-({8[(3(3)-cholest-5-en-3- yloxy]octylIoxy)N,Ndimethy1-3-[(9Z,12Z)-octadeca-9,12-dien-l-yloxy]propan-1-amine (Octyl-CLinDMA), (2R)-2-({8-[(3(3)-cholest-5-en-3-yloxy]octylIoxy)-N,N-dimethy1-3- [(9Z,12Z)-octadeca-9,12-dien-l-yloxy]propan-1-amine(Octyl-CLinDMA (2R)), and (2S) 2- ({8-[(3(3)-chole st-5-en-3 -yloxy] octyl } oxy)-N,N-dimethyl-3 -[(9Z,12Z)-octadeca-9,12-di en-1 -yloxy]propan-l-amine (Octyl-CLinDMA (2S)), 4-hydroxybutyl ) azanediyl)bis (hexane- 6,1-diyl)bis(2-hexyldecanoate (ALC-0315), heptadecan-9-yl 8-((2-hydroxyethyl) (6-oxo-6- (undecyloxy) hexyl) amino) octanoate (SM-102), (9Z,12Z)-3-((4,4- Bis(octyloxy)butanoyl)oxy)-2-((((3-(diethylamino)propoxy)carbonyl)oxy)methyl)propyl octadeca-9,12-dienoate (LP01). In addition to these, an ionizable cationic lipid may also be a lipid including a cyclic amine group. Ionizable cationic lipids can also be the compounds disclosed in International Publication No. WO2017075531, hereby incorporated by reference in its entirety. Ionizable cationic lipids can also be the compounds disclosed in International Publication No. WO2015199952, hereby incorporated by reference in its entirety. In one embodiment, the ionizable cationic lipid may be selected from, but not limited to, an ionizable cationic lipid described in International Publication Nos. WO2012040184, WO2011153120, WO2011149733, WO2011090965, WO2011043913, WO2011022460, WO2012061259, WO2012054365, WO2012044638, WO2010080724, WO201021865, WO2008103276, WO2013086373 and WO2013086354, US Patent Nos.7,893,302, 7,404,969, 8,283,333, and 8,466,122 and US Patent Publication No. US20100036115, US20120202871, US20130064894, US20130129785, US20130150625, US20130178541 and US20130225836; the contents of each of which are herein incorporated by reference in their entirety. In some embodiments, an ionizable cationic lipid comprises between 2 and 6 hydrophobic chains, often alkyl or alkenyl such as C6-C24 alkyl or alkenyl groups, but may have at least 1 or more that 6 tails. In some embodiments of the lipid nanoparticles, the cationic ionizable lipids are assembled using the differential reactivity of the acrylate and methacrylate groups with amines and thiols. The cationic ionizable lipids may include secondary or tertiary amines and thioethers formed by the reaction of an acrylate group with a primary or secondary amine and a methacrylate with a mercapto group. The ionizable cationic lipids may contain one or more asymmetrically-substituted carbon or nitrogen atoms, and may be isolated in optically active or racemic form. Thus, all chiral, diastereomeric, racemic form, epimeric form, and all geometric isomeric forms of a chemical formula are intended, unless the specific stereochemistry or isomeric form is specifically indicated. Ionizable cationic lipids may occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. In some embodiments, a single diastereomer is obtained. The chiral centers of the ionizable cationic lipids of the present application can have the S or the R configuration. Furthermore, it is contemplated that one or more of the ionizable cationic lipids may be present as constitutional isomers. In some embodiments, the compounds have the same formula but different connectivity to the nitrogen atoms of the core. Without wishing to be bound by any theory, it is believed that such ionizable cationic lipids exist because the starting monomers react first with the primary amines and then statistically with any secondary amines present. Thus, the constitutional isomers may present the fully reacted primary amines and then a mixture of reacted secondary amines. Chemical formulas used to represent ionizable cationic lipids will typically only show one of possibly several different tautomers. For example, many types of ketone groups are known to exist in equilibrium with corresponding enol groups. Similarly, many types of imine groups exist in equilibrium with enamine groups. Regardless of which tautomer is depicted for a given formula, and regardless of which one is most prevalent, all tautomers of a given chemical formula are intended. In addition, atoms making up the ionizable cationic lipids are intended to include all isotopic forms of such atoms. Isotopes, as used herein, include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include13C and14C. It should be recognized that the particular anion or cation forming a part of any salt form of an ionizable cationic lipids provided herein is not critical, so long as the salt, as a whole, is pharmacologically acceptable. Additional examples of pharmaceutically acceptable salts and their methods of preparation and use are presented in Handbook of Pharmaceutical Salts: Properties, and Use (2002), which is incorporated herein by reference. In some embodiments of the lipid nanoparticle, the ionizable lipid is a dendrimer or dendron. In some embodiments, the ionizable cationic lipid comprises an ammonium group which is positively charged at physiological pH and contains at least two hydrophobic groups. In some embodiments, the ammonium group is positively charged at a pH from about 6 to about 8. In some embodiments, the ionizable cationic lipid is a dendrimer or dendron. In some embodiments, the ionizable cationic lipid comprises at least two C6-C24alkyl or alkenyl groups. In some embodiments of the lipid composition, the ionizable cationic lipid comprises at least two C8-C24alkyl groups. In some embodiments, the ionizable cationic lipid is a dendrimer further defined by the formula: Core-(Repeating Unit)n-Terminating Group (D-I) wherein one or more hydrogen atoms of the core are replaced with a repeating unit and wherein: the core has the formula: wherein: X1is amino or C1-C12alkylamino, C1-C12dialkylamino, C3-C12heterocycloalkyl, C5-C12 heteroaryl, or a substituted version thereof; R1is amino, hydroxy, mercapto, C1-C12alkylamino, or C1-C12dialkylamino, or a substituted version of either of these groups; and a is 1, 2, 3, 4, 5, or 6; or the core has the formula: (D-III) wherein: X2 is N(R5)y; R5 is hydrogen, C1-C18 alkyl, or substituted C1-C18 alkyl; and y is 0, 1, or 2, provided that the sum of y and z is 3; R2 is amino, hydroxy, mercapto, C1-C12 alkylamino, or C1-C12 dialkylamino, or a substituted version of either of these groups; b is 1, 2, 3, 4, 5, or 6; and z is 1, 2, or 3; provided that the sum of z and y is 3; or the core has the formula: wherein: X3 is −NR6−, wherein R6 is hydrogen, C1-C8 alkyl, or C1-C8 substituted alkyl, −O−, or C1-C8alkylaminodiyl, C1-C8alkoxydiyl, C6-C8arenediyl, C5-C8heteroarenediyl, C3-C8 heterocycloalkanediyl, or a substituted version of any of these groups; R3 and R4 are each independently amino, hydroxy, mercapto, C1-C12 alkylamino, or C1-C12dialkylamino, or a substituted version of either of these groups; or a group of the formula: −N(Rf)f(CH2CH2N(Rc))eRd, wherein: e and f are each independently 1, 2, or 3; provided that the sum of e and f is 3; Rc, Rd, and Rf are each independently hydrogen, C1-C6 alkyl, or substituted C1-C6alkyl; c and d are each independently 1, 2, 3, 4, 5, or 6; or the core is C1-C18alkylamine, C1-C36dialkylamine, C3-C12heterocycloalkane, or a substituted version of any of these groups; wherein the repeating unit comprises a degradable diacyl or a degradable diacyl and a linker; the degradable diacyl group has the formula: wherein: A1 and A2 are each independently −O− , -S-, or −NRa−, wherein: Rais hydrogen, C1-C6alkyl, or substituted C1-C6alkyl; Y3 is C1-C12 alkanediyl, C1-C12 alkenediyl, C6-C12 arenediyl, or a substituted version of any of these groups; or a group of the formula: wherein: X3 and X4 are C1-C12 alkanediyl, C2-C12 alkenediyl, C6-C12 arenediyl, or a substituted version of any of these groups; Y5 is a covalent bond, C1-C12 alkanediyl, C1-C12 alkenediyl, C6- C12arenediyl, or a substituted version of any of these groups; and R9is C1-C8alkyl or substituted C1-C8alkyl; the linker group has the formula: (D-VI) wherein: Y1 is C1-C12 alkanediyl, C1-C12 alkenediyl, C6-C12 arenediyl, or a substituted version of any of these groups; and wherein each ependently denotes a point of attachment to another repeating unit or a terminating group; and the terminating group has the formula: wherein: Y4is alkanediyl or an C1-C18alkanediyl wherein one or more of the hydrogen atoms on the C1-C18 alkanediyl has been replaced with −OH, −F, −Cl, −Br, −I, −SH, −OCH3, −OCH2CH3, −SCH3, or −OC(O)CH3; R10 is hydrogen, carboxy, hydroxy, C6-C12aryl, C1-C12alkylamino, C1-C12dialkylamino, C3-C12N- heterocycloalkyl, −C(O)N(R11)− C1-C6 alkanediyl− C3-C12 heterocycloalkyl, −C(O)− C1-C12alkylamino, −C(O)− C1-C12dialkylamino, or −C(O)− C3-C12 N-heterocycloalkyl, wherein: R11is hydrogen, C1-C6alkyl, or substituted C1-C6alkyl; wherein the final degradable diacyl in the chain is attached to a terminating group; n is 0, 1, 2, 3, 4, 5, or 6; or a pharmaceutically acceptable salt thereof. In some embodiments, the terminating group is further defined by the formula: wherein: Y4is C1-C18alkanediyl; and R10 is hydrogen. In some embodiments, A1 and A2 are each independently −O− or −NRa−. In some embodiments of the dendrimer of formula (D-I), the terminating group is a structure selected from the structures in Table 1. In some embodiments of the dendrimer of formula (D-I), the core is further defined by the formula: (D-III) wherein: X2is N(R5)y; R5 is hydrogen or C1-C8 alkyl, or substituted C1-C18 alkyl; and y is 0, 1, or 2, provided that the sum of y and z is 3; R2 is amino, hydroxy, or mercapto, or C1-C12 alkylamino, C1-C12 dialkylamino, or a substituted version of either of these groups; b is 1, 2, 3, 4, 5, or 6; and z is 1, 2, 3; provided that the sum of z and y is 3. In some embodiments of the dendrimer of formula (D-I), the core is further defined by the formula: wherein: X3is −NR6−, wherein R6is hydrogen, C1-C8alkyl, or substituted C1-C8alkyl, −O−, or C1-C8 alkylaminodiyl, C1-C8 alkoxydiyl, C1-C8 arenediyl, C1-C8 heteroarenediyl, C1-C8heterocycloalkanediyl, or a substituted version of any of these groups; R3and R4are each independently amino, hydroxy, or mercapto, or C1-C12alkylamino, dialkylamino, or a substituted version of either of these groups; or a group of the wherein: e and f are each independently 1, 2, or 3; provided that the sum of e and f is 3; Rc, Rd, and Rfare each independently hydrogen, C1-C6alkyl, or substituted C1-C6 alkyl; c and d are each independently 1, 2, 3, 4, 5, or 6. In some embodiments of the dendrimer of formula (I), the terminating group is represented by the formula: wherein: Y4 is alkanediyl(C≤18); and R10 is hydrogen. In some embodiments of the dendrimer of formula (D-I), a core of the structure of formula (D-IV) is: In some embodiments of the dendrimer of formula (D-I), the core comprises a structural 20 formula set forth in Table 2 and pharmaceutically acceptable salts thereof, wherein * indicates a point of attachment of the core to a repeating unit (i.e., where a hydrogen of the core is replaced with a repeating unit). In some embodiments of the dendrimer of formula (D-I), the degradable diacyl is further defined as: . In some embodiments of the dendrimer of formula (D-I), the linker is further defined as wherein Y1 is C1-C8 alkanediyl or substituted C1-C12 alkanediyl. In some embodiments, in the core of formula (D-IV), R6is H. In some embodiments, in the core of formula (D-IV), R6 is C1-C8 alkyl. In some embodiments, in the core of formula (D-IV), R6 is substituted alkyl (e.g., alkyl substituted with -NH2, alkyl substituted with - NHCH3, or alkyl substituted with -NHCH2CH3). In some embodiments one or two hydrogen atoms of the core are replaced with a repeating unit. In some embodiments three or four hydrogen atoms of the core is replaced with a repeating unit. In some embodiments five hydrogen atoms of the core is replaced with a repeating unit. In some embodiments six hydrogen atoms of the core is replaced with a repeating unit. In some embodiments, the compound of formula (D-I)is selected from the group consisting of:

[0003] and pharmaceutically acceptable salts thereof. In some embodiments, wherein in compound of the disclosure, the core of Formula D- II, D-III, or D-IV has a structure of Table 1 and the terminating group of formula D-VII has a structure of Table 2. In each of the structures of Tables 1 and 2, denotes a point of attachment to the following structure: core of Table 1 and the terminating group of Table 2 are attached at opposite ends of the structure. Table 1. Example core structures I I I I In some embodiments the core of Formula D-II, D-III, or D-IV comprises a structural fo

[0004] maceutically acceptable salts thereof, wherein * indicates a point of attachment of the core to a branch of the plurality of branches. Table 2. Example terminating groups I I I 226. In some embodiments, the ionizable cationic lipid is selected from those set forth in Table 3 and pharmaceutically acceptable salts thereof. Table 3. Example ionizable cationic lipids

[0005]

[0006]

[0007]

[0008]

[0009]

[0010]

[0011]

[0012] I 5 S Other Ionizable cationic lipids In some embodiments of the lipid composition, the ionizable cationic lipid comprises a structural formula (D-I’): R1 wherein: a is 1 and b is 2, 3, or 4; or, alternatively, b is 1 and a is 2, 3, or 4; m is 1 and n is 1; or, alternatively, m is 2 and n is 0; or, alternatively, m is 2 and n is 1; and R1, R2, R3, R4, R5, and R6are each independently selected from the group consisting of H, -CH2CH(OH)R7, -CH(R7)CH2OH, -CH2CH2C(=O)OR7, -CH2CH2C(=O)NHR7, and - CH2R7, wherein R7is independently selected from C3-C18alkyl, C3-C18alkenyl having one C=C double bond, a protecting group for an amino group, -C(=NH)NH2, a poly(ethylene glycol) chain, and a receptor ligand; provided that at least two moieties among R1to R6are independently selected from - CH2CH(OH)R7, -CH(R7)CH2OH, -CH2CH2C(=O)OR7, -CH2CH2C(=O)NHR7, or -CH2R7, wherein R7is independently selected from C3-C18 alkyl or C3-C18 alkenyl having one C=C double bond; and wherein one or more of the nitrogen atoms indicated in formula (D-I’) may be protonated to provide an ionizable cationic lipid. In some embodiments of the ionizable cationic lipid of formula (D-I’), a is 1. In some embodiments of the ionizable cationic lipid of formula (D-I’), b is 2. In some embodiments of the ionizable cationic lipid of formula (D-I’), m is 1. In some embodiments of the ionizable cationic lipid of formula (D-I’), n is 1. In some embodiments of the ionizable cationic lipid of formula (D-I’), R1, R2, R3, R4, R5, and R6are each independently H or -CH2CH(OH)R7. In some embodiments of the ionizable cationic lipid of formula (D-I’), R1, R2, R3, R4, R5, and R6are each independently H or . e embodiments of the ionizable cationic lipid of formula (D-I’), R1, R2, R3, R4, R5, and R6are each independently H or . In s embodiments of the ionizable cationic liid of formula (D-I’), R7is C3-C18 alkyl (e.g., C6-C12 alkyl).

[0013] In some embodiments, the ionizable cationic lipid of formula (D-I’) is 13,16,20-tris(2- hydroxydodecyl)-13,16,20,23-tetraazapentatricontane-11,25-diol: . In some embodiments, the ionizable cationic lipid of formula (D-I’) is (11R,25R)- 13,16,20-tris((R)-2-hydroxydodecyl)-13,16,20,23-tetraazapentatricontane-11,25-diol: Additional ionizable cationic lipids that can be used in the compositions and methods of the present application include those ionizable cationic lipids as described in International Patent Publication WO2010144740, WO2013149140, WO2016118725, WO2016118724, WO2013063468, WO2016205691, WO2015184256, WO2016004202, WO2015199952, WO2017004143, WO2017075531, WO2017117528, WO2017049245, WO2017173054 and WO2015095340, which are incorporated herein by reference for all purposes. Examples of those ionizable cationic lipids include but are not limited to those as shown in Table 4 and Table 5. Table 4. Examplary Ionizable cationic lipids

[0014] Table 5. Selected Exemplary Ionizable Cationic Lipids ii. Helper lipids in lipid nanoparticles In some embodiments, lipid nanoparticles described herein comprise one or more helper lipids. A. Phospholipids In some embodiments, the helper lipid is a phospholipid. Phospholipids, as defined herein, are any lipid that comprise a phosphate group. The lipid component of a lipid nanoparticle composition may include one or more phospholipids, such as one or more (poly) unsaturated lipids. Phospholipids may assemble into one or more lipid bilayers. In general, phospholipids may include a phospholipid moiety and one or more fatty acid moieties. A phospholipid moiety may be selected from the non-limiting group consisting of phosphatidyl choline, phosphatidyl ethanolamine, phosphatidyl glycerol, phosphatidyl serine, phosphatidic acid, 2-lysophosphatidyl choline, and a sphingomyelin. A fatty acid moiety may be selected from the non-limiting group consisting of lauric acid, myristic acid, myristoleic acid, palmitic acid, palmitoleic acid, stearic acid, oleic acid, linoleic acid, alpha-linolenic acid, erucic acid, phytanoic acid, arachidic acid, arachidonic acid, eicosapentaenoic acid, behenic acid, docosapentaenoic acid, and docosahexaenoic acid. Phospholipids useful or potentially useful in the compositions and methods described herein may comprise a: phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, phosphatidylserine, or a derivative or analog thereof. Phospholipids useful or potentially useful in the compositions and methods described herein may be selected from: 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 1,2- dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), 1,2-dilinoleoyl-sn-glycero-3- phosphocholine (DLPC), 1,2-dimyristoyl-sn-glycero-phosphocholine (DMPC), 1,2- Dimyristoyl-sn-glycero-3-phosphoethanolamine (DMPE), 1,2-dioleoyl-sn-glycero-3- phosphocholine (DOPC), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2- distearoyl-sn-glycero-3-phosphorylethanolamine (DSPE), 1,2-diundecanoyl-sn-glycero- phosphocholine (DUPC), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), 1,2-di- O-octadecenyl-sn-glycero-3-phosphocholine (18:0 Diether PC), 1-oleoyl-2- cholesterylhemisuccinoyl-sn-glycero-3-phosphocholine (OChemsPC), 1-hexadecyl-sn- glycero-3-phosphocholine (C16 Lyso PC), 1,2-dilinolenoyl-sn-glycero-3-phosphocholine, 1,2- diarachidonoyl-sn-glycero-3-phosphocholine, 1,2-didocosahexaenoyl-sn-glycero-3- phosphocholine, 1,2-diphytanoyl-sn-glycero-3-phosphoethanolamine (ME 16.0 PE), 1,2- diphytanoyl-sn-glycero-3-phosphocholine (4ME 16:0 PC), 1,2-diphytanoyl-sn-glycero-3- phospho-(1'-rac-glycerol) (sodium salt) (4ME 16:0 PG), 1,2-diphytanoyl-sn-glycero-3- phospho-L-serine (sodium salt) (4ME 16:0 PS), 1,2-distearoyl-sn-glycero-3- phosphoethanolamine, 1,2-dilinoleoyl-sn-glycero-3-phosphoethanolamine, 1,2-dilinolenoyl- sn-glycero-3-phosphoethanolamine, 1,2-diarachidonoyl-sn-glycero-3-phosphoethanolamine, 1,2-didocosahexaenoyl-sn-glycero-3-phosphoethanolamine, and 1,2-dioleoyl-sn-glycero-3- phospho-rac-(1-glycerol) sodium salt (DOPG), and sphingomyelin. As described herein, phosphatidylcholine and phosphocholine may be used interchangeably. In some embodiments, the phosphatidylcholine is selected from: 1,2- distearoyl-sn-glycero-3-phosphocholine (DSPC), 1,2-dilinoleoyl-sn-glycero-3- phosphocholine (DLPC), 1,2-dimyristoyl-sn-glycero-phosphocholine (DMPC), 1,2- dilinoleoyl-sn-glycero-3-phosphocholine (DLPC), 1,2-dimyristoyl-sn-glycero- phosphocholine (DMPC), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2- dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-diundecanoyl-sn-glycero- phosphocholine (DUPC), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), 1,2-di- O-octadecenyl-sn-glycero-3-phosphocholine (18:0 Diether PC), 1-oleoyl-2- cholesterylhemisuccinoyl-sn-glycero-3-phosphocholine (OChemsPC), 1-hexadecyl-sn- glycero-3-phosphocholine (C16 Lyso PC), 1,2-dilinolenoyl-sn-glycero-3-phosphocholine, 1,2- diarachidonoyl-sn-glycero-3-phosphocholine, 1,2-didocosahexaenoyl-sn-glycero-3- phosphocholine, and 1,2-diphytanoyl-sn-glycero-3-phosphocholine (4ME 16:0 PC). In some embodiments, the lipid nanoparticle comprises a phospholipid selected from the group consisting of: 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 1,2-distearoyl- sn-glycero-3-phosphorylethanolamine (DSPE), 1,2-dioleoyl-sn-glycero-3- phosphoethanolamine (DOPE), 1,2-dilinoleoyl-sn-glycero-3-phosphocholine (DLPC), 1,2- dimyristoyl-sn-glycero-phosphocholine (DMPC), 1,2-Dimyristoyl-sn-glycero-3- phosphoethanolamine (DMPE), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2- dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-diundecanoyl-sn-glycero- phosphocholine (DUPC), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), 1,2-di- O-octadecenyl-sn-glycero-3-phosphocholine (18:0 Diether PC), 1-oleoyl-2- cholesterylhemisuccinoyl-sn-glycero-3-phosphocholine (OChemsPC), 1-hexadecyl-sn- glycero-3-phosphocholine (C16 Lyso PC), 1,2-dilinolenoyl-sn-glycero-3-phosphocholine, 1,2- diarachidonoyl-sn-glycero-3-phosphocholine, 1,2-didocosahexaenoyl-sn-glycero-3- phosphocholine, 1,2-diphytanoyl-sn-glycero-3-phosphoethanolamine (ME 16.0 PE), 1,2- diphytanoyl-sn-glycero-3-phosphocholine (4ME 16:0 PC), 1,2-diphytanoyl-sn-glycero-3- phospho-(1'-rac-glycerol) (sodium salt) (4ME 16:0 PG), 1,2-diphytanoyl-sn-glycero-3- phospho-L-serine (sodium salt) (4ME 16:0 PS), 1,2-distearoyl-sn-glycero-3- phosphoethanolamine, 1,2-dilinoleoyl-sn-glycero-3-phosphoethanolamine, 1,2-dilinolenoyl- sn-glycero-3-phosphoethanolamine, 1,2-diarachidonoyl-sn-glycero-3-phosphoethanolamine, 1,2-didocosahexaenoyl-sn-glycero-3-phosphoethanolamine, and 1,2-dioleoyl-sn-glycero-3- phospho-rac-(1-glycerol) sodium salt (DOPG), and sphingomyelin. In some embodiments, the lipid nanoparticle comprises a phospholipid selected from the group consisting of: 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 1,2-distearoyl- sn-glycero-3-phosphorylethanolamine (DSPE), 1,2-dioleoyl-sn-glycero-3- phosphoethanolamine (DOPE), 1,2-dilinoleoyl-sn-glycero-3-phosphocholine (DLPC), 1,2- dimyristoyl-sn-glycero-phosphocholine (DMPC), 1,2-Dimyristoyl-sn-glycero-3- phosphoethanolamine (DMPE), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2- dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-diundecanoyl-sn-glycero- phosphocholine (DUPC). In some embodiments, the lipid nanoparticle comprises a phospholipid selected from the group consisting of: 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 1,2-distearoyl- sn-glycero-3-phosphorylethanolamine (DSPE), 1,2-dioleoyl-sn-glycero-3- phosphoethanolamine (DOPE), 1,2-dilinoleoyl-sn-glycero-3-phosphocholine (DLPC), 1,2- dimyristoyl-sn-glycero-phosphocholine (DMPC), 1,2-Dimyristoyl-sn-glycero-3- phosphoethanolamine (DMPE). In some embodiments, the lipid nanoparticle comprises 1,2-distearoyl-sn-glycero-3- phosphocholine (DSPC). In some embodiments, the lipid composition comprises 1,2-dioleoyl- sn-glycero-3-phosphoethanolamine (DOPE). In some embodiments, the lipid composition comprises 1,2-dilinoleoyl-sn-glycero-3-phosphocholine (DLPC). In some embodiments, the lipid composition comprises 1,2-dimyristoyl-sn-glycero-phosphocholine (DMPC). In some embodiments, the lipid composition comprises 1,2-Dimyristoyl-sn-glycero-3- phosphoethanolamine (DMPE). In some embodiments, the lipid composition comprises 1,2- distearoyl-sn-glycero-3-phosphorylethanolamine (DSPE). In some embodiments, the lipid nanoparticle comprises a phospholipid selected from the group consisting of: 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), 1,2- dimyristoyl-sn-glycero-3-phosphoethanolamine (DMPE) 1,2-dimyristoyl-sn-glycero-3- phosphocholine (DMPC), dipalmitoylphosphatidylcholine (DPPC), and 1,2-distearoyl-sn- glycero-3-phosphorylethanolamine (DSPE). In some embodiments, the lipid nanoparticle comprises a phospholipid selected from 1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine (DMPE) 1,2-dimyristoyl-sn-glycero-3- phosphocholine (DMPC), dipalmitoylphosphatidylcholine (DPPC), and 1,2-distearoyl-sn- glycero-3-phosphorylethanolamine (DSPE). In some embodiments, the phospholipid may contain one or two long chain (e.g., C6- C24) alkyl or alkenyl groups, a glycerol or a sphingosine, one or two phosphate groups, and, optionally, a small organic molecule. The small organic molecule may be an amino acid, a sugar, or an amino substituted alkoxy group, such as choline or ethanolamine. In some embodiments, the phospholipid is a phosphatidylcholine. In some embodiments, the phospholipid is distearoylphosphatidylcholine or dioleoylphosphatidylethanolamine. In some embodiments, other zwitterionic lipids are used, where zwitterionic lipid defines lipid and lipid-like molecules with both a positive charge and a negative charge. In some embodiments of the lipid nanoparticle of the present application, the phospholipid is present in the composition at a molar percentage from about 7.5% to about 30%. In some embodiments of the lipid nanoparticle of the present application, the phospholipid is present in the composition at a molar percentage about 5%, about 7.5%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, or about 60%. In some embodiments of the lipid nanoparticle of the present application, the phospholipid is present in the composition at a molar percentage from about 5% to about 25%, from about 5% to about 50%, from about 10% to about 50%, from about 10% to about 40%, from about 10% to about 30%, from about 10% to about 25%, from about 10% to about 20%, from about 12% to about 30%, from about 12% to about 25%, from about 12% to about 20%, from about 14% to about 30%, from about 14% to about 25%, from about 14% to about 20%, from about 15% to about 60%, from about 15% to about 50%, from about 15% to about 40%, from about 15% to about 30%, from about 15% to about 20%, from about 16% to about 30%, from about 16% to about 20%, from about 20% to about 60%, from about 20% to about 50%, from about 20% to about 40%, from about 20% to about 30%, or from about 10% to about 25%. In some embodiments of the lipid nanoparticle of the present application, the phospholipid is present at a molar percentage of at least (about) 5%, at least (about) 10%, at least (about) 15%, at least (about) 20%, at least (about) 25%, or at least (about) 30%. In some embodiments of the lipid nanoparticle of the present application, the phospholipid is present at a molar percentage of at most (about) 5%, at most (about) 10%, at most (about) 15%, at most (about) 20%, at most (about) 25%, or at most (about) 30%. In some embodiments, the phospholipid is present in an amount of about 10 mol % of the total lipids in the lipid nanoparticle. In some embodiments, the phospholipid is present in an amount of about 11 mol % of the total lipids in the lipid nanoparticle. In some embodiments, the phospholipid is present in an amount of about 12 mol % of the total lipids in the lipid nanoparticle. In some embodiments, the phospholipid is present in an amount of about 13 mol % of the total lipids in the lipid nanoparticle. In some embodiments, the phospholipid is present in an amount of about 14 mol % of the total lipids in the lipid nanoparticle. In some embodiments, the phospholipid is present in an amount of about 15 mol % of the total lipids in the lipid nanoparticle. In some embodiments, the phospholipid is present in an amount of about 16 mol % of the total lipids in the lipid nanoparticle. In some embodiments, the phospholipid is present in an amount of about 17 mol % of the total lipids in the lipid nanoparticle. In some embodiments, the phospholipid is present in an amount of about 18 mol % of the total lipids in the lipid nanoparticle. In some embodiments, the phospholipid is present in an amount of about 19 mol % of the total lipids in the lipid nanoparticle. In some embodiments, the phospholipid is present in an amount of about 20 mol % of the total lipids in the lipid nanoparticle. B. Structural lipids or Sterols The lipid nanoparticle may include one or more structural lipids. Structural lipids can be sterols, steroids or steroid derivatives. In some embodiments of the lipid nanoparticle of the present application, the lipid nanoparticle further comprises a steroid or steroid derivative. In some embodiments, the steroid or steroid derivative comprises any steroid or steroid derivative. As used herein, in some embodiments, the term “steroid” is a class of compounds with a four ring 17 carbon cyclic structure which can further comprises one or more substitutions including alkyl groups, alkoxy groups, hydroxy groups, oxo groups, acyl groups, or a double bond between two or more carbon atoms. In one aspect, the ring structure of a steroid comprises three fused cyclohexyl rings and a fused cyclopentyl ring as shown in the formula: . some embodiments, a steroid derivative comprises the ring structure above with one or more non-alkyl substitutions. In some embodiments, the steroid or steroid derivative is a sterol wherein the formula is further defined as: embodiments of the present application, the steroid or steroid derivative is a cholestane or cholestane derivative. In a cholestane, the ring structure is further defined by the formula: ibed above, a cholestane derivative comprises one or more non-alkyl substitution of the above ring system. In some embodiments, the cholestane or cholestane derivative is a cholestene or cholestene derivative or a sterol or a sterol derivative. In other embodiments, the cholestane or cholestane derivative is both a cholesterol and a sterol or a derivative thereof. Sterol useful or potentially useful in the compositions and methods may be selected from: cholesterol, fecosterol, sitosterol, ergosterol, campesterol, stigmasterol, brassicasterol, tomatidine, ursolic acid, and alpha-tocopherol. In some embodiments of the lipid nanoparticle of the present application, the sterol is present in the composition at a molar percentage from about 20% to about 50%. In some embodiments of the lipid nanoparticle of the present application, the sterol is present in the composition at a molar percentage about 10%, about 15%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 30%, about 35%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 50%, about 55%, or about 60%. In some embodiments of the lipid nanoparticle of the present application, the sterol is present in the composition at a molar percentage from about 10% to about 60%, from about 20% to about 50%, from about 20% to about 40%, from about 20% to about 30%, from about 20% to about 25%, from about 25% to about 50%, from about 25% to about 40%, from about 25% to about 30%, from about 30% to about 50%, from about 30% to about 40%, from about 30% to about 35%, from about 35% to about 50%, from about 35% to about 45%, from about 35% to about 40%, from about 40% to about 50%, from about 40% to about 45%, or from about 45% to about 50%. In some embodiments of the lipid nanoparticle of the present application, the sterol is present at a molar percentage of at least (about) 20%, at least (about) 25%, at least (about) 30%, at least (about) 35%, at least (about) 40%, or at least (about) 50%. In some embodiments of the lipid composition of the present application, the ionizable lipid is present at a molar percentage of at most (about) 60%, at most (about) 15%, at most (about) 45%, at most (about) 40%, at most (about) 35%, at most (about) 30%, at most (about) 25%, or at most (about) 20%. E. Payloads The present disclosure contemplates delivery of various payloads useful in the treatment of a disease. Payloads comprise therapeutic polypeptides or polynucleotides encoding polypeptides. For example, the payload may be a polynucleotide encoding a gene related to a disease, or a polynucleotide encoding a gene editor for editing a gene related to a disease. In some embodiments, lipid nanoparticle compositions described herein further comprise a payload. In some embodiments, the payload comprises a polypeptide or a protein. In some embodiments, the payload comprises a small interfering RNA (siRNA). In some embodiments, the payload comprises an mRNA. In some embodiments, the mRNA encodes a gene editing system of component thereof. In some embodiments the gene editing system of component thereofcomprises a cluster regularly interspaced short palindromic repeats (CRISPR) related nucleic acid, a single guide RNA (sgRNA), a CRISPR-RNA (crRNA), a trans-activating crRNA (tracrRNA), and a guide RNA. A. Polypeptides In some embodiments, the disclosure provides polypeptides comprising one or more therapeutic proteins. Therapeutic proteins comprise, but are not limited to cytokines, chemokines, interleukins, interferons, growth factors, coagulation factors, anti-coagulants, blood factors, bone morphogenic proteins, immunoglobulins, or enzymes. Some non-limiting examples of particular therapeutic proteins include Erythropoietin (EPO), Granulocyte colony- stimulating factor (G-CSF), Alpha-galactosidase A, Alpha-L-iduronidase, Thyrotropin a, N- acetylgalactosamine-4-sulfatase (rhASB), Dornase alfa, Tissue plasminogen activator (TP A) Activase, Glucocerebrosidase, Interferon (IF) b-la, Interferon b-lb, Interferon gamma, Interferon alpha, TNF-alpha, IL-1 through IL-36, Human growth hormone (rHGH), Human insulin (BHI), Human chorionic gonadotropin a, Darbepoetin a, Follicle-stimulating hormone (FSH), and Factor VIII. In some embodiments, the polypeptide comprises a peptide or protein that restores the function of a defective protein in a subject. For example, the polynucleotide encodes a cystic fibrosis transmembrane conductance regulator (CFTR) protein, Dynein axonemal heavy chain 5, Dynein axonemal heavy chain 11, Bone morphogenetic protein receptor type 2, Fumarylacetoacetate hydrolase, Phenylalanine hydroxylase, Alpha-L-iduronidase, Collagen type IV alpha 3 chain, Collagen type IV alpha 4 chain, Collagen type IV alpha 5 chain, Poly cystin 1, Polycystin 2, Fibrocystin (or polyductin), Solute carrier family 3 member 1, Solute carrier family 7 member 9, Paired box gene 9, Myosin VIIA, Cadherin related 23, Usherin, Clarin 1, Gap junction beta-2 protein, Gap junction beta-6 protein, Rhodopsin, dystrophia myotonica protein kinase , Dystrophin, Sodium voltage-gated channel alpha subunit 1, Sodium voltage-gated channel beta subunit 1, Coagulation factor VIII, Coagulation factor IX ,N- glycanase 1, Palmitoyl-protein thioesterase 1, Tripeptidyl peptidase l,Kvl 1.1 (alpha subunit of potassium ion channel), Palmitoyl-protein thioesterase 1, ATM serine / threonine kinase, or Fibrillin 1. B. Polynucleotides In some embodiments, the lipid nanoparticles described herein comprises one or more polynucleotides. In some embodiments, the polynucleotides encode for one or more polypeptides described herein. Exemplary nucleic acids or polynucleotides of the invention include, but are not limited to, ribonucleic acids (RNAs), deoxyribonucleic acids (DNAs), threose nucleic acids (TNAs), glycol nucleic acids (GNAs), peptide nucleic acids (PNAs), locked nucleic acids (LNAs, including LNA having a β-D-ribo configuration, α-LNA having an α-L-ribo configuration (a diastereomer of LNA), 2′-amino-LNA having a 2′-amino functionalization, and 2′-amino-α- LNA having a 2′-amino functionalization), ethylene nucleic acids (ENA), cyclohexenyl nucleic acids (CeNA) or hybrids or combinations thereof. In addition, it should be clear that the present disclosure is not limited to the specific polynucleotides disclosed herein. The present disclosure is not limited in scope to any particular source, sequence, or type of polynucleotides, however, as one of ordinary skill in the art could readily identify related homologs in various other sources of the polynucleotides including polynucleotides from non-human species (e.g., mouse, rat, rabbit, dog, monkey, gibbon, chimp, ape, baboon, cow, pig, horse, sheep, cat and other species). It is contemplated that the polynucleotides used in the present disclosure can comprise a sequence based upon a naturally-occurring sequence. Allowing for the degeneracy of the genetic code, sequences that have at least about 50%, usually at least about 60%, more usually about 70%, most usually about 80%, preferably at least about 90% and most preferably about 95% of nucleotides that are identical to the nucleotide sequence of the naturally-occurring sequence. In some embodiments, the polynucleotide is a complementary sequence to a naturally occurring sequence, or complementary to at least 75%, at least 80%, at least 85%, at least 90%, at least 95% and 100%. Longer polynucleotides encoding 250, 500, 1000, 1212, 1500, 2000, 2500, 3000 or longer are contemplated herein. In some embodiments, the polynucleotide used herein may be derived from genomic DNA, i.e., cloned directly from the genome of a particular organism. In some embodiments, the polynucleotide comprises complementary DNA (cDNA). Also contemplated is a cDNA plus a natural intron or an intron derived from another gene; such engineered molecules are sometime referred to as “mini–genes”. The term “cDNA” is intended to refer to DNA prepared using messenger RNA (mRNA) as template. The advantage of using a cDNA, as opposed to genomic DNA or DNA polymerized from a genomic, non- or partially-processed RNA template, is that the cDNA primarily contains coding sequences of the corresponding protein. There may be times when the full or partial genomic sequence is preferred, such as where the non-coding regions are required for optimal expression or where non-coding regions such as introns are to be targeted in an antisense strategy. In some embodiments, the polynucleotide comprises one or more segments comprising a small interfering ribonucleic acid (siRNA), a short hairpin RNA (shRNA), a micro- ribonucleic acid (miRNA), a primary micro-ribonucleic acid (pri-miRNA), a long non-coding RNA (lncRNA), a messenger ribonucleic acid (mRNA), a plasmid deoxyribonucleic acid (pDNA), a transfer ribonucleic acid (tRNA), an antisense oligonucleotide (ASO), an antisense ribonucleic acid (RNA), a guide ribonucleic acid, deoxyribonucleic acid (DNA), a double stranded deoxyribonucleic acid (dsDNA), a single stranded deoxyribonucleic acid (ssDNA), a single stranded ribonucleic acid (ssRNA), a or double stranded ribonucleic acid (dsRNA). In some embodiments, the polynucleotide encodes at least one of the therapeutic agent (or prophylactic agent) described herein. In some embodiments, the polynucleotide is greater than 30 nucleotides, greater than 50 nucleotides, greater than 100 nucleotides, greater than 200 nucleotides, greater than 300 nucleotides, greater than 400 nucleotides, greater than 500 nucleotides, greater than 600 nucleotides, greater than 700 nucleotides, greater than 800 nucleotides, greater than 900 nucleotides, greater than 1000 nucleotides, greater than 1500 nucleotides, greater than 2000 nucleotides, greater than 2500 nucleotides, greater than 3000 nucleotides, greater than 3500 nucleotides, greater than 4000 nucleotides, greater than 4500 nucleotides, or greater than 5000 nucleotides in length. In some embodiments, the mRNA is about 50 nucleotides in length. In some embodiments, the mRNA molecule is about 100 nucleotides in length. In some embodiments, the mRNA molecule is about 200 nucleotides in length. In some embodiments, the mRNA molecule is about 300 nucleotides in length. In some embodiments, the mRNA molecule is about 400 nucleotides in length. In some embodiments, the mRNA molecule is about 500 nucleotides in length. In some embodiments, the mRNA molecule is about 600 nucleotides in length. In some embodiments, the mRNA molecule is about 700 nucleotides in length. In some embodiments, the mRNA molecule is about 800 nucleotides in length. In some embodiments, the mRNA molecule is about 900 nucleotides in length. In some embodiments, the mRNA molecule is about 1000 nucleotides in length. In some embodiments, the mRNA molecule is about 2000 nucleotides in length. In some embodiments, the mRNA molecule is about 3000 nucleotides in length. In some embodiments, the mRNA molecule is about 4000 nucleotides in length. In some embodiments, the mRNA molecule is about 5000 nucleotides in length. In some embodiments, the polynucleotide comprises about 50 to about 100000 nucleotides. In some embodiments, the polynucleotide comprises about 50 to about 5000 nucleotides. In some embodiments, the polynucleotide comprises about 50 to about 2500 nucleotides. In some embodiments, the polynucleotide comprises about 50 to about 1000 nucleotides. In some embodiments, the polynucleotide comprises about 50 to about 500 nucleotides. In some embodiments, the polynucleotide comprises about 50 to about 300 nucleotides. In some embodiments, the polynucleotide comprises about 50 to about 200 nucleotides. In some embodiments, the polynucleotide comprises about 50 to about 100 nucleotides. In some embodiments, the polynucleotide comprises about 100 to about 100000 nucleotides. In some embodiments, the polynucleotide comprises about 100 to about 5000 nucleotides. In some embodiments, the polynucleotide comprises about 100 to about 2500 nucleotides. In some embodiments, the polynucleotide comprises about 100 to about 1000 nucleotides. In some embodiments, the polynucleotide comprises about 100 to about 500 nucleotides. In some embodiments, the polynucleotide comprises about 100 to about 300 nucleotides. In some embodiments, the polynucleotide comprises about 100 to about 200 nucleotides. In some embodiments, the polynucleotide comprises about 500 to about 100000 nucleotides. In some embodiments, the polynucleotide comprises about 500 to about 5000 nucleotides. In some embodiments, the polynucleotide comprises about 500 to about 2500 nucleotides. In some embodiments, the polynucleotide comprises about 500 to about 1000 nucleotides. In some embodiments, the polynucleotide comprises about 1000 to about 100000 nucleotides. In some embodiments, the polynucleotide comprises about 1000 to about 5000 nucleotides. In some embodiments, the polynucleotide comprises about 1000 to about 2500 nucleotides. In some embodiments, the polynucleotide comprises about 1000 to about 2000 nucleotides. In some embodiments, the LNP composition comprises mRNA at a lipid:mRNA (weight / weight) ratio is between 5:1 and 40:1. In some embodiments, the LNP comprises mRNA at a lipid:mRNA ratio between 10:1 and 40:1, between 15:1 and 40:1, between 20:1 and 40:1, between 25:1 and 40:1, between 30:1 and 40:1, between 35:1 and 40:1, between 20:1 and 35:1, between 25:1 and 35:1, between 30:1 and 35:1, between 20:1 and 30:1, between 25:1 and 30:1, between 20:1 and 25:1, between 25:1 and 30:1, between 25:1 and 35:1, between 20:1 and 36:1, between 25:1 and 36:1, between 5:1 and 45:1, between 20:1 and 40:1, between 25:1 and 40:1, between 35:1 and 40:1, or between 30:1 and 40:1. In some embodiments, the LNP comprises mRNA at a lipid:mRNA ratio of 30:1. In some embodiments, the LNP comprises mRNA at a lipid:mRNA ratio of 40:1. F. Formulations In some embodiments, in any of the methods or compositions provided herein, the therapeutic agents provided herein may be present in intravenous compositions. In some embodiments, the therapeutic agents provided herein may be present in aerosol compositions. In some embodiments, the lipid composition may be formulated as an aerosol. In some embodiments, the compositions provided herein may be formulated as an aerosol dosage form. In other embodiments, the compositions provided herein are formulated as intravenous dosage forms. In some embodiments, the lipid composition may be formulated as a nebulizer. In some embodiments, the compositions described herein are dispensed via a nebulizer. In some embodiments, the lipid composition may be dispensed as an aerosol. In some embodiments, the compositions described herein may be stored at or below -70 °C. In some embodiments, the compositions described herein may be formulated as a dispersion. In some embodiments, the concentration of the dispersion is about 0.5 mg / mL to about 5 mg / mL. In some embodiments, the concentration of the dispersion is about 0.5 mg / mL to about 1 mg / mL. In some embodiments, the concentration of the dispersion is about 0.5 mg / mL to about 2 mg / mL. In some embodiments, the concentration of the dispersion is about 0.5 mg / mL to about 3 mg / mL. In some embodments, the concentration of the dispersion is about 2 mg / mL to about 3 mg / mL. In some embodiments, the concentration of the dispersion is about 2 mg / mL to about 4 mg / mL. In some embodiments, the concentration of the dispersion is no more than 5 mg / mL. In some embodiments, the concentration of the dispersion is 1 mg / mL. In some embodiments, the compositions described herein are dispersed at pH 7.5. In some embodiments, the compositions provided herein are administered to a human. In some embodiments, the compositions provided herein are administered to an adult. In other embodiments, the compositions provided herein are administered to a child. In some embodiments, the compositions provided herein are administered to a patient with a body mass index of 18 to 35 kg / m2.In other embodiments, the compositions provided herein are administered to a patient with a total body weight of ≥50 kg. In some embodiments, the compositions described herein are administered intravenously. In some embodiments, the compositions described herein are delivered via inhalation. In some embodiments, the compositions described herein may comprise administration by nebulization. In some embodiments, the compositions described herein may comprise administration to a lung by nebulization. In some embodiments, the compositions described herein are administered at least once a week. In some embodiments, the compositions described herein are administered at least twice a week. In any of the compositions or methods provided herein, the compositions are administered in any suitable dose. In some embodiments, the dose refers to the amount of the composition. In some embodiments the dose refers to the amount of the therapeutic agent. In some embodiments, the administered dose is about 1 mg to about 30 mg. In some embodiments, the administered dose is about 1 mg to about 2.5 mg, about 1 mg to about 5 mg, about 1 mg to about 7.5 mg, about 1 mg to about 10 mg, about 1 mg to about 15 mg, about 1 mg to about 20 mg, about 1 mg to about 25 mg, about 1 mg to about 30 mg, about 2.5 mg to about 5 mg, about 2.5 mg to about 7.5 mg, about 2.5 mg to about 10 mg, about 2.5 mg to about 15 mg, about 2.5 mg to about 20 mg, about 2.5 mg to about 25 mg, about 2.5 mg to about 30 mg, about 5 mg to about 7.5 mg, about 5 mg to about 10 mg, about 5 mg to about 15 mg, about 5 mg to about 20 mg, about 5 mg to about 25 mg, about 5 mg to about 30 mg, about 7.5 mg to about 10 mg, about 7.5 mg to about 15 mg, about 7.5 mg to about 20 mg, about 7.5 mg to about 25 mg, about 7.5 mg to about 30 mg, about 10 mg to about 15 mg, about 10 mg to about 20 mg, about 10 mg to about 25 mg, about 10 mg to about 30 mg, about 15 mg to about 20 mg, about 15 mg to about 25 mg, about 15 mg to about 30 mg, about 20 mg to about 25 mg, about 20 mg to about 30 mg, or about 25 mg to about 30 mg. In some embodiments, the administered dose is about 1 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, or about 30 mg. In some embodiments, the administered dose is at least about 1 mg, about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 15 mg, about 20 mg, or about 25 mg. In some embodiments, the administered dose is at most about 2.5 mg, about 5 mg, about 7.5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, or about 30 mg. In some embodiments, the administered dose is about 2.5 mg. In some embodiments, the administered dose is about 5.0 mg. In some embodiments, the admistered dose is about 10.0 mg. In some embodiments, the administered dose is about 20.0 mg. In any of the compositions or methods provided herein, the dose may be determined in reference to body weight. In any of these compositions or methods, any suitable dose may be used. In some embodiments, the dose is about 0.01 mg / kg body weight to about 1 mg / kg body weight. In some embodiments, the dose is about 0.01 mg / kg body weight to about 0.05 mg / kg body weight, about 0.01 mg / kg body weight to about 0.1 mg / kg body weight, about 0.01 mg / kg body weight to about 0.5 mg / kg body weight, about 0.01 mg / kg body weight to about 0.8 mg / kg body weight, about 0.01 mg / kg body weight to about 1 mg / kg body weight, about 0.05 mg / kg body weight to about 0.1 mg / kg body weight, about 0.05 mg / kg body weight to about 0.5 mg / kg body weight, about 0.05 mg / kg body weight to about 0.8 mg / kg body weight, about 0.05 mg / kg body weight to about 1 mg / kg body weight, about 0.1 mg / kg body weight to about 0.5 mg / kg body weight, about 0.1 mg / kg body weight to about 0.8 mg / kg body weight, about 0.1 mg / kg body weight to about 1 mg / kg body weight, about 0.5 mg / kg body weight to about 0.8 mg / kg body weight, about 0.5 mg / kg body weight to about 1 mg / kg body weight, or about 0.8 mg / kg body weight to about 1 mg / kg body weight. In some embodiments, the dose is about 0.01 mg / kg body weight, about 0.05 mg / kg body weight, about 0.1 mg / kg body weight, about 0.5 mg / kg body weight, about 0.8 mg / kg body weight, or about 1 mg / kg body weight. In some embodiments, the dose is at least about 0.01 mg / kg body weight, about 0.05 mg / kg body weight, about 0.1 mg / kg body weight, about 0.5 mg / kg body weight, or about 0.8 mg / kg body weight. In some embodiments, the dose is at most about 0.05 mg / kg body weight, about 0.1 mg / kg body weight, about 0.5 mg / kg body weight, about 0.8 mg / kg body weight, or about 1 mg / kg body weight. In some embodiments, a dose comprises no more than about 1.0, 0.5, 0.1, 0.05, or 0.01 mg / kg body weight. The following are examples of compositions and evaluations of compositions of the disclosure. It is understood that various other embodiments may be practiced, given the general description provided above. G. Examples Before the embodiments of the disclosure are described, it is to be understood that such embodiments are provided by way of example only, and that various alternatives to the embodiments of the disclosure described herein may be employed in practicing the invention. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. Example 1 A. Polymer chemical structure modulates polymer lipid LNP mRNA delivery efficacy To examine whether alternative chemical structures and physical properties of synthetic polymers could function as substitutes to currently used DMG-PEG2000 in LNPs, a chemically diverse series of polymer lipids containing two lipid tails, an ester linker, and polymer chains derived from various radically polymerizable monomers (FIG. 1B) we designed. First, we synthesized a diacyl lipid initiator, DMG-Br, was designed to be used for construction of polymer lipids by ATRP. ATRP was selected for its high compatibility with functional groups and physical properties, as well as control over molecular weight (Mw) and polydispersity index. Monomers with different physiochemical characteristics were chosen, including those varying hydrophilicity, positive and negative charge, PEG mimetics, and zwitterionic motifs. Polymers were initially designed to have a similar Mw with DMG-PEG2000, where the Mw of PEG is 2,000 g / mol. LNPs were formed by the ethanol dilution method via mixing an ionizable amino lipid 4A3-SC7, DOPE, cholesterol, and polymer lipid ethanol solution with an acidic buffer solution of mRNA as established in a recent protocol. (Wang et al., 2023) Luc mRNA was used to quantify the delivery efficacy of LNPs, where luciferase protein is produced after the successful cellular uptake, endosomal escape, and mRNA translation. In vitro Luc transfection by these LNPs was first measured in HepG2 cells as a representative liver cell line, where nearly all polymer lipid stabilized LNPs were efficacious (FIG. 2). However, when transitioning to in vivo delivery, a much smaller hit rate (40%) was observed (FIG.1C & 1D). PEG-lipids protect LNPs from clearance by evading mononuclear phagocyte system (MPS) recognition during systemic circulation. Thus, LNPs without DMG-PEG2000 showed no signals in the main organs. Interestingly, polyHEMA and polyHPMA, which are considered as effective PEG substitutes in many reports, also failed to transfect tissues in vivo. This may be due to the additional extracellular and intracellular barriers faced by LNPs versus PEGylation drug conjugate products. Encouragingly, LNPs prepared with polyDEMEMA, polyAEMA, polyNIPAM, and polyDMAM containing positive charges transfected the liver and / or spleen, and LNP prepared with zwitterionic polymer, polySBMA, also transfected the liver and spleen with high efficacy. Among all the polymer lipids examined, polyEG9MA, a brush-shaped polymer with ethylene glycol (EG) side chains, exhibited the highest in vivo transfection efficacy and was selected for further studies. B. Polymer architectures were controlled using synthetic chemistry to correlate mRNA delivery efficacy Advanced synthetic techniques, including ATRP, can precisely control individual parameters hypothesized to modulate LNP stability and efficacy when incorporated into LNPs. Polymers are macromolecules composed of defined numbers of repeat units across multiple points in brush shaped designs including the initiator, monomer type, and degree of polymerization (DP). Specifically, the brush-shaped architecture of lipid functionalized polyEGMAs provided versatile handles to examine three factors that affect the polymer chemical structure: the alkyl length of the initiator, the DP of the side chain, and the DP of the polymer backbone, as demonstrated in FIG.1A. Once EGMA type monomers emerged from initial in vitro and in vivo evaluation of diverse monomer types, we speculated that these three parameters would be tunable to reduce anti-PEG antibody binding, enable repeat dosing, and maximizing efficacy. The structure-activity relationships (SARs) were first investigated by careful control of polymer architectures using EGMA as a base structure. DMG-PEGxMA (x=1, 2, 3, 5, 9, 19) were obtained where they shared the identical lipid initiator DMG and similar DP, but varying side chain length (x) (FIG.3A). BP LNPs (BPLs) were formulated with constant 4A3-SC7, constant DOPE, constant cholesterol, variable synthetic BPs, and Luc mRNA. The size distribution was first measured by DLS (FIG.3C). Incremental increase in the side chain length (x) resulted in increased hydrophilicity that assisted in the formation and stability of LNPs. LNPs with large size over 500 nm were formed using DMG-PEG1MA43and DMG-PEG2MA41. LNP size sharply decreased when the side chain length (x) reached 5 and maintained around 120 nm for DMG-PEG5MA39, DMG-PEG9MA36, and DMG-PEG19MA36, which was similar to DMG-PEG2000 and suitable for in vivo study. All BPLs showed high encapsulation efficiency (>90%) and low cytotoxicity (FIGS.4A and 4B). BPL with the longest side chain length, DMG-PEG19MA36 BPL produced the highest luminescence signal in vivo, achieving 2.73×107photons / s / cm2 / s in the liver (FIGS. 3B and 3D, FIG. 4C). Additionally, BPLs containing hEPO mRNA were administered in mice and hEPO concentrations in serum were measured by enzyme-linked immunosorbent assay (ELISA). Higher hEPO levels were detected when the EG side chain length was increased from 5 to 19, demonstrating that increased EG side chain length benefitted mRNA delivery efficacy (FIG.3E). Overall, both in vitro and in vivo mRNA delivery studies demonstrated that increased side chain length improved BPL transfection efficacy. Since polymer length can affect hydrophilicity and flexibility of extended chains, the effect of backbone DP on mRNA delivery was examined. DMG-PEG19MAy (y=5, 10, 21, 36, 60, 77) were synthesized by ATRP and were systematically evaluated (FIG. 3F). Since polymer lipids extend from the surface of LNPs in aqueous solvents, BPLs formed with BPs with longer DPs led to a slight increase in the LNP size (FIG.3H). Luc transfection efficacy increased with increasing DP, maximized at DP of 36, and dropped down when DP further increased (FIGS. 3G and 3I, FIG. 4D-4F). A similar result was also found in the DMG- PEG9MAypolymer series with different DPs (FIG. 5), further confirming that a moderate polymer length (y=36) benefits mRNA transfection. Delivery of hEPO mRNA by DMG- PEG19MAyBPLs also confirmed that DP of 36 maximized mRNA transfection efficacy (FIG. 3J). This finding may be related to both hydrophilicity and the shielding effect of PEGMA polymers. When the DP is low (for example, DMG-PEG19MA5), the polymer chain is too short for stealth effects. Conversely, when the DP is high (for example, DMG-PEG19MA77), the long polymer may inhibit cellular uptake and hinder the release of mRNA, leading to a decrease in delivery efficacy. (Garofalo et al., 2014) Polymer lipid incorporate into LNPs through hydrophobic interactions between hydrophobic anchors of polymer lipid and LNP lipid components. (Zhou et al., 2020) Tuning of lipid anchor chemistry alters the hydrophobicity and shedding rate of polymer lipids from LNPs. (Dillard et al., 2021; Dillard & Siegwart, 2023) Therefore, lipid anchors with varying length (n=4,8,10,12,14) were appended as ATRP initiators to synthesize BPs with fixed side chain length (x=9 or 19) and backbone DP (y~36) (FIG.3K). BPLs with short anchors, for example, DOG-terminated polymers (n=4), exhibited larger LNP size because the weaker hydrophobic interaction led to a loose LNP structure (FIG.3M, FIG.6B). In addition, DOG- terminated polymers are also easy to desorb from LNPs thereby allowing quick clearance by the MPS. Thus, the weakest luminescence signals were detected after injection of LNPs containing DOG-PEG19MA37 and DOG-PEG9MA43 (FIG. 3L and 3N, FIG. 6F). At the other end of the spectrum, less effective Luc mRNA delivery was also observed for LNPs containing DSG-terminated polymers (n=14) (FIG. 3L and 3N, FIG. 6F). The strong hydrophobic interaction hinders desorption from LNPs to expose the LNP membrane for the binding of serum proteins, leading to low mRNA delivery efficacy by DSG polymers. (Zhou et al., 2020) Lower hEPO levels by i.v. administered DOG- (n=4), DLG- (n=8), and DSG (n=14)-terminated BPLs were also observed compared to DMG (n=10) and DPG (n=12) BLPs (FIG. 3O). Therefore, moderate alkyl chain lengths (n=10,12), possess appropriate hydrophobic interactions to shed from LNPs, and achieve high mRNA transfection efficacy in vivo. C. Modulation of brush and mushroom regimes alters in vivo delivery outcomes Having established the optimized alkyl length anchor, further optimization towards the polymer regimes enabled on the LNP surfaces with respect to polymer backbone DP and side chain length, as these chemical differences govern the resulting polymer architectures and density on the surface. Keeping both the anchor chemistry and the molar ratios of lipids in LNP formulation constant, we analyzed the singular effects of the polymer structures on delivery outcomes. The ability to modulate x and y enabled us to compare brush and mushroom regimes. The brush and mushroom regimes were determined by the values of distance (D) of polymers on the surface and Flory radius (RF) of polymers. (Kenworthy et al., 1995) When D > RF, this wide and fluid space allows polymers to tend to exist as random coils in the solution, exhibiting a mushroom regime. When D < RF, the narrow space forces polymers to extend out, exhibiting a brush regime. RFis calculated by equation RF= aN3 / 5, where a represents the persistence length of monomer, and N is the number of monomer unit. As a brush-shaped polymer, RFvalues of backbone and side chain were calculated individually. RF values of different EG side chain lengths were calculated in FIG.7A. D here refers to distance between each EG monomer, which is the length of two carbon-carbon single bonds. Thus, the RF values of different EG side chain lengths are all larger than D, indicating that the side chains are in brush regime. For the polymer backbone, RFvalues are presented in FIG.7A. The molar ratio of polymer lipids were fixed at 4.76%, resulting in a D value around 29 Å. (Kenworthy et al., 1995) Thus, a mushroom to brush transition occurred from a DP of 36 to DP of 60. A representative schematic illustration of mushroom and brush regimes of brushed polymers on LNP surfaces is presented in FIG.7B. Mushroom regimes cover more surface area than brush regimes at a same density of polymer lipids. The high surface coverage reduces the exposure of hydrophobic domain of LNPs and weakens the protein absorption driven by hydrophobic interactions. Moreover, reduced surface space of mushroom regimes inhibits protein insertion, repels protein absorption, and maximizes the steric effect of the polymer layer. Therefore, polymer lipids in mushroom regimes are beneficial for prolonging the circulation by impeding protein absorption-mediated blood clearance, such as ApoE, opsonins, and anti-PEG antibodies. D. BPLs increase blood circulation half-life and exhibit reduced anti-PEG antibody binding affinity over DMG-PEG2000 LNPs PEG lipids stabilize LNPs and function to reduce systemic clearance and prolong the blood circulation time in vivo. To examine the differences in pharmacokinetics (PK) profiles of LNPs composed of DMG-PEG2000 and different BPs, an assay designed to avoid artificial contributions of reporter dyes or metals was utilized. (Allen et al., 1995) LNPs with cholesterol (partially) substituted by cholesteryl methyl ether (CME), a metabolic inactive sterol species, were prepared and measured plasma CME level by GC-MS to profile the PK of LNPs (FIG. 8). (Chen et al., 2016) Notably, all BPLs showed prolonged circulation than linear DMG- PEG2000 LNPs, indicating the advantage of brush shaped polymers in reducing biofouling. Longer side chain lengths BPLs (DMG-PEGxMA, x = 9, 19) exhibited longer circulation times than shorter counterpart (x = 5) (FIGS.7C and 7D), which is in coincidence with linear PEG with longer PEG showing prolonged half-life. (Greenwald, 2001; Gref et al., 1994) On the other hand, increased polymer backbone DP (y) led to decreased circulation time (FIGS.7E and 7F), which may be related to the mushroom to brush regime transition as y increases. Evidently, the interspace between neighboring polymers on LNP surface is more spacious for blood proteins absorption and phagocytic cell uptake in the brush regimes, leading to the rapid clearance of BPLs with longer polymer backbone DP (DMG-PEG19MAy, y=60, 77). In the mushroom regimes, transition to interdigitated mushroom to mushroom occurred with the increased polymer length. DMG-PEG19MA5polymer was more condensed to random coil model, while DMG-PEG19MA36 lost some conformational freedom and tended to behave between mushroom and brush regimes. Thus, there is more room for protein absorption in DMG-PEG19MA36 LNP than DMG-PEG19MA5 LNP, leading to faster clearance. The difference in alkyl length (n) also plays a role in the protein absorption-mediated clearance, where LNPs composed of BPLs with longer alkyl tails (n=12,14) exhibited increased circulation time than that of shorter counterparts (n=8,10) (FIGS.7G and 7H) PEGylation is widely used in clinical therapeutics to improve bioavailability of PEGylated therapeutics, (Harris & Chess, 2003) but limited by the generation of anti-PEG antibodies. (Stavnsbjerg et al., 2022; Emam et al., 2021) To measure the anti-PEG antibody binding affinity, biolayer interferometry (BLI) assay was employed and the association and disassociation kinetics between anti-PEG antibody, which is immobilized on the biosensor surface, and LNPs across a series of concentrations were measured (FIG. 7I). Standard, well established DMG- PEG2000 containing LNPs exhibited a strong binding affinity with the lowest equilibrium constant (KD) of 6.52 × 10-10M among all the LNPs tested, indicating that linear PEG is more likely to bind antibodies than brush shaped PEG polymer. For BPLs, only the side chain length (x) and polymer backbone DP (y) affected KD. Weaker anti-PEG antibody binding correlated with shorter side chain length (x), as evidenced by DMG-PEG3MA36with the highest KDof 1.24 × 10-6M and DMG-PEG19MA36 with the lowest KD of 2.32 × 10-7M (FIGS.7J and 7K). Mechanistically, anti-PEG antibody binds to approximately 3 linear EG monomer subunits of a PEG chain. Thus, increased EG side chain length increased the possibility of antibody binding and thus resulted in a stronger binding affinity with decreased KD. On the other hand, KDdecreased with increased backbone DP (y), indicating that the binding affinity enhanced with longer polymer length due to the increased EG amount (FIGS.7L and 7M). It is noteworthy that a sharp decrease in KD was observed when y increased from 36 (DMG-PEG19MA36, KD=2.32 × 10-7M) to 60 (DMG-PEG19MA60, KD=2.74 × 10-8M), which is exactly the predicted range of DP for the mushroom to brush conformation transition. The brush regime allows the antibody to squeeze between the chains and bind to EG segments in the side chain, leading to the drastic decrease in KD. No significant difference was found in different alkyl length group (n) (FIG.7N and 7O), indicating that these effects are dominated by the polymer chemistry not the shedding of PEG lipid from LNP. Overall, BPLs reduced anti-PEG antibody binding affinity compared to linear PEG even at higher EG amounts. In brush shaped polymers, the increased EG side chain length (x) and polymer backbone length (y) both increased the number of EG units that can bind anti-PEG antibody, leading to a stronger binding affinity. In addition, polymer regimes also affect the antibody binding affinity associated with the surface coverage of LNPs. E. BPLs improved protein production consistency of repeat dosing over DMG- PEG2000 LNPs Having validated that novel polymer lipid architectures and regimes lead to a reduction in anti-PEG antibody binding affinity, we next examined whether this would contribute to consistent in vivo mRNA translation upon repeat dosing. FIG.9A demonstrated the design to study the correlation of polymer lipid chemistry with repeat dose efficacy. Mice were i.v. administrated with LNP on day 1 and received the same LNP injection again on day 30. Due to the strong binding affinity of DMG-PEG2000 with anti-PEG antibody, second dose of DMG-PEG2000 LNPs suffered rapid clearance and sharp decrease (87.3%) of in vivo Luc mRNA transfection efficacy in liver (FIGS. 9B and 9C, FIG. 10A). In contrast, BPLs exhibited longer circulation in second dose and demonstrated similar mRNA delivery efficacy in first and second dose. SARs of BPs in enabling repeat dose transfection consistency were systematically studied. Increase of side chain length (x) resulted in less effective repeat dose efficacy, as evidenced by a very small Luc liver delivery reduction of 9.0% for DMG- PEG5MA39 (x=5) LNPs and 35.4% for DMG-PEG19MA36 (x=19) LNPs (FIGS. 9B and 9C, FIG.10A). Similarly, higher polymer backbone DP (y) resulted in higher reduction of delivery efficacy in second dose as demonstrated by the surprising increase of second dose Luc delivery in liver for DMG-PEG19MA5LNPs compared with first dose, and increasing degree of decrease for BPLs with longer backbone DP (DMG-PEG19MAy, y=36,60,77) in repeat dose scenario (FIGS. 9E and 9F, FIG. 10C). Altering alkyl tail length (n) did not lead to distinguishable difference in repeat dose delivery efficacy, which was attributed to similar polymer backbone DP and side chain length (FIGS.9H and 9I, FIG.10E). Overall, BPLs demonstrated much better maintenance in repeat dose delivery efficacy than DMG-PEG2000 LNPs due to the weakened anti-PEG antibody binding affinity. Without wishing to be bound by any theory, it is believed that LNPs with weak anti- PEG antibody affinity may induce weak immune response that contributes to slow clearance and maintained efficacy after multiple doses. Another repeat dosing experiment was then performed with different LNPs injected on day 1 followed by standard DMG-PEG2000 LNPs administration on day 30 (FIG.9K). The side chain length (x) and backbone DP (y) parameters were studied due to their structure related difference in anti-PEG antibody binding affinity. Strong Luc transfection was observed in all BPLs over DMG-PEG2000 LNPs. Among BPLs as first dose, liver Luc transfection efficacy in second dose decreased with the increment of side chain length (x) with the highest decrease observed in DMG-PEG19MA36 (x=19) BPL (FIGS.9L and 9M, FIG.11A). Without wishing to be bound by any theory, it is believed that DMG-PEG2000 LNPs in the second dose was quicker to be cleared after first injection of DMG-PEG19MA36(x=19) BPL with stronger anti-PEG antibody binding than DMG- PEG5MA39(x=5). On the other hand, decrement of liver Luc transfection was also observed with the DP increased from 5 to 36 and 77 (FIGS. 9O and 9P, FIG. 11C), indicating that LNPs with strong anti-PEG antibody binding affinity are more likely to be cleared in the second dose. Giving the evidence for superior BPL efficacy upon both repeated dosing scenarios, hEPO mRNA was then employed as a proof-of-concept protein replacement therapy. For standard DMG-PEG2000 LNPs, 70.8% reduction in hEPO protein production was measured after the second dose (FIG.9D, FIG.10B). In contrast, all BPLs showed less reduction than DMG-PEG2000 LNPs, indicating the advantage of brush-shaped polymers over linear polymers for reduced antibody binding and maintained protein production consistency. Polymer lipid chemistry with anti-PEG antibody affinity related repeat dose efficacy was observed across the side chain length (x), backbone DP (y) and alkyl length (n). Repeat dose efficacy with same hEPO mRNA containing LNP injection across 30 days was first evaluated. When the side chain length (x) increased from 5 to 9 and 19, the reduction in second dose efficacy increased from 4.4% to 53.7% and 61.5% respectively (FIG.9D, FIG.10B). Higher reduction in hEPO secretion was associated by longer polymer backbone DP (y), as evidenced by a 43.1% reduction for DMG-PEG19MA5 (y=5) BPL and 61.5% reduction for DMG- PEG19MA36(y=36) BPL (FIG.9G, FIG. 10D). On the contrary, similar reduction of hEPO levels was observed in BPLs across different alkyl length (n) due to their similar anti-PEG antibody binding affinity (FIG.9G, FIG.10E). As expected, the same trend was also observed in the hEPO mRNA repeated delivery by DMG- PEG2000 LNPs, priming by different BPLs. Increased side chain length (x) decreased hEPO production in the second dose, where 34.8% reduction was observed in DMG- PEG5MA39(x=5) BPL and 47.9% reduction in DMG-PEG19MA36(x=19) BPL as the first dose (FIG.9N, FIG.11B). Furthermore, priming by BPLs with longer backbone DP (y) decreased repeating dose efficacy. Almost 2-fold reduction of hEPO production was observed in DMG- PEG19MA77 (y=77) BPL compared to DMG- PEG19MA5 (y=5) BPL (FIG. 9Q, FIG. 11D). Therefore, the redosing efficacy was related to the side chain length (x) and DP (y) of LNPs in the first doses. The success of repeated hEPO mRNA delivery signified the immense potential of BPLs for protein replacement treatment compared to standard DMG-PEG2000 LNPs. F. BPLs overcome anti-PEG antibody inhibitory effect produced by DMG-PEG2000 LNPs Having established the advantage of BPLs in reduced anti-PEG antibody binding and the fact of widely existence of anti-PEG antibody produced by PEGylated drugs, the inventors next examined if the inhibitory effect raised by anti-PEG antibody production following DMG- PEG2000 LNPs injection could be overcome (FIG.12A). Mice were first administered with DMG-PEG2000 LNPs on day 1. On day 30, mice received DMG-PEG2000 LNPs or BPLs injection. The second LNP administration exhibited reduced activity due to priming by DMG-PEG2000 LNPs. However, all BPLs exhibited prolonged circulation time versus DMG-PEG2000 LNPs with higher plasma CME level (FIG. 12D), indicating their excellent ability in overcoming the inhibitory effect of anti-PEG antibodies. Particularly, some BPLs displayed superior mRNA delivery efficacy in the second dose compared to DMG-PEG2000 LNPs; for example, DMG-PEG19MA36and DPG-PEG19MA36BPLs maximized Luc mRNA delivery efficacy and thus best overcame the neutralization of anti-PEG antibodies (FIGS.12Band 12C). Turning to hEPO mRNAdelivery as a protein replacementtherapy, DMG-PEG19MA36 and DPG-PEG19MA36 BPLs also produced higher hEPO levels (70% increase) than DMG-PEG2000 LNPs (FIG.12E). Overall, BPLs were capable of overcoming the anti- PEG antibody inhibitory effect stimulated by the systemic administration of DMG-PEG2000 LNPs, demonstrating potential in protein replacement therapy even in the backdrop of widespread existence of anti-PEG antibodies. G. BPL LNPs extend survival in protein replacement therapy Next, a genetically engineered mouse model of hepatorenal tyrosinemia type 1 was used to compare mRNA-based protein replacement therapy of BPL LNPs to benchmark DMG- PEG2000 LNPs. Fumarylacetoacetate hydrolase (FAH)-encoding mRNA was delivered i.v. to FAH knock-out (FAH− / −) mice (FIG.13A) in a repeated dosing therapeutic setting. It was first verified that BPL LNPs and DMG-PEG2000 LNPs could deliver FAH mRNA in vitro and in vivo, which resulted in clear protein expression in both cells and liver tissues (FIGS.14 & 15). To mimic the clinical scenario that billions of people worldwide may have developed APAs, the generation of APAs in FAH− / − mice was induced by i.v. administering DMG-PEG2000 LNPs 30 days before the start of protein replacement therapy. Groups of mice then received LNP treatment at a dose of 0.3 mg kg−1 every three days after nitisinone (NTBC)-containing water was removed. Animals receiving phosphate buffered saline (PBS) treatment lost more than 20% of their body weight within 21 days (FIGS. 13B & 16). By contrast, protein replacement therapy slowed body weight loss. At the study end-point of 33 days, 100% of mice receiving repeated injections of DMG-PEG19MA36BPL LNPs were alive (FIG. 13C). By contrast, only 37.5% of mice receiving repeated injections of DMG-PEG2000 LNPs were alive. FAH protein expression in DMG-PEG19MA36-LNP-treated and DPG-PEG19MA36-LNP- treated animals was substantially higher than that in DMG-PEG2000-LNP-treated animals (FIGS.13D, 13E, and 17-19). Moreover, bilirubin levels were most significantly reduced in the DMG-PEG19MA36 BPL LNP group (FIG. 20). Overall, DMG-PEG19MA36 and DPG- PEG19MA36BPL LNPs demonstrated a promising protein replacement therapeutic benefit and extended survival in diseased mice. H. BPL LNP genome editing and protein inhibition The delivery capability of BPL LNPs was investigated for in vivo genome editing. We selected PCSK9 as a target gene, which functions in blood cholesterol level regulation and is associated with hypercholesterolaemia and atherosclerotic cardiovascular disease. Cas9 mRNA and single guide RNA targeting PCSK9 (sgPCSK9) were co-delivered to C57BL / 6 mice with pre-existing APAs (FIG.13F). DMG-PEG19MA36and DPG-PEG19MA36BPL LNPs induced 47.7% and 49.5%, respectively, insertions and deletions (indels) at the PCSK9 locus in livers 10 days after the i.v. injection, while DMG-PEG2000 LNPs induced only 13.1% indels at the same dose (FIGS.13G and 21). Next-generation sequencing demonstrated that indels were threefold higher in the treatment with BPL LNPs than that with DMG-PEG2000 (FIG. 13H). The high genome editing efficacy mediated by BPL LNPs led to ~100% reduction in PCSK9 protein levels in the liver and serum, whereas DMG-PEG2000 LNPs mediated only a 60% reduction in PCSK9 protein in the liver and serum (FIGS.13I-13K & 22). In addition, apparent reductions in both serum cholesterol and triglyceride levels were also observed in animals treated with BPL LNPs (FIG.23). No obvious liver or kidney damage was found after treatment (FIG.24 & 25). These results provide an exciting insight that modulating polymer lipids with reduced APA binding can increase in vivo genome editing efficacy, which can benefit therapy. Example 2 - Discussion Efficient and consistent delivery of mRNA across repeat dosing is an essential prerequisite for the shift of mRNA from vaccines to therapeutic protein replacement applications. Polymer chemistry provides rational and precise opportunities to improve stability, reduce anti-PEG antibody binding, prolong blood circulation time, and improve the repeat dose consistency of mRNA LNPs. Here, a library of polymer lipids were reported as substitutes for PEG lipids used in LNPs that enable mRNA delivery with high efficacy following repeated dosing. mRNA delivery efficacy was related to the polymer lipid structure, including side chain length (x), backbone DP (y), and alkyl length (n). Polymer lipids with longer side chain length, moderate DP, and moderate alkyl length demonstrated superior mRNA delivery efficacy. The conformation of polymer lipids on LNPs surface was further calculated and evidenced to be a factor of LNP fate in vivo. Taking advantage of higher surface coverage of brush shaped polymers versus linear DMG-PEG2000, BPLs achieved prolonged blood circulation time over DMG-PEG2000 LNPs. Moreover, polymer lipids in the mushroom regime performed better than brush regime in reducing anti-PEG antibody binding, which enabled longer circulation and better performance during repeated dosing in vivo. Careful control over polymer chemistry and physical architecture facilitated novel BPLs to maintain high efficacy across multiple doses due to their weak binding affinity with anti-PEG antibodies generated after the first administration. The anti-PEG antibody binding affinity measured by BLI assay revealed that polymer structures and regimes both affected antibody binding. DMG-PEG2000 had the strongest binding affinity because of the linear structure of EG chain which affords flexibility in fitting with the binding site. For BPs, higher binding affinity was found in longer side chain length (x) and larger DP (y) with more EG amount. In addition, the transition from mushroom regime to brush regime increased the physical space on LNPs for protein absorption, which sharply increased anti-PEG antibody binding. In mice that received multiple mRNA LNP doses, DMG-PEG2000 LNPs lost activity, whereas as BPLs maintained high efficacy. Notably, BPLs successfully overcame the anti-PEG antibody inhibitory effect induced by DMG-PEG2000 LNPs. These outcomes support the promise of BPLs to effectively evade the immune system and maintain a robust therapeutic efficacy in multiple dosing. Example 3 – Methods and Materials A. Materials DOPE was purchased from Avanti lipids. DMG-PEG2000 was purchased from NOF America. 1,3- dimyristoyl glycerol (DOG-OH), 1,3-dilauroyl glycerol (DLG-OH), 1,3- dimyristoyl glycerol (DMG-OH), 1,3-dipalmitoyl glycerol (DPG-OH), and 1,3-distearoyl glycerol (DSG-OH) were obtained from Cayman Chemicals. Cholesterol, CuBr, 2,2’-bipyridyl (bpy), N,N,N′,N′′,N′′-pentamethyldiethylenetriamine (PMDETA), 1,1,4,7,10,10- hexamethyltriethylenetetramine (TPMA), and all monomers were purchased from Millipore- Sigma. Anti-PEG antibody clone 6.3 was purchased from Sigma.4A3-SC7 was synthesized following a previous report. (Wang et al., 2023) The Quant-iT RiboGreen RNA assay kit was purchased from Life Technologies. ONE-Glo + Tox luciferase assay kit was purchased from Promega. d-Luciferin firefly, sodium salt monohydrate was purchased from Gold Biotechnology. AMC biosensor was purchased from Satorius. B. Synthesis of polymer lipids Lipid functionalized ATRP initiators were synthesized by esterification reaction between lipid-OH and 2-bromoisobutyryl bromide. Typically, 1,3-dimyristoyl glycerol (DMG- OH, 1000.0 mg, 1.95 mmol) and pyridine (231.4 mg, 2.93 mmol) were dissolved in 7.0 mL chloroform. 2-bromoisobutyryl bromide (672.5 mg, 2.93 mmol) was dissolved in 5.0 mL chloroform and added dropwise into the above solution on ice. The mixture was allowed to react at room temperature for 3 days. The mixture was washed twice with 4% NaHCO3 and dried with Na2SO4. Solvent was evaporated and the final product DMG-Br was obtained through vacuum drying. Polymer lipids were synthesized by ATRP using lipid-Br as initiator, bpy, PMDETA, or TPMA as ligand of CuBr, which depends on the monomers. For example, to synthesize DMG-PEG9MA4, DMG-Br (50.0 mg, 0.076 mmol), poly(ethylene glycol) methyl ether methacrylate with average Mnof 500 (EG9MA, 151.4 mg, 1.211 mmol), and PMDETA (31.5 mg, 0.182 mmol) were first dissolved in 2 mL isopropanol and degassed with nitrogen for 30 min. CuBr (13.0 mg, 0.091 mmol) was then added to the reaction and further degassed for 15 min. The mixture was reacted at 50 °C under the protection of nitrogen for 24 h. After that, CuBr was removed, and the mixture was dialysis against DI water for 2 days to remove unreacted monomer and organic solvent. DMG-PEG9MA4 polymer-lipid was obtained after freeze-drying. C. LNP formation and characterization LNPs were formulated by ethanol dilution method.4A3-SC7, DOPE, cholesterol, and polymer lipids were dissolved in ethanol or mixture of ethanol / DMSO at a molar ratio of 15 / 15 / 30 / 3. mRNA was diluted in citrate buffer (10 mM, pH 4.0). The two phases were rapidly mixed by pipette or vortex at an organic solvent to aqueous volume ratio of 1 / 3. The weight ratio of 4A3-SC7 and mRNA was fixed to 17 / 1. The mixture was stabilized at room temperature for 15 min before dialysis against 1× PBS for further use. Standard DMG-PEG2000 LNP was formulated with 4A3-SC7, DOPE, cholesterol, and DMG-PEG2000 instead of polymer-lipid at a same molar ratio of 15 / 15 / 30 / 3 using the same protocol as described above. DLS (Malvern, v.7.13) was applied to measure the size of LNPs. LNPs were diluted 10 folds with 1× PBS for DLS studies. The encapsulation efficiency was measured using RiboGreen assay. D. Anti-PEG antibody binding assay Biolayer interferometry (BLI, Octet RED384) was employed to analyze the anti-PEG antibody binding affinity with LNPs. To study antibody binding to LNPs, we loaded the pre- equilibrated Anti-Mouse IgG Fc Capture (AMC) biosensors (in 1× kinetics buffer from Sartorius) with 100 nM anti-PEG antibody, clone 6.3. Then, binding curves with LNPs of different concentrations from 20 μM to 312.5 nM were measured. The time for each step was fixed as follows: 60 s for baseline phase, 120 s for loading phase, 300 s for association phase, 300 s for dissociation phase, and 20 s for regeneration phase. The kinetic curves (association and dissociation steps) were fitted to 1:1 kinetics model to calculate KD, ka (on), and kd (off) by Octet System Data Analysis Software (FortéBio). E. mRNA synthesis Firefly luciferase and hEPO mRNAs were synthesized by in vitro transcription (IVT). IVT reactions were performed following standard protocols but with N1-methylpseudouridine- 5'-triphosphate replacing the typical uridine triphosphate. Finally, the mRNA was capped (Cap- 1) using the ScriptCap system (CellScript). F. In vitro transfection In vitro luciferase transfection was performed in HepG2 cells. Cells were seeded on a 96 well plate at a density of 10000 cells per well. After incubation for 1 day, the medium was discarded and 100 μL of fresh medium with LNPs were added to each well (50 ng mRNA per well). LNPs were incubated with cells for another 24 h. And the cytotoxicity and luciferase transfection efficacy were measured followed the instruction of ONE-Glo + Tox luciferase assay kit. G. Pharmacokinetics (PK) study The PK profile of LNPs was evaluated using GC-MS. Cholesteryl methyl ether was used instead of cholesterol. All LNPs were formulated at the same ratio described above. Male C57BL / 6J mice were i.v. injected with LNPs at an mRNA dose of 0.1 mg / kg. Blood samples were collected at pre-determined timepoints, i.e., 15 min, 30 min, 1 h, 3 h, 6 h, 12 h, 24 h, 48 h, 72 h, 96 h, and 120 h. Plasma was obtained following production instruction and the content of cholesteryl methyl ether was analyzed via GC-MS. H. In vivo Luc mRNA delivery C57BL / 6J mice were i.v. injected with LNPs at a Luc mRNA dose of 0.1 mg / kg. At 6 h post injection, mice were anaesthetized with isoflurane, and 100 μL of D-luciferin (30.0 mg / mL in PBS) was i.p. injected. After 5 min, main organs were harvested, and the luciferase activity was measured using Ami imaging system (Spectral Instruments Imaging AMI-HTX). I. In vivo hEPO mRNA delivery C57BL / 6J mice were i.v. injected with LNPs at an hEPO mRNA dose of 0.3 mg / kg. At 6 h post injection, mice were anaesthetized with isoflurane, and blood samples were collected to obtain serum. Serum hEPO level was evaluated by enzyme-linked immunosorbent assay (ELISA) following standard protocol. J. Repeat dosing Rechallenge study was performed by i.v. injecting LNPs containing Luc mRNA (0.1 mg / kg) or hEPO mRNA (0.3 mg / kg) between one month. Briefly, C57BL / 6J mice were injected with LNPs at a Luc mRNA dose of 0.1 mg / kg via tail vein. After 30 days, mice were injected with same LNP at a same dose. At 6 h post injection, the luciferase activity of main organs was evaluated, and plasma samples were collected for detecting plasma LNP levels. C57BL / 6J mice was i.v. injected with different BPLs (Luc mRNA dose: 0.1 mg / kg) at day 1. After 30 days, standard DMG-PEG2000 LNP (Luc mRNA dose: 0.1 mg / kg) was i.v. injected. At 6 h post injection, the luciferase activity of main organs was evaluated, and plasma samples were collected to measure plasma LNP levels. C57BL / 6J mice was injected with standard DMG-PEG2000 LNP at a Luc mRNA dose of 0.1 mg / kg via tail vein at day 1. After 30 days, a second dose of different BPLs (Luc mRNA dose: 0.1 mg / kg) were injected via tail vein. At 6 h post injection, the luciferase activity of main organs was evaluated, and plasma samples were collected to measure plasma LNP levels. *************** It is contemplated that any method or composition described herein can be implemented with respect to any other method or composition described herein. Other objects, features and advantages of the present disclosure will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating specific embodiments of the disclosure, are given by way of illustration only, since various changes and modifications within the spirit and scope of the disclosure will become apparent to those skilled in the art from this detailed description.

[0015] REFERENCES The following references, to the extent that they provide exemplary procedural or other details supplementary to those set forth herein, are specifically incorporated herein by reference. Allen, T. M., Hansen, C. B. & de Menezes, D. E. L. Pharmacokinetics of long-circulating liposomes. Adv. Drug Delivery Rev.16, 267-284 (1995). Boutin, S. et al. Prevalence of serum igg and neutralizing factors against adeno- associated virus (AAV) types 1, 2, 5, 6, 8, and 9 in the healthy population: Implications for gene therapy using AAV vectors. Hum. Gene Ther.21, 704-712 (2010). Cacicedo, M. L., Limeres, M. J. & Gehring, S. mRNA-based approaches to treating liver diseases. Cells 11, 3328 (2022). Chen, S. et al. Influence of particle size on the in vivo potency of lipid nanoparticle formulations of sirna. J. Controlled Release 235, 236-244 (2016). Cheng, Q. et al. Selective organ targeting (SORT) nanoparticles for tissue-specific mRNA delivery and CRISPR–Cas gene editing. Nat. 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Claims

1. WHAT IS CLAIMED IS:

1. A compound of the formula:wherein: R1 and R1 are each independently alkyl(C6-24), alkenyl(C6-24), or a substituted version of either group; R2and R2are each independently alkyl(C1-8)or substituted alkyl(C1-8); R3 is alkyl(C1-8) or substituted alkyl(C1-8); X1, X2, and X3 are each independently O or NRa, wherein: Ra is hydrogen, alkyl(C1-6), or substituted alkyl(C1-6); Y1is OR4or NR4′R4′′, wherein: R4, R4′, and R4′′ are each independently selected from a sugar moiety, alkyl(C1-8), substituted alkyl(C1-8), or −Y2−R5, wherein Y2 is alkanediyl(C1-6) or substituted alkanediyl(C1-6); and R5 is alkoxy(C1-8), substituted alkoxy(C1-8), heterocycloalkyl(C1-8), substituted heterocycloalkyl(C1-8), or NR(R′)(R′′), wherein R, R′, and R′′, are each independently absent, hydrogen, alkyl(C1-6), substituted alkyl(C1-6), or Y1 is: −(OCH2CH2)yRb, wherein Rb is hydroxy, alkoxy(C1-6), or substituted alkoxy(C1-6), and y is 1-30; and x is 1-100; or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, wherein the compound is further defined as:wherein: R1 and R1′ are each independently alkyl(C6-24), alkenyl(C6-24), or a substituted version of either group; Y1 is −(OCH2CH2)yRb, wherein Rb is hydroxy, alkoxy(C1-6), or substituted alkoxy(C1-6), and y is 5-30; and x is 1-100; or a pharmaceutically acceptable salt thereof.3.The compound of claim1, wherein X1 is O.

4. The compound of either claim 1 or claim 3, wherein X2 is O.

5. The compound according to any one of claims 1, 3, and 4, wherein X3 is O.

6. The compound according to any one of claims 1 and 3-5, wherein R2 is alkyl(C1-8).

7. The compound of claim 6, wherein R2is methyl.

8. The compound according to any one of claims 1 and 3-7, wherein R2′ is alkyl(C1-8).

9. The compound of claim 8, wherein R2′ is methyl.

10. The compound according to any one of claims 1 and 3-9, wherein R3 is alkyl(C1-8).

11. The compound of claim 10, wherein R3 is methyl.

12. The compound according to any one of claims 1-11, wherein R1 is alkyl(C6-24) or substituted alkyl(C6-24).13.The compound according to any one of claims1-12, wherein R1 is alkyl(C6-24).

14. The compound according to any one of claims 1-13, wherein R1 is alkyl(C8-20).

15. The compound according to any one of claims 1-14, wherein R1 is alkyl(C10-20).

16. The compound according to any one of claims 1-15, wherein R1 is alkyl(C10-18).

17. The compound according to any one of claims 1-16, wherein R1is alkyl(C12-16).

18. The compound according to any one of claims 1-17, wherein R1′ is alkyl(C6-24)or substituted alkyl(C6-24).

19. The compound according to any one of claims 1-18, wherein R1′ is alkyl(C6-24).

20. The compound according to any one of claims 1-19, wherein R1′ is alkyl(C8-20).

21. The compound according to any one of claims 1-20, wherein R1′ is alkyl(C10-20).

22. The compound according to any one of claims 1-21, wherein R1′ is alkyl(C10-18).23.The compound according to any one of claims1-22, wherein R1′ is alkyl(C12-16).

24. The compound according to any one of claims 1-23, wherein y is 5-30.

25. The compound according to any one of claims 1-24, wherein y is 7-30.

26. The compound according to any one of claims 1-25, wherein y is 10-25.

27. The compound according to any one of claims 1-23, wherein the compound is further defined as:wherein: R1and R1′ are each independently alkyl(C6-24), alkenyl(C6-24), or a substituted version of either group; Y1 is −(OCH2CH2)yRb, wherein Rb is methoxy and y is 19; and x is 5-100; or a pharmaceutically acceptable salt thereof.

28. The compound according to any one of claims 1-27, wherein x is 15-70.

29. The compound according to any one of claims 1-28, wherein x is 20-60.

30. The compound according to any one of claims 1-29, wherein x is 30-50.

31. The compound according to any one of claims 1-30, wherein the compound is further defined as:wherein: R1 and R1′ are each independently alkyl(C12-16) or substituted alkyl(C12-16); Y1 is −(OCH2CH2)yRb, wherein Rb is methoxy and y is 19; and x is 30-50; or a pharmaceutically acceptable salt thereof.

32. A lipid nanoparticle comprising a compound according to any one of claims 1-31.

33. The lipid nanoparticle of claim 32, wherein the lipid nanoparticle comprises one or more ionizable cationic lipids.

34. The lipid nanoparticles of claim 33, wherein the ionizable cationic lipid is an ionizable amine lipid.

35. The lipid nanoparticle according to any one of claims 32-34, wherein the lipid nanoparticle further comprises one or more phospholipids.

36. The lipid nanoparticle of claim 35, wherein the phospholipid is a zwitterionic phospholipid.

37. The lipid nanoparticle according to any one of claims 32-36, wherein the lipid nanoparticle further comprises one or more sterol.

38. The lipid nanoparticle of claim 37, wherein the sterol is cholesterol.

39. The lipid nanoparticle according to any one of claims 32-38, wherein the lipid nanoparticle further comprises a payload.

40. The lipid nanoparticle of claim 39, wherein the payload is a nucleic acid.

41. The lipid nanoparticle of claim 40, wherein the nucleic acid is siRNA, a miRNA, a pri-miRNA, a messenger RNA (mRNA), a cluster regularly interspaced shortpalindromic repeats (CRISPR) related nucleic acid, a single guide RNA (sgRNA), a CRISPR-RNA (crRNA), a trans-activating crRNA (tracrRNA), a plasmid DNA (pDNA), a transfer RNA (tRNA), an antisense oligonucleotide (ASO), a guide RNA, a double stranded DN A (dsDNA), a single stranded DN A (ssDNA), a single stranded RNA (ssRNA), and a double stranded RNA (dsRNA).

42. The lipid nanoparticle of either claim 40 or claim 41, wherein the nucleic acid is a therapeutic nucleic acid.

43. The lipid nanoparticle of claim 39, wherein the payload is a peptide or protein.

44. The lipid nanoparticle of claim 39, wherein the payload is a peptide, protein, a nucleic acid, or a combination thereof.

45. A pharmaceutical composition comprising: (A) a lipid nanoparticle of claim 32; and (B) an excipient.

46. A method of treating or preventing a disease or disorder in a patient in need thereof comprising administering to the patient a lipid nanoparticle or a pharmaceutical composition according to any one of claims 32-45 to the patient.

47. The method of claim 46, wherein the lipid nanoparticle comprises a payload that is useful in treating the disease or disorder.

48. A method of increasing the effectiveness of a nucleic acid therapeutic in a patient comprising administering to the patient a lipid nanoparticle or a pharmaceutical composition according to any one of claims 32-45 to the patient.

49. The method of claim 48, wherein the lipid nanoparticle or a pharmaceutical results in reduced binding of an antibody against polyethylene glycol (PEG).

50. A method of decreasing the effects of antibodies against polyethylene glycol (PEG) on a therapeutic agent comprising using a lipid nanoparticle or pharmaceutical composition comprising a compound according to any one of claims 1-31.

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