Compositions and methods for hematopoietic stem cell (HSC) targeted delivery of therapeutic agents

Abstract

The present disclosure relates, in part, to hematopoietic stem cell (HSC) targeted lipid nanoparticle (LNP) compositions, and methods of use thereof for delivery of nucleic acids and / or therapeutic agents to HSCs. In certain embodiments, the LNPs of the disclosure are suitable for in utero administration. In another aspect, the disclosure provides methods for treating, preventing, and / or ameliorating HSC-related disease and / or disorders, including but not limited to hemoglobinopathies and immunodeficiencies.

Description

[0001]Attorney Docket No.046483-7452WO1(03831) TITLE OF THE INVENTION Compositions and Methods for Hematopoietic Stem Cell (HSC) Targeted Delivery of Therapeutic Agents CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Patent Application No.63 / 623,674, filed January 22, 2024, which is incorporated herein by reference in its entirety. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT This invention was made with government support under TR002776, DK123049, and HL152427 awarded by the National Institutes of Health. The government has certain rights in the invention. BACKGROUND Monogenic blood diseases, including sickle cell disease and α / β thalassemia, are among the most common genetic disorders worldwide. These diseases result in significant pediatric morbidity, including painful vaso-occlusive crises, severe anemia, increased susceptibility to life-threatening infections, and in some cases fetal demise. mRNA-based therapeutics hold great promise for treatment of these diseases, providing a template to produce missing or defective blood proteins or correcting specific disease-causing mutations in hematopoietic stem cells (HSCs). Recent advances in CRISPR-based gene editing technology and ex vivo gene delivery to HSCs have enabled FDA-approval of autologous HSC-based gene therapies for treatment of severe sickle cell disease and β thalassemia. These first-in-kind therapies rely on physical or viral methods for gene editing of patient-derived CD34+ HSCs. Modified cells are then transplanted back into patients pre-treated with myeloablative conditioning. While clinical outcomes for these treatments are promising, ex vivo HSC gene therapy is an expensive ($2-3 million per dose) and time-consuming (months) process, requiring a highly-specialized cell processing center and extensive HSC transplantation expertise. In addition, the high-dose chemotherapy required to reach clinically-relevant HSC engraftment levels can be toxic and may result in prolonged hospital stays. Importantly, the resource and infrastructure requirements for these novel gene therapies limits their utility in low- and middle-income - 1 - 53762388.1 Attorney Docket No.046483-7452WO1(03831) countries, where the majority of monogenic blood disease burden exists. In contrast, in vivo gene therapy for monogenic blood diseases offers a more facile and potentially lower cost treatment paradigm without a need for HSC collection, ex vivo culture, pre-conditioning, or transplant. HSCs may be modified directly within their niche in vivo after intravenous (IV) administration of a therapy in an outpatient center. An in vivo approach also unlocks the possibility to treat disease in utero prior to the onset of disease pathogenesis. The clinical translation of in vivo gene therapies for monogenic blood diseases has been hindered by a limited number of effective and non-toxic platforms designed to facilitate gene delivery to HSCs. For example, viral vectors have been designed for in vivo modification of HSCs; however, viral delivery platforms may have toxicity and immunogenicity concerns at high dose. Non-viral delivery carriers, such as ionizable lipid nanoparticles (LNPs), have demonstrated clinical success for in vivo vaccine and liver disease applications, yet extra-hepatic tropism and efficacy require significant optimization. While others have developed LNPs targeting HSCs in vivo, these studies are limited by the delivery of small reporter gene editing cargos and assessment in adult mouse models, when disease processes may have already matured. Thus, there is a need for a safe and effective in vivo approach to target hematopoietic stem cells prior to onset of monogenic blood disease. The present disclosure addresses this need. BRIEF SUMMARY In one aspect, the disclosure provides a hematopoietic stem cell targeted lipid nanoparticle (LNP). In certain embodiments, the LNP comprises at least one ionizable lipid. In certain embodiments, the LNP comprises at least one neutral lipid. In certain embodiments, the LNP comprises cholesterol and / or a modified derivative thereof. In certain embodiments, the LNP comprises at least one polymer conjugated lipid and / or a modified derivative thereof. In certain embodiments, the LNP comprises a cell targeting domain specific to binding to a surface molecule of an hematopoietic stem cell. In certain embodiments, the cell targeting domain is covalently conjugated to at least one component of the LNP.. In certain embodiments, the LNP comprises at least one neutral lipid, cholesterol and / or a modified derivative thereof, at least one polymer conjugated lipid and / or a modified derivative thereof, a cell targeting domain specific to binding to a surface molecule of an hematopoietic stem cell, wherein the cell targeting domain is covalently conjugated to at least one component of the LNP. - 2 - 53762388.1 Attorney Docket No.046483-7452WO1(03831) In certain embodiments, the at least one ionizable lipid is a compound of Formula (I), or a salt, solvate, stereoisomer, or isotopologue thereof, wherein R1a, R1b, R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2gare defined elsewhere herein: . In certain embodiments, of the polymer conjugated lipid is a compound of Formula (II), or a or isotopologue thereof, wherein L2, Z, R5a, R5b, and Dct are defined elsewhere herein: . In certain . In . In another aspect, the disclosure provides a pharmaceutical composition comprising the lipid nanoparticle (LNP) of the disclosure and at least one pharmaceutically acceptable carrier. In another aspect, the disclosure provides a method of treating, preventing, and / or ameliorating a hematopoietic stem cell-based disease and / or disorder in a subject. In certain embodiments, the method comprises administering to the subject the lipid nanoparticle (LNP) of the disclosure and / or the pharmaceutical composition of the disclosure. In another aspect, the disclosure provides a method of treating, preventing, and / or ameliorating a monogenic blood disease and / or disorder in a subject, the method comprises administering to the subject the lipid nanoparticle (LNP) of the disclosure and / or the pharmaceutical composition of the disclosure. In certain embodiments, the monogenic blood disease and / or disorders comprises sickle cell disease or α / β thalassemia. In another aspect, the disclosure provides a method of treating, preventing, and / or ameliorating a metabolic and / or genetic abnormality in a subject, the method comprises - 3 - 53762388.1 Attorney Docket No.046483-7452WO1(03831) administering to the subject the lipid nanoparticle (LNP) of the disclosure and / or the pharmaceutical composition of the disclosure. BRIEF DESCRIPTION OF THE FIGURES The drawings illustrate generally, by way of example, but not by way of limitation, various embodiments of the present application. FIGs.1A-1F: Design and characterization of CD45R targeted LNPs. FIG.1A: Schematic describing the overall experimental rationale of the disclosure. In brief, LNPs conjugated to CD45 antibody fragments are directed to CD45 receptors expressed on the surface of HSCs within the fetal mouse liver microenvironment. Following LNP internalization and in utero transfection, gene edited HSCs will undergo normal physiological migration to the bone marrow, where they will engraft and coordinate hematopoiesis of myeloid and lymphoid progeny that also possess the progenitor cell edit. FIG.1B: Untargeted LNP formulation scheme that involves C14-490 ionizable lipid, DOPE, cholesterol, C14- PEG2K, and a C18-PEG2K-Malemide (Mal) linker in the organic phase mixed via a microfluidic device with designated RNA cargo. FIG.1C: Schematic visualizing CD45 F(ab’)2 antibody generation and conjugation to untargeted LNPs to generate targeted LNPs. FIGs.1D-1E: Characterizing the size (FIG.1D), polydispersity (PDI) (FIG.1E), and encapsulation efficiency (FIG.1F) of untargeted LNPs (left bar) and targeted LNPs (right bar). Unpaired parametric Student’s t test (p < 0.05) was used to compare the physiochemical properties of untargeted and targeted LNPs (ns = non-significant, *** = p < 0.001); all data reported as the mean ± SEM (minimum n = 3). FIGs.2A-2I: Investigating the efficacy, safety, and mechanism of CD45R targeted LNPs. FIG.2A: Percentage of Jurkats expressing GFP 24 h after treatment with untargeted LNPs or targeted LNPs encapsulating GFP mRNA at a dose of 100 ng / 30,000 cells, visualized via histogram (left) and plotted (right). PBS-treatment was used as a negative control. FIG.2B: Viability of Jurkats following treatment used in FIG.2A. FIG.2C: Effect of dose (per 30,000 cells) on fold improvement in mRNA delivery to Jurkats (targeted LNP / untargeted LNP). FIG.2D: Effect of antibody substitution (CD45 to IgG isotype control) on targeted LNP efficacy in mRNA delivery to Jurkats. FIGs.2E-2F: Effect of CD45 antibody (FIG.2E) or IgG antibody (FIG.2F) pre-treatment on the fold improvement in mRNA delivery to Jurkats (targeted LNP / untargeted LNP). FIG.2G: Percentage of HepG2 cells expressing GFP 24 h after treatment with untargeted LNPs or targeted LNPs encapsulating GFP mRNA at a dose of 25 ng / 30,000 cells. FIG.2H: Volcano plot summarizing the - 4 - 53762388.1 Attorney Docket No.046483-7452WO1(03831) differentially abundant proteins within the corona of plasma-incubated untargeted LNPs and targeted LNPs. FIG.2I: Percentage of Jurkats expressing GFP after cells were treated with the approach used in FIG.2A with (P) or without (NP) pre-incubation in plasma. One-way ANOVA with post hoc Dunnett’s test was used to compare the effect of untargeted LNP or targeted LNP treatment in vitro (FIGs.2A-2C, FIGs.2F-2G, and FIG.2I). Unpaired parametric Student’s t test (p < 0.05) was used to compare the efficacy of CD45 and IgG targeted LNPs (FIG.2D) (ns = non-significant, * = p < 0.05, ** = p < 0.01, *** = p < 0.001, **** p < 0.0001); all data reported as the mean ± SEM (minimum n = 3). FIGs.3A-3K: Efficacy and safety of targeted LNPs in utero. FIG.3A: Percentage of hepatocytes (CD45-) or HSCs (Lin-, Sca1+, cKit+) expressing GFP, 60 h after E13.5 R26mT / mGfetal mice were treated with either untargeted LNPs (left two bars in graph) or targeted LNPs (right two bars in graph) encapsulating Cre mRNA at a dose of 1 mg / kg. FIG. 3B: Histological representation of an E15 Balb / c mouse fetus (left) and corresponding fetal livers (right) from mice treated via in utero IV injection with untargeted LNPs or targeted LNPs encapsulating mCherry mRNA at a dose of 1 mg / kg. Co-localization of CD45 and RFP indicates delivery to CD45+ cells. FIG.3C: Percentage of GFP+ hepatocytes and HSCs, 60 h after 12-week-old adult R26mT / mGmice were treated as described in FIG.3A. FIG.3D: Percentage of GFP+ hepatocytes and bone marrow HSCs, 4 months after E13.5 R26mT / mGfetal mice were treated as described in FIG.3A. FIG.3E: Percentage of myeloid or lymphoid cells in recipient mice expressing GFP at terminal harvest of R26mT / mGmice treated in utero. FIG.3F: Percentage of GFP+ hepatocytes and bone marrow HSCs, 4 months after 12-week- old adult R26mT / mGmice were treated as described in FIG.3A. FIG.3G: R26mT / mGfetus survival to birth following in utero IV injection of PBS, untargeted LNPs, or targeted LNPs. FIGs.3H-3K: Serum aspartate transaminase (AST) (FIG.3H), alanine transaminase (FIG. 3I), alkaline phosphatase (FIG.3J), and serum cytokine (FIG.3K) levels of R26mT / mGfetal mice treated at E13.5 with PBS, untargeted LNPs, or targeted LNPs and harvested after 24 h. One-way ANOVA with post hoc Dunnett’s test was used to compare efficacy (FIGs.3A, 3C- 3D, and 3F) and safety (FIGs.3G-3J) of untargeted and targeted LNPs. Two-way ANOVA with post hoc Šídák’s multiple comparisons test was used to compare the effect of untargeted and targeted LNP treatment on multi-lineage hematopoietic cell transfection (FIG.3E) and induction of acute cytokine response (FIG.3K) (ns = non-significant, * = p < 0.05, ** = p < 0.01, *** = p < 0.001, **** p < 0.0001); all data reported as the mean ± SEM (minimum n = 3). FIGs.4A-4D: Secondary transplant of HSCs modified via targeted LNPs in utero. - 5 - 53762388.1 Attorney Docket No.046483-7452WO1(03831) FIG.4A: Schematic of secondary transplant study. E13.5 R26mT / mGfetuses were treated with targeted LNPs encapsulating Cre mRNA via in utero IV injection at a dose of 1 mg / kg and followed for 4 months prior to whole bone marrow (WBM) isolation (donor) and secondary transplanted into lethally irradiated wild-type adult mice (recipient). Recipient mice were subsequently followed for 4 months via peripheral blood draw prior to terminal BM harvest and assessment of gene modulation in engrafted HSCs. FIG.4B: Percentage of CD45+ cells in recipient mice expressing green fluorescent protein (GFP) at a given month following secondary transplant. FIG.4C: Percentage of myeloid or lymphoid cells in recipient mice expressing GFP at terminal harvest after 4 months. FIG.4D: Percentage of HSCs (Lin-, Sca1+, cKit+) expressing GFP within the bone marrow of donor and recipient mice. One-way ANOVA with post hoc Dunnett’s test was used to compare the level of GFP positivity in recipient mouse CD45+ cells over time (FIG.4B) (ns = non-significant); all data reported as the mean ± SEM (minimum n = 3). FIGs.5A-5I: Optimization and delivery of gene editing cargo to HSCs in utero. FIG. 5A: Schematic of design of experiments (DOE) approach depicting the design space (4x4x4x4) and sequential library generation (Library A to Library B). FIG.5B: Screening LNPs from Library A encapsulating Cas9 mRNA and GFP sgRNA in HepG2-GFP cells at a dose of 100 ng / 30,000 cells. Flow cytometry was used to capture resultant GFP knockout after 5 days. Data normalized to the standard formulation (A0, dotted line). FIG.5C: Screening LNPs from Library B via the same approach used in FIG.5B. FIG.5D: Cross- validating B5 LNP formulation encapsulating Cas9 mRNA and GFP sgRNA in Jurkats-GFP (hematopoietic lineage cells) at a dose of 100 ng / 30,000 cells. Flow cytometry was used to capture resultant GFP knockout after 5 days. FIG.5E: Testing the gene editing efficacy of unoptimized (A0) and optimized (B5) LNPs encapsulating Cas9 mRNA and TTR sgRNA after in utero IV administration at a dose of 1 mg / kg into E13.5 wild-type mice. Genomic DNA from fetal liver was harvested after 5 days, and insertions and deletions (indels) at the intended locus were quantified via next-generation sequencing (NGS). PBS-injected fetuses were used as a negative control. FIG.5F: Schematic of experiment evaluating the gene editing efficacy of optimized untargeted LNPs (B5) and optimized targeted LNPs (STEM) via the same approach used in FIG.5E, although HSCs (Lin-, Sca1+, cKit+) were also isolated and sequenced. FIG.5G: Indels at the intended locus in genomic DNA from the fetal liver of animals treated with PBS, B5 LNPs, or STEM LNPs. FIG.5H: Indels at the intended locus in genomic DNA from HSCs of animals treated with PBS, B5 LNPs, or STEM LNPs. One-way ANOVA with post hoc Dunnett’s test was used to compare gene editing efficacy of - 6 - 53762388.1 Attorney Docket No.046483-7452WO1(03831) LNP formulations (FIGs.5B-5H) (ns = non-significant, * = p < 0.05, ** = p < 0.01, *** = p < 0.001, **** p < 0.0001); all data reported as the mean ± SEM (minimum n = 4). FIG.5I: Exemplary GFP expression data in Jurkats with administration of compositions of the disclosure. FIG.6: provides bar graphs showing that targeted LNPs facilitate reporter mRNA delivery ex vivo in primary human hematopoietic progenitor cells. FIG.7 provides a schematic of the differentiation pathway of hematopoietic stem cells. FIG.8 provides a schematic depicting in utero treatment of congenital blood diseases according to methods contemplated in the disclosure. FIG.9 provides exemplary data showing baseline HSC transfection after in utero intravenous injection of C14-490 LNPs of the disclosure. FIG.10 provides exemplary data showing that targeted LNPs produce a similar protein corona ex vivo. For example, 55 proteins are differentially abundant in the coronas surrounding untargeted and targeted LNPs. DETAILED DESCRIPTION OF THE INVENTION Reference will now be made in detail to certain embodiments of the disclosed subject matter, examples of which are illustrated in part in the accompanying drawings. While the disclosed subject matter will be described in conjunction with the enumerated claims, it will be understood that the exemplified subject matter is not intended to limit the claims to the disclosed subject matter. Throughout this document, values expressed in a range format should be interpreted in a flexible manner to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. For example, a range of "about 0.1% to about 5%" or "about 0.1% to 5%" should be interpreted to include not just about 0.1% to about 5%, but also the individual values (e.g., 1%, 2%, 3%, and 4%) and the sub-ranges (e.g., 0.1% to 0.5%, 1.1% to 2.2%, 3.3% to 4.4%) within the indicated range. The statement "about X to Y" has the same meaning as "about X to about Y," unless indicated otherwise. Likewise, the statement "about X, Y, or about Z" has the same meaning as "about X, about Y, or about Z," unless indicated otherwise. In this document, the terms "a," "an," or "the" are used to include one or more than one unless the context clearly dictates otherwise. The term "or" is used to refer to a - 7 - 53762388.1 Attorney Docket No.046483-7452WO1(03831) nonexclusive "or" unless otherwise indicated. The statement "at least one of A and B" or "at least one of A or B" has the same meaning as "A, B, or A and B." In addition, it is to be understood that the phraseology or terminology employed herein, and not otherwise defined, is for the purpose of description only and not of limitation. Any use of section headings is intended to aid reading of the document and is not to be interpreted as limiting; information that is relevant to a section heading may occur within or outside of that particular section. All publications, patents, and patent documents referred to in this document are incorporated by reference herein in their entirety, as though individually incorporated by reference. In the methods described herein, the acts can be carried out in any order, except when a temporal or operational sequence is explicitly recited. Furthermore, specified acts can be carried out concurrently unless explicit claim language recites that they be carried out separately. For example, a claimed act of doing X and a claimed act of doing Y can be conducted simultaneously within a single operation, and the resulting process will fall within the literal scope of the claimed process. Description Ex vivo HSC-based gene therapies are increasingly being used for the treatment of monogenic blood diseases. However, the high cost and infrastructure requirements for these therapies can be limiting, especially for patients in under resourced settings where these diseases are most prevalent. In addition, the chemotherapy involved in these therapies is not well-tolerated by some patients and has also been associated with short- and long-term toxicity. Since this pathology often begins before birth, monogenic blood diseases are associated with significant childhood morbidity and an elevated rate of fetal demise. Thus, there is a need for a safe and effective in vivo approach to target hematopoietic cells prior to onset of monogenic blood disease. Previous studies have demonstrated feasibility of in utero gene editing therapies in mouse models of congenital disease. In these studies, transfection of fetal stem and progenitor cells facilitated effective long-term genome correction in target tissues. To realize the potential of in utero gene editing therapies for monogenic blood disease, a targeted LNP platform was designed to mediate in vivo gene editing of fetal HSCs, as described herein. This design approach leverages fetal and developmental biology to overcome conventional biological barriers in mRNA-LNP delivery to HSCs. Notably, residence of fetal hematopoiesis, and consequentially fetal HSCs, within the liver during development provides a more accessible compartment for gene delivery in comparison to the postnatal bone marrow - 8 - 53762388.1 Attorney Docket No.046483-7452WO1(03831) niche. Using a top-performing LNP from a prior study assessing the feasibility of in utero mRNA-LNP delivery, a strong LNP-mediated transfection of the fetal liver was demonstrated, but low-level genome modification of fetal HSCs was also observed in vivo. To boost genome modification within HSCs, CD45 antibody F(ab’)2fragments were conjugated to the surface of these LNPs using thiol-maleimide chemistry. It was hypothesized that targeted LNPs would engage the CD45R found ubiquitously expressed on the surface of hematopoietic cells residing in the fetal liver and facilitate LNP internalization into these cells. Indeed, relative to untargeted LNPs, targeted LNPs enhanced mRNA delivery to hematopoietic-lineage cells by 8-fold in vitro and genome modification in HSCs by 7-fold in vivo following in utero IV administration to mid-gestation fetal mice. Others have utilized CD117 (c-Kit) antibody fragments to target HSCs in vivo. Although CD117 is a more specific HSC marker, its broad role in other developmental processes, including stemness in other organs and germline cell maturation, made LNP conjugation to CD117 antibody fragments a less ideal approach for gene editing in the fetus. Interestingly, targeted LNPs were unable to transfect bone marrow HSCs after IV administration in adult mice. It was hypothesized that active targeting was unable to boost transfection efficiency in adult mice given undetectable baseline transfection of bone marrow HSCs after IV administration of untargeted LNPs. However, the antibody conjugation approach utilized in this study is highly modular and could be adapted for any base LNP formulation to target any desired surface receptor on a fetal stem or progenitor population. HSCs migrate from the fetal liver to the bone marrow late in development, where they reside and regulate definitive hematopoiesis. We hypothesized that HSCs edited via targeted LNPs within the fetal liver would naturally engraft in the bone marrow niche and produce myeloid and lymphoid daughter cells carrying the same edit during adult life. Excitingly, after 4 months, it was observed that bone marrow HSCs of mice treated in utero with targeted LNPs remained transfected at a higher efficiency than mice treated in utero with untargeted LNPs. When the peripheral blood of these cohorts of mice were examined, it was found that hematopoietic lineage cells were transfected at the same proportion as their HSC progenitors. Importantly, targeted LNPs neither induced a significant acute cytokine response nor transaminitis, and fetal mice treated with targeted LNPs had a similar rate of survival to birth as PBS- and untargeted LNP-treated mice. To further validate that targeted LNPs durably transfect HSCs, a secondary transplant study was conducted. Indeed, lethally-irradiated wild-type mice were rescued by bone marrow transplant from donor mice treated in utero with targeted LNPs, and transfection of - 9 - 53762388.1 Attorney Docket No.046483-7452WO1(03831) HSCs and hematopoietic lineage cells matched donor whole bone marrow transfection levels. Together, these data support that targeted LNPs are safe for fetal administration and robustly transfect self-renewing and multipotent HSCs. CRISPR-based gene editing strategies have the potential to revolutionize the treatment of congenital blood diseases, as exemplified by recent approval of CasgevyTMand LyfgeniaTMfor the treatment of hemoglobinopathies. Fully realizing the potential of in vivo HSC gene therapies requires the co-delivery of large genome editors (5-6 kb). Prior work has aimed to reduce the size of genome editors, split editing cargos across vectors, or deliver them in unoptimized nanocarriers. Here, by using high-throughput DOE to investigate a large (4x4x4x4) design space of LNP formulations, a set of LNP formulation parameters optimized for the co-delivery of Cas9 mRNA and sgRNA was identified. The resultant B5 formulation resulted in 2.5-fold improved knockout in hematopoietic lineage cells in vitro and 3-fold greater indels at the proof-of-concept TTR locus in the fetal liver in vivo. Combining the optimized LNP formulation with the CD45 targeting strategy resulted in STEM LNPs, a platform engineered specifically for gene editing fetal HSCs. Upon in utero IV administration, STEM LNPs facilitated equivalent gene editing in the fetal liver and 3.5-fold greater indels at the TTR locus in fetal HSCs in comparison to untargeted controls. More broadly, substitution of the editing cargo within STEM LNPs for disease-specific sgRNAs could produce in vivo therapeutic strategies for a range of disorders, including hemoglobinopathies, immunodeficiencies, multiple sclerosis, and lysosomal storage diseases. This disclosure provides the first non-viral nucleic acid platform targeting HSCs in utero. This platform can be leveraged with novel gene editing strategies to engineer curative, nontoxic, and accessible in vivo gene therapies for congenital blood disease. Definitions The term "about" as used herein can allow for a degree of variability in a value or range, for example, within 10%, within 5%, or within 1% of a stated value or of a stated limit of a range, and includes the exact stated value or range. The term “alkenyl” as used herein refers to straight and branched chain and cyclic alkyl groups as defined herein, except that at least one double bond exists between two carbon atoms. Thus, alkenyl groups have from 2 to 40 carbon atoms, or 2 to about 20 carbon atoms, or 2 to 12 carbon atoms or, in some embodiments, from 2 to 8 carbon atoms. Examples include, but are not limited to vinyl, -CH=C=CCH2, -CH=CH(CH3), - CH=C(CH3)2, -C(CH3)=CH2, -C(CH3)=CH(CH3), -C(CH2CH3)=CH2, cyclohexenyl, - 10 - 53762388.1 Attorney Docket No.046483-7452WO1(03831) cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, and hexadienyl among others. The term “alkoxy” as used herein refers to an oxygen atom connected to an alkyl group, including a cycloalkyl group, as are defined herein. Examples of linear alkoxy groups include but are not limited to methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, and the like. Examples of branched alkoxy include but are not limited to isopropoxy, sec-butoxy, tert-butoxy, isopentyloxy, isohexyloxy, and the like. Examples of cyclic alkoxy include but are not limited to cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like. An alkoxy group can include about 1 to about 12, about 1 to about 20, or about 1 to about 40 carbon atoms bonded to the oxygen atom, and can further include double or triple bonds, and can also include heteroatoms. For example, an allyloxy group or a methoxyethoxy group is also an alkoxy group within the meaning herein, as is a methylenedioxy group in a context where two adjacent atoms of a structure are substituted therewith. The term “alkyl” as used herein refers to straight chain and branched alkyl groups and cycloalkyl groups having from 1 to 40 carbon atoms, 1 to about 20 carbon atoms, 1 to 12 carbons or, in some embodiments, from 1 to 8 carbon atoms. Examples of straight chain alkyl groups include those with from 1 to 8 carbon atoms such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl groups. Examples of branched alkyl groups include, but are not limited to, isopropyl, iso-butyl, sec-butyl, t-butyl, neopentyl, isopentyl, and 2,2- dimethylpropyl groups. As used herein, the term “alkyl” encompasses n-alkyl, isoalkyl, and anteisoalkyl groups as well as other branched chain forms of alkyl. Representative substituted alkyl groups can be substituted one or more times with any of the groups listed herein, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups. The term “alkynyl” as used herein refers to straight and branched chain alkyl groups, except that at least one triple bond exists between two carbon atoms. Thus, alkynyl groups have from 2 to 40 carbon atoms, 2 to about 20 carbon atoms, or from 2 to 12 carbons or, in some embodiments, from 2 to 8 carbon atoms. Examples include, but are not limited to – C^CH, -C^C(CH3), -C^C(CH2CH3), -CH2C^CH, -CH2C^C(CH3), and -CH2C^C(CH2CH3) among others. The term “alkylene” or “alkylenyl” as used herein refers to a bivalent saturated aliphatic radical (e.g., -CH2-, -CH2CH2-, and -CH2CH2CH2-, inter alia). In certain embodiments, the term may be regarded as a moiety derived from an alkene by opening of the double bond or from an alkane by removal of two hydrogen atoms from the same (e.g., - CH2-) different (e.g., -CH2CH2-) carbon atoms. Similarly, the terms “heteroalkylenyl”, - 11 - 53762388.1 Attorney Docket No.046483-7452WO1(03831) “cycloalkylenyl”, “heterocycloalkylenyl”, and the like, as used herein, refer to a divalent radical of the moiety corresponding to the base group (e.g., heteroalkyl, cycloalkyl, and / or heterocycloalkyl). A divalent radical possesses two open valencies at any position(s) of the group, wherein each radical may be on a carbon atom or heteroatom. Thus, the divalent radical may form a single bond to two distinct atoms or groups, or may form a double bond with one atom. The term “anionic lipid” refers to any lipid that is negatively charged at physiological pH. These lipids include phosphatidylglycerol, cardiolipin, diacylphosphatidylserine, diacylphosphatidic acid, N-dodecanoylphosphatidylethanolamines, N- succinylphosphatidylethanolamines, N-glutarylphosphatidylethanolamines, lysylphosphatidylglycerols, palmitoyloleyolphosphatidylglycerol (POPG), and other anionic modifying groups joined to neutral lipids. The term “antibody,” as used herein, refers to an immunoglobulin molecule, which specifically binds with an antigen. Antibodies can be intact immunoglobulins derived from natural sources or from recombinant sources and can be immunoreactive portions of intact immunoglobulins. Antibodies are typically tetramers of immunoglobulin molecules. The antibodies in the present invention may exist in a variety of forms including, for example, polyclonal antibodies, monoclonal antibodies, Fv, Fab and F(ab)2, as well as single chain antibodies and humanized antibodies (Harlow et al., 1999, In: Using Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press, NY; Harlow et al., 1989, In: Antibodies: A Laboratory Manual, Cold Spring Harbor, New York; Houston et al., 1988, Proc. Natl. Acad. Sci. USA 85:5879-5883; Bird et al., 1988, Science 242:423-426). The term “antibody fragment” refers to a portion of an intact antibody and refers to the antigenic determining variable regions of an intact antibody. Examples of antibody fragments include, but are not limited to, Fab, Fab’, F(ab’)2, and Fv fragments, linear antibodies, scFv antibodies, and multispecific antibodies formed from antibody fragments. An “antibody heavy chain,” as used herein, refers to the larger of the two types of polypeptide chains present in all antibody molecules in their naturally occurring conformations. An “antibody light chain,” as used herein, refers to the smaller of the two types of polypeptide chains present in all antibody molecules in their naturally occurring conformations. ^ and ^ light chains refer to the two major antibody light chain isotypes. By the term “synthetic antibody” as used herein, is meant an antibody, which is - 12 - 53762388.1 Attorney Docket No.046483-7452WO1(03831) generated using recombinant DNA technology, such as, for example, an antibody expressed by a bacteriophage. The term should also be construed to mean an antibody which has been generated by the synthesis of a DNA molecule encoding the antibody and which DNA molecule expresses an antibody protein, or an amino acid sequence specifying the antibody, wherein the DNA or amino acid sequence has been obtained using synthetic DNA or amino acid sequence technology which is available and well known in the art. The term should also be construed to mean an antibody, which has been generated by the synthesis of an RNA molecule encoding the antibody. The RNA molecule expresses an antibody protein, or an amino acid sequence specifying the antibody, wherein the RNA has been obtained by transcribing DNA (synthetic or cloned) or other technology, which is available and well known in the art. The term “antigen” or “Ag” as used herein is defined as a molecule that provokes an adaptive immune response. This immune response may involve either antibody production, or the activation of specific immunogenically-competent cells, or both. The skilled artisan will understand that any macromolecule, including virtually all proteins or peptides, can serve as an antigen. Furthermore, antigens can be derived from recombinant or genomic DNA or RNA. A skilled artisan will understand that any DNA or RNA, which comprises a nucleotide sequences or a partial nucleotide sequence encoding a protein that elicits an adaptive immune response therefore encodes an “antigen” as that term is used herein. Furthermore, one skilled in the art will understand that an antigen need not be encoded solely by a full length nucleotide sequence of a gene. It is readily apparent that the present invention includes, but is not limited to, the use of partial nucleotide sequences of more than one gene and that these nucleotide sequences are arranged in various combinations to elicit the desired immune response. Moreover, a skilled artisan will understand that an antigen need not be encoded by a “gene” at all. It is readily apparent that an antigen can be generated synthesized or can be derived from a biological sample. Such a biological sample can include, but is not limited to a tissue sample, a tumor sample, a cell or a biological fluid. The term “amine” as used herein refers to primary, secondary, and tertiary amines having, e.g., the formula N(group)3wherein each group can independently be H or non-H, such as alkyl, aryl, and the like. Amines include but are not limited to R-NH2, for example, alkylamines, arylamines, alkylarylamines; R2NH wherein each R is independently selected, such as dialkylamines, diarylamines, aralkylamines, heterocyclylamines and the like; and R3N wherein each R is independently selected, such as trialkylamines, dialkylarylamines, alkyldiarylamines, triarylamines, and the like. The term “amine” also includes ammonium - 13 - 53762388.1 Attorney Docket No.046483-7452WO1(03831) ions as used herein. The term “amino group” as used herein refers to a substituent of the form -NH2, - NHR, -NR2, -NR3+, wherein each R is independently selected, and protonated forms of each, except for -NR3+, which cannot be protonated. Accordingly, any compound substituted with an amino group can be viewed as an amine. An “amino group” within the meaning herein can be a primary, secondary, tertiary, or quaternary amino group. An “alkylamino” group includes a monoalkylamino, dialkylamino, and trialkylamino group. The term “anionic lipid” refers to any lipid that is negatively charged at physiological pH. These lipids include phosphatidylglycerol, cardiolipin, diacylphosphatidylserine, diacylphosphatidic acid, N-dodecanoylphosphatidylethanolamines, N- succinylphosphatidylethanolamines, N-glutarylphosphatidylethanolamines, lysylphosphatidylglycerols, palmitoyloleyolphosphatidylglycerol (POPG), and other anionic modifying groups joined to neutral lipids. The term “aryl” as used herein refers to cyclic aromatic hydrocarbon groups that do not contain heteroatoms in the ring. Thus aryl groups include, but are not limited to, phenyl, azulenyl, heptalenyl, biphenyl, indacenyl, fluorenyl, phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, biphenylenyl, anthracenyl, and naphthyl groups. In some embodiments, aryl groups contain about 6 to about 14 carbons in the ring portions of the groups. Aryl groups can be unsubstituted or substituted, as defined herein. Representative substituted aryl groups can be mono-substituted or substituted more than once, such as, but not limited to, a phenyl group substituted at any one or more of 2-, 3-, 4-, 5-, or 6-positions of the phenyl ring, or a naphthyl group substituted at any one or more of 2- to 8-positions thereof. The term “monovalent cation” as used herein refers to any positively charged (+1) organic or inorganic ion. Non-limiting examples include H+, NH4+, Li+, Na+, K+, Cu+, Ag+, Cs+, and Au+. The term “cationic lipid” refers to any of a number of lipid species that carry a net positive charge at a selected pH, such as physiological pH (e.g., pH of about 7.0). It has been found that cationic lipids comprising alkyl chains with multiple sites of unsaturation, e.g., at least two or three sites of unsaturation, are particularly useful for forming lipid particles with increased membrane fluidity. A number of cationic lipids and related analogs, which are also useful in the present disclosure, have been described in U.S. Patent Publication Nos. 20060083780 and 20060240554; U.S. Pat. Nos.5,208,036; 5,264,618; 5,279,833; 5,283,185; 5,753,613; and 5,785,992; and PCT Publication No. WO 96 / 10390, the disclosures of which - 14 - 53762388.1 Attorney Docket No.046483-7452WO1(03831) are herein incorporated by reference in their entirety for all purposes. Non-limiting examples of cationic lipids are described in detail herein. In some cases, the cationic lipids comprise a protonatable tertiary amine (e.g., pH titratable) head group, C18 alkyl chains, ether linkages between the head group and alkyl chains, and 0 to 3 double bonds. Such lipids include, e.g., DSDMA, DLinDMA, DLenDMA, and DODMA. The term “conjugated lipid” as used herein refers to a lipid which is conjugated to one or more polymeric groups, which inhibits aggregation of lipid particles. Such lipid conjugates include, but are not limited to, polyamide oligomers (e.g., ATTA-lipid conjugates), PEG-lipid conjugates, such as PEG coupled to dialkyloxypropyls, PEG coupled to diacylglycerols, PEG coupled to cholesterol, PEG coupled to phosphatidylethanolamines, PEG conjugated to ceramides (e.g., U.S. Pat. No.5,885,613, the disclosure of which is herein incorporated by reference in its entirety for all purposes), cationic PEG lipids, and mixtures thereof. PEG can be conjugated directly to the lipid or may be linked to the lipid via a linker moiety. Any linker moiety suitable for coupling the PEG to a lipid can be used including, e.g., non-ester containing linker moieties and ester-containing linker moieties. In preferred embodiments, non-ester containing linker moieties are used. The term “cycloalkyl” as used herein refers to cyclic alkyl groups such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In some embodiments, the cycloalkyl group can have 3 to about 8-12 ring members, whereas in other embodiments the number of ring carbon atoms range from 3 to 4, 5, 6, or 7. Cycloalkyl groups further include polycyclic cycloalkyl groups such as, but not limited to, norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl, and carenyl groups, and fused rings such as, but not limited to, decalinyl, and the like. Cycloalkyl groups also include rings that are substituted with straight or branched chain alkyl groups as defined herein. Representative substituted cycloalkyl groups can be mono-substituted or substituted more than once, such as, but not limited to, 2,2-, 2,3-, 2,4- 2,5- or 2,6-disubstituted cyclohexyl groups or mono-, di- or tri-substituted norbornyl or cycloheptyl groups, which can be substituted with, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups. The term “cycloalkenyl” alone or in combination denotes a cyclic alkenyl group. A “disease” is a state of health of an animal wherein the animal cannot maintain homeostasis, and wherein if the disease is not ameliorated then the animal’s health continues to deteriorate. In contrast, a “disorder” in an animal is a state of health in which the animal is able to maintain homeostasis, but in which the animal’s state of health is less favorable than it would - 15 - 53762388.1 Attorney Docket No.046483-7452WO1(03831) be in the absence of the disorder. Left untreated, a disorder does not necessarily cause a further decrease in the animal’s state of health. A disease or disorder is “alleviated” if the severity of a symptom of the disease or disorder, the frequency with which such a symptom is experienced by a patient, or both, is reduced. As used herein, the terms “effective amount,” “pharmaceutically effective amount” and “therapeutically effective amount” refer to a nontoxic but sufficient amount of an agent to provide the desired biological result. That result may be reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. An appropriate therapeutic amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation. In particular, in the case of a mRNA, and “effective amount” or “therapeutically effective amount” of a therapeutic nucleic acid as relating to a mRNA is an amount sufficient to produce the desired effect, e.g., mRNA-directed expression of an amount of a protein that causes a desirable biological effect in the organism within which the protein is expressed. For example, in some embodiments, the expressed protein is an active form of a protein that is normally expressed in a cell type within the body, and the therapeutically effective amount of the mRNA is an amount that produces an amount of the encoded protein that is at least 50% (e.g., at least 60%, or at least 70%, or at least 80%, or at least 90%) of the amount of the protein that is normally expressed in the cell type of a healthy individual. For example, in some embodiments, the expressed protein is a protein that is normally expressed in a cell type within the body, and the therapeutically effective amount of the mRNA is an amount that produces a similar level of expression as observed in a healthy individual in an individual with aberrant expression of the protein (i.e., protein deficient individual). Suitable assays for measuring the expression of an mRNA or protein include, but are not limited to dot blots, Northern blots, in situ hybridization, ELISA, immunoprecipitation, enzyme function, as well as phenotypic assays known to those of skill in the art. The term “encode” as used herein refers to the product specified (e.g., protein and RNA) by a given sequence of nucleotides in a nucleic acid (i.e., DNA and / or RNA), upon transcription or translation of the DNA or RNA, respectively. In certain embodiments, the term “encode” refers to the RNA sequence specified by transcription of a DNA sequence. In certain embodiments, the term “encode” refers to the amino acid sequence (e.g., polypeptide or protein) specified by translation of mRNA. In certain embodiments, the term “encode” refers to the amino acid sequence specified by transcription of DNA to mRNA and - 16 - 53762388.1 Attorney Docket No.046483-7452WO1(03831) subsequent translation of the mRNA encoded by the DNA sequence. In certain embodiments, the encoded product may comprise a direct transcription or translation product. In certain embodiments, the encoded product may comprise post-translational modifications understood or reasonably expected by one skilled in the art. The term “fully encapsulated” indicates that the active agent or therapeutic agent in the lipid particle is not significantly degraded after exposure to serum or a nuclease or protease assay that would significantly degrade free DNA, RNA, or protein. In a fully encapsulated system, preferably less than about 25% of the active agent or therapeutic agent in the particle is degraded in a treatment that would normally degrade 100% of free active agent or therapeutic agent, more preferably less than about 10%, and most preferably less than about 5% of the active agent or therapeutic agent in the particle is degraded. In the context of nucleic acid therapeutic agents, full encapsulation may be determined by an OLIGREEN® assay. OLIGREEN® is an ultra-sensitive fluorescent nucleic acid stain for quantitating oligonucleotides and single-stranded DNA or RNA in solution (available from Invitrogen Corporation; Carlsbad, Calif.). “Fully encapsulated” also indicates that the lipid particles are serum stable, that is, that they do not rapidly decompose into their component parts upon in vivo administration. The terms “halo,” “halogen,” or “halide” group, as used herein, by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. The term “haloalkyl” group, as used herein, includes mono-halo alkyl groups, poly- halo alkyl groups wherein all halo atoms can be the same or different, and per-halo alkyl groups, wherein all hydrogen atoms are replaced by halogen atoms, such as fluoro. Examples of haloalkyl include trifluoromethyl, 1,1-dichloroethyl, 1,2-dichloroethyl, 1,3-dibromo-3,3- difluoropropyl, perfluorobutyl, and the like. The term “helper lipid” as used herein refers to a lipid capable of increasing the effectiveness of delivery of lipid-based particles such as cationic lipid-based particles to a target, preferably into a cell. The helper lipid can be neutral, positively charged, or negatively charged. In certain embodiments, the helper lipid is neutral or negatively charged. Non- limiting examples of helper lipids include 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 1,2-di-(9Z-octadecenoyl)-sn-glycero-3-phosphoethanolamine (DOPE), 1-palmitoyl- 2-oleoyl-sn-glycero-3phosphocholin (POPC) and 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC). The term “heteroalkyl” as used herein by itself or in combination with another term, - 17 - 53762388.1 Attorney Docket No.046483-7452WO1(03831) means, unless otherwise stated, a non-cyclic stable straight or branched chain, or combinations thereof, including at least one carbon atom and at least one heteroatom selected from the group consisting of O, N, P, Si, and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. The heteroatom(s) (e.g., O, N, P, and S) may be placed at any interior position of the heteroalkyl group or at either terminal position at which the group is attached to the remainder of the molecule. The term “heteroaryl” as used herein refers to aromatic ring compounds containing 5 or more ring members, of which, one or more is a heteroatom such as, but not limited to, N, O, and S; for instance, heteroaryl rings can have 5 to about 8-12 ring members. A heteroaryl group is a variety of a heterocyclyl group that possesses an aromatic electronic structure. A heteroaryl group designated as a C2-heteroaryl can be a 5-ring with two carbon atoms and three heteroatoms, a 6-ring with two carbon atoms and four heteroatoms and so forth. Likewise a C4-heteroaryl can be a 5-ring with one heteroatom, a 6-ring with two heteroatoms, and so forth. The number of carbon atoms plus the number of heteroatoms sums up to equal the total number of ring atoms. Heteroaryl groups include, but are not limited to, groups such as pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups. Heteroaryl groups can be unsubstituted, or can be substituted with groups as is discussed herein. Representative substituted heteroaryl groups can be substituted one or more times with groups such as those listed herein. Additional examples of aryl and heteroaryl groups include but are not limited to phenyl, biphenyl, indenyl, naphthyl (1-naphthyl, 2-naphthyl), N-hydroxytetrazolyl, N- hydroxytriazolyl, N-hydroxyimidazolyl, anthracenyl (1-anthracenyl, 2-anthracenyl, 3- anthracenyl), thiophenyl (2-thienyl, 3-thienyl), furyl (2-furyl, 3-furyl) , indolyl, oxadiazolyl, isoxazolyl, quinazolinyl, fluorenyl, xanthenyl, isoindanyl, benzhydryl, acridinyl, thiazolyl, pyrrolyl (2-pyrrolyl), pyrazolyl (3-pyrazolyl), imidazolyl (1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), triazolyl (1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl 1,2,3-triazol-4-yl, 1,2,4-triazol-3-yl), oxazolyl (2-oxazolyl, 4-oxazolyl, 5-oxazolyl), thiazolyl (2-thiazolyl, 4- thiazolyl, 5-thiazolyl), pyridyl (2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl), pyrazinyl, pyridazinyl (3- pyridazinyl, 4- - 18 - 53762388.1 Attorney Docket No.046483-7452WO1(03831) pyridazinyl, 5-pyridazinyl), quinolyl (2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6- quinolyl, 7-quinolyl, 8-quinolyl), isoquinolyl (1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5- isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl), benzo[b]furanyl (2-benzo[b]furanyl, 3-benzo[b]furanyl, 4-benzo[b]furanyl, 5-benzo[b]furanyl, 6-benzo[b]furanyl, 7- benzo[b]furanyl), 2,3-dihydro-benzo[b]furanyl (2-(2,3-dihydro-benzo[b]furanyl), 3-(2,3- dihydro-benzo[b]furanyl), 4-(2,3-dihydro-benzo[b]furanyl), 5-(2,3-dihydro-benzo[b]furanyl), 6-(2,3-dihydro-benzo[b]furanyl), 7-(2,3-dihydro-benzo[b]furanyl), benzo[b]thiophenyl (2- benzo[b]thiophenyl, 3-benzo[b]thiophenyl, 4-benzo[b]thiophenyl, 5-benzo[b]thiophenyl, 6- benzo[b]thiophenyl, 7-benzo[b]thiophenyl), 2,3-dihydro-benzo[b]thiophenyl, (2-(2,3- dihydro-benzo[b]thiophenyl), 3-(2,3-dihydro-benzo[b]thiophenyl), 4-(2,3-dihydro- benzo[b]thiophenyl), 5-(2,3-dihydro-benzo[b]thiophenyl), 6-(2,3-dihydro- benzo[b]thiophenyl), 7-(2,3-dihydro-benzo[b]thiophenyl), indolyl (1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl), indazole (1-indazolyl, 3-indazolyl, 4-indazolyl, 5-indazolyl, 6-indazolyl, 7-indazolyl), benzimidazolyl (1-benzimidazolyl, 2-benzimidazolyl, 4-benzimidazolyl, 5-benzimidazolyl, 6-benzimidazolyl, 7-benzimidazolyl, 8-benzimidazolyl), benzoxazolyl (1-benzoxazolyl, 2-benzoxazolyl), benzothiazolyl (1- benzothiazolyl, 2-benzothiazolyl, 4-benzothiazolyl, 5-benzothiazolyl, 6-benzothiazolyl, 7-benzothiazolyl), carbazolyl (1-carbazolyl, 2-carbazolyl, 3-carbazolyl, 4-carbazolyl), 5H-dibenz[b,f]azepine (5H-dibenz[b,f]azepin-1-yl, 5H-dibenz[b,f]azepine-2-yl, 5H-dibenz[b,f]azepine-3-yl, 5H-dibenz[b,f]azepine-4-yl, 5H-dibenz[b,f]azepine-5-yl), 10,11-dihydro-5H-dibenz[b,f]azepine (10,11-dihydro-5H-dibenz[b,f]azepine-1-yl, 10,11-dihydro-5H-dibenz[b,f]azepine-2-yl, 10,11-dihydro-5H-dibenz[b,f]azepine-3-yl, 10,11-dihydro-5H-dibenz[b,f]azepine-4-yl, 10,11-dihydro-5H-dibenz[b,f]azepine-5-yl), and the like. The term “heterocycloalkyl” as used herein refers to an aliphatic, partially unsaturated or fully saturated, 3- to 14-membered ring system, including single rings of 3 to 8 atoms and bi- and tricyclic ring systems where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. A heterocycloalkyl can include one to four heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein a nitrogen and sulfur heteroatom optionally can be oxidized and a nitrogen heteroatom optionally can be substituted. Representative heterocycloalkyl groups include, but are not limited, to the following exemplary groups: pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl. - 19 - 53762388.1 Attorney Docket No.046483-7452WO1(03831) The term “heterocyclyl” as used herein refers to aromatic and non-aromatic ring compounds containing three or more ring members, of which one or more is a heteroatom such as, but not limited to, N, O, and S. Thus, a heterocyclyl can be a cycloheteroalkyl, or a heteroaryl, or if polycyclic, any combination thereof. In some embodiments, heterocyclyl groups include 3 to about 20 ring members, whereas other such groups have 3 to about 15 ring members. A heterocyclyl group designated as a C2-heterocyclyl can be a 5-ring with two carbon atoms and three heteroatoms, a 6-ring with two carbon atoms and four heteroatoms and so forth. Likewise a C4-heterocyclyl can be a 5-ring with one heteroatom, a 6-ring with two heteroatoms, and so forth. The number of carbon atoms plus the number of heteroatoms equals the total number of ring atoms. A heterocyclyl ring can also include one or more double bonds. A heteroaryl ring is an embodiment of a heterocyclyl group. The phrase “heterocyclyl group” includes fused ring species including those that include fused aromatic and non-aromatic groups. For example, a dioxolanyl ring and a benzdioxolanyl ring system (methylenedioxyphenyl ring system) are both heterocyclyl groups within the meaning herein. The phrase also includes polycyclic ring systems containing a heteroatom such as, but not limited to, quinuclidyl. Heterocyclyl groups can be unsubstituted, or can be substituted as discussed herein. Heterocyclyl groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, dihydrobenzofuranyl, indolyl, dihydroindolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups. Representative substituted heterocyclyl groups can be mono-substituted or substituted more than once, such as, but not limited to, piperidinyl or quinolinyl groups, which are 2-, 3-, 4-, 5-, or 6- substituted, or disubstituted with groups such as those listed herein. The term “hydrocarbon” or “hydrocarbyl” as used herein refers to a molecule or functional group that includes carbon and hydrogen atoms. The term can also refer to a molecule or functional group that normally includes both carbon and hydrogen atoms but wherein all the hydrogen atoms are substituted with other functional groups. The term “ionizable lipid” as used herein refers to a lipid (e.g., a cationic lipid) having at least one protonatable or deprotonatable group, such that the lipid is positively charged at a pH at or below physiological pH (e.g., pH 7.4), and neutral at a second pH, preferably at or above physiological pH. It will be understood by one of ordinary skill in the art that the - 20 - 53762388.1 Attorney Docket No.046483-7452WO1(03831) addition or removal of protons as a function of pH is an equilibrium process, and that the reference to a charged or neutral lipid refers to the nature of the predominant species and does not require that all of the lipid be present in the charged or neutral form. Generally, ionizable lipids have a pKaof the protonatable group in the range of about 4 to about 7. As used herein, the term “hydrocarbyl” refers to a functional group derived from a straight chain, branched, or cyclic hydrocarbon, and can be alkyl, alkenyl, alkynyl, aryl, cycloalkyl, acyl, or any combination thereof. Hydrocarbyl groups can be shown as (Ca- Cb)hydrocarbyl, wherein a and b are integers and mean having any of a to b number of carbon atoms. For example, (C1-C4)hydrocarbyl means the hydrocarbyl group can be methyl (C1), ethyl (C2), propyl (C3), or butyl (C4), and (C0-Cb)hydrocarbyl means in certain embodiments there is no hydrocarbyl group. The term “immune cell,” as used herein refers to any cell involved in the mounting of an immune response. Such cells include, but are not limited to, T cells, B cells, NK cells, antigen-presenting cells (e.g., dendritic cells and macrophages), monocytes, neutrophils, eosinophils, basophils, and the like. The term “independently selected from” as used herein refers to referenced groups being the same, different, or a mixture thereof, unless the context clearly indicates otherwise. Thus, under this definition, the phrase “X1, X2, and X3are independently selected from noble gases” would include the scenario where, for example, X1, X2, and X3are all the same, where X1, X2, and X3are all different, where X1and X2are the same but X3is different, and other analogous permutations. The term “ionizable lipid” as used herein refers to a lipid (e.g., a cationic lipid) having at least one protonatable or deprotonatable group, such that the lipid is positively charged at a pH at or below physiological pH (e.g., pH 7.4), and neutral at a second pH, preferably at or above physiological pH. It will be understood by one of ordinary skill in the art that the addition or removal of protons as a function of pH is an equilibrium process, and that the reference to a charged or neutral lipid refers to the nature of the predominant species and does not require that all of the lipid be present in the charged or neutral form. Generally, ionizable lipids have a pKaof the protonatable group in the range of about 4 to about 7. The term “local delivery,” as used herein, refers to delivery of an active agent or therapeutic agent such as a messenger RNA directly to a target site within an organism. For example, an agent can be locally delivered by direct injection into a disease site such as a tumor or other target site such as a site of inflammation or a target organ such as the liver, heart, pancreas, kidney, and the like. - 21 - 53762388.1 Attorney Docket No.046483-7452WO1(03831) The term “lipid” refers to a group of organic compounds that include, but are not limited to, esters of fatty acids and are characterized by being insoluble in water, but soluble in many organic solvents. They are usually divided into at least three classes: (1) “simple lipids,” which include fats and oils as well as waxes; (2) “compound lipids,” which include phospholipids and glycolipids; and (3) “derived lipids” such as steroids. The term “conjugated lipid” as used herein refers to a lipid which is conjugated to one or more polymeric groups, which inhibits aggregation of lipid particles. Such lipid conjugates include, but are not limited to, polyamide oligomers (e.g., ATTA-lipid conjugates), PEG-lipid conjugates, such as PEG coupled to dialkyloxypropyls, PEG coupled to diacylglycerols, PEG coupled to cholesterol, PEG coupled to phosphatidylethanolamines, PEG conjugated to ceramides (e.g., U.S. Pat. No.5,885,613, the disclosure of which is herein incorporated by reference in its entirety for all purposes), cationic PEG lipids, and mixtures thereof. PEG can be conjugated directly to the lipid or may be linked to the lipid via a linker moiety. Any linker moiety suitable for coupling the PEG to a lipid can be used including, e.g., non-ester containing linker moieties and ester-containing linker moieties. In preferred embodiments, non-ester containing linker moieties are used. As used herein, “lipid encapsulated” can refer to a lipid particle that provides an active agent or therapeutic agent, such as a nucleic acid (e.g., a protein cargo), with full encapsulation, partial encapsulation, or both. In a preferred embodiment, the nucleic acid is fully encapsulated in the lipid particle (e.g., to form an SPLP, pSPLP, SNALP, or other nucleic acid-lipid particle). The term “lipid nanoparticle” refers to a particle having at least one dimension on the order of nanometers (e.g., 1-1,000 nm) which includes one or more lipids and / or additional agents. The term “lipid particle” is used herein to refer to a lipid formulation that can be used to deliver an active agent or therapeutic agent, such as a nucleic acid (e.g., mRNA), to a target site of interest. In the lipid particle of the disclosure, which is typically formed from a cationic lipid, a non-cationic lipid, and a conjugated lipid that prevents aggregation of the particle, the active agent or therapeutic agent may be encapsulated in the lipid, thereby protecting the agent from enzymatic degradation. The term “monovalent” as used herein refers to a substituent connecting via a single bond to a substituted molecule. When a substituent is monovalent, such as, for example, F or Cl, it is bonded to the atom it is substituting by a single bond. The term “mRNA” or “messenger RNA” as used herein refers to a ribonucleic acid - 22 - 53762388.1 Attorney Docket No.046483-7452WO1(03831) sequences which encodes a peptide or protein. In certain embodiments, the mRNA may comprise a “transcript” that is produced by using a DNA template and encodes a peptide or protein. Typically, mRNA comprises 5’-UTR, protein coding region and 3’-UTR. mRNA can be produced by in vitro transcription from a DNA template. Methods of in vitro transcription are known to those of skill in the art. For example, various in vitro transfer kits are commercially available. According to the present invention, mRNA can be modified by further stabilizing modifications and cap formation in addition to the modifications according to the invention. The term “neutral lipid” refers to any of a number of lipid species that exist either in an uncharged or neutral zwitterionic form at a selected pH. At physiological pH, such lipids include, for example, diacylphosphatidylcholine, diacylphosphatidylethanolamine, ceramide, sphingomyelin, cephalin, cholesterol, cerebrosides, and diacylglycerols. The term “non-cationic lipid” refers to any amphipathic lipid as well as any other neutral lipid or anionic lipid. The term “nucleic acid” as used herein refers to a polymer containing at least two deoxyribonucleotides or ribonucleotides in either single- or double-stranded form and includes DNA and RNA. DNA may be in the form of, e.g., antisense molecules, plasmid DNA, pre-condensed DNA, a PCR product, vectors (Pl, PAC, BAC, YAC, artificial chromosomes), expression cassettes, chimeric sequences, chromosomal DNA, or derivatives and combinations of these groups. RNA may be in the form of siRNA, asymmetrical interfering RNA (aiRNA), microRNA (miRNA), mRNA, tRNA, rRNA, tRNA, viral RNA (vRNA), and combinations thereof. Nucleic acids include nucleic acids containing known nucleotide analogs or modified backbone residues or linkages, which are synthetic, naturally occurring, and non-naturally occurring, and which have similar binding properties as the reference nucleic acid. Examples of such analogs include, without limitation, phosphorothioates, phosphoramidates, methyl phosphonates, chiral-methyl phosphonates, 2’- O-methyl ribonucleotides, and peptide-nucleic acids (PNAs). Unless specifically limited, the term encompasses nucleic acids containing known analogues of natural nucleotides that have similar binding properties as the reference nucleic acid. Unless otherwise indicated, a particular nucleic acid sequence also implicitly encompasses conservatively modified variants thereof (e.g., degenerate codon substitutions), alleles, orthologs, SNPs, and complementary sequences as well as the sequence explicitly indicated. Specifically, degenerate codon substitutions may be achieved by generating sequences in which the third position of one or more selected (or all) codons is substituted with mixed-base and / or - 23 - 53762388.1 Attorney Docket No.046483-7452WO1(03831) deoxyinosine residues (Batzer et al., Nucleic Acid Res., 19:5081 (1991); Ohtsuka et al., J. Biol. Chem., 260:2605-2608 (1985); Rossolini et al., Mal. Cell. Probes, 8:91-98 (1994)). As used herein, the term “nucleic acid” includes any oligonucleotide or polynucleotide, with fragments containing up to 60 nucleotides generally termed oligonucleotides, and longer fragments termed polynucleotides. In particular embodiments, oligonucleotides of the disclosure are from about 15 to about 60 nucleotides in length. Nucleic acid may be administered alone in the lipid particles of the disclosure, or in combination (e.g., co-administered) with lipid particles of the disclosure comprising peptides, polypeptides, or small molecules such as conventional drugs. In other embodiments, the nucleic acid may be administered in a viral vector. “Nucleotides” contain a sugar deoxyribose (DNA) or ribose (RNA), a base, and a phosphate group. Nucleotides are linked together through the phosphate groups. “Bases” include purines and pyrimidines, which further include natural compounds adenine, thymine, guanine, cytosine, uracil, inosine, and natural analogs, and synthetic derivatives of purines and pyrimidines, which include, but are not limited to, modifications which place new reactive groups such as, but not limited to, amines, alcohols, thiols, carboxylates, and alkyl halides. Unless otherwise indicated, a particular nucleic acid sequence also implicitly encompasses conservatively modified variants thereof (e.g., degenerate codon substitutions), alleles, orthologs, SNPs, and complementary sequences as well as the sequence explicitly indicated. Specifically, degenerate codon substitutions may be achieved by generating sequences in which the third position of one or more selected (or all) codons is substituted with mixed-base and / or deoxyinosine residues (Batzer et al., Nucleic Acid Res., 19:5081 (1991); Ohtsuka et al., J. Biol. Chem., 260:2605-2608 (1985); Rossolini et al., Mol. Cell. Probes, 8:91-98 (1994)). The terms “patient,” “subject,” or “individual” are used interchangeably herein, and refer to any animal, or cells thereof whether in vitro or in situ, amenable to the methods described herein. In a non-limiting embodiment, the patient, subject or individual is a human. As used herein, the term “pharmaceutically acceptable” refers to a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively non-toxic, i.e., the material may be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained. As used herein, the language “pharmaceutically acceptable salt” refers to a salt of the - 24 - 53762388.1 Attorney Docket No.046483-7452WO1(03831) administered compounds prepared from pharmaceutically acceptable non-toxic acids or bases, including inorganic acids or bases, organic acids or bases, solvates, hydrates, or clathrates thereof. As used herein, the terms “peptide,” “polypeptide,” and “protein” are used interchangeably, and refer to a compound comprised of amino acid residues covalently linked by peptide bonds. A protein or peptide must contain at least two amino acids, and no limitation is placed on the maximum number of amino acids that can comprise a protein’s or peptide’s sequence. Polypeptides include any peptide or protein comprising two or more amino acids joined to each other by peptide bonds. As used herein, the term refers to both short chains, which also commonly are referred to in the art as peptides, oligopeptides and oligomers, for example, and to longer chains, which generally are referred to in the art as proteins, of which there are many types. “Polypeptides” include, for example, biologically active fragments, substantially homologous polypeptides, oligopeptides, homodimers, heterodimers, variants of polypeptides, modified polypeptides, derivatives, analogs, fusion proteins, among others. The polypeptides include natural peptides, recombinant peptides, synthetic peptides, or a combination thereof. The term “siRNA” or “small interfering RNA” as used herein refers to a small (e.g. generally less than 30 nucleotides) non-coding RNA molecule which functions in transcriptional and post-transcriptional regulation of gene expression. Generally, a siRNA specifically targets 1 nucleic acid. In general, a siRNA comprises a double-stranded RNA molecule that ranges from about 15 to about 29 nucleotides in length. In some embodiments, the siRNA may be 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 or 29 nucleotides in length. In some embodiments, the siRNA may be less than 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 or 29 nucleotides in length. In some embodiments, the siRNA may be more than 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 or 29 nucleotides in length. A siRNA may optionally further comprise one or two single-stranded overhangs, e.g., a 5′ overhang on one or both ends, a 3′ overhang on one or both ends, or a combination thereof. The siRNA may be formed from two RNA molecules that hybridize together or, alternatively, may be generated from a short hairpin RNA (shRNA). In some embodiments, the two strands of the siRNA may be completely complementary, such that no mismatches or bulges exist in the duplex formed between the two sequences. In other embodiments, the two strands of the siRNA may be substantially complementary, such that one or more mismatches and / or bulges may exist in the duplex formed between the two sequences. In certain embodiments, one or both of the 5′ ends of the siRNA may have a phosphate group, while in other embodiments - 25 - 53762388.1 Attorney Docket No.046483-7452WO1(03831) one or both of the 5′ ends lack a phosphate group. In other embodiments, one or both of the 3′ ends of the siRNA may have a hydroxyl group, while in other embodiments one or both of the 5′ ends lack a hydroxyl group. Typically, siRNAs are targeted to exonic sequences of the target nucleic acid. One strand of the siRNA, which is referred to as the “antisense strand” or “guide strand,” includes a portion that hybridizes with a target nucleic acid. A target nucleic acid refers to a nucleic acid sequence expressed by a cell for which it is desired expression be disrupted. In the context of a therapeutic composition of the invention, disrupting expression of a target nucleic acid may produce a beneficial effect. Those of skill in the art are familiar with programs, algorithms, and / or commercial services that design siRNAs for target genes. For example, the Rosetta siRNA Design Algorithm (Rosetta Inpharmatics, North Seattle, Wash.), MISSION® siRNA (Sigma-Aldrich, St. Louis, Mo.) and siGENOME siRNA (Thermo Scientific) may be used. Suitable pharmaceutically acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid. Examples of inorganic acids include hydrochloric, hydrobromic, hydriodic, nitric, carbonic, sulfuric (including sulfate and hydrogen sulfate), and phosphoric acids (including hydrogen phosphate and dihydrogen phosphate). Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which include formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, malonic, saccharin, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, trifluoromethanesulfonic, 2- hydroxyethanesulfonic, p-toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, stearic, alginic, β-hydroxybutyric, salicylic, galactaric and galacturonic acid. Suitable pharmaceutically acceptable base addition salts of compounds described herein include, for example, ammonium salts, metallic salts including alkali metal, alkaline earth metal and transition metal salts such as, for example, calcium, magnesium, potassium, sodium and zinc salts. Pharmaceutically acceptable base addition salts also include organic salts made from basic amines such as, for example, N,N’-dibenzylethylene-diamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. All of these salts may be prepared from the corresponding compound by reacting, for example, the appropriate acid or base with the compound. As used herein, the term “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” means a pharmaceutically acceptable material, composition or carrier, - 26 - 53762388.1 Attorney Docket No.046483-7452WO1(03831) such as a liquid or solid filler, stabilizer, dispersing agent, suspending agent, diluent, excipient, thickening agent, solvent or encapsulating material, involved in carrying or transporting a compound described herein within or to the patient such that it may perform its intended function. Typically, such compounds are carried or transported from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation, including the compound(s) described herein, and not injurious to the patient. Some examples of materials that may serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; surface active agents; alginic acid; pyrogen-free water; isotonic saline; Ringer’s solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic compatible substances employed in pharmaceutical formulations. As used herein, “pharmaceutically acceptable carrier” also includes any and all coatings, antibacterial and antifungal agents, and absorption delaying agents, and the like that are compatible with the activity of the compound(s) described herein, and are physiologically acceptable to the patient. Supplementary active compounds may also be incorporated into the compositions. The “pharmaceutically acceptable carrier” may further include a pharmaceutically acceptable salt of the compound(s) described herein. Other additional ingredients that may be included in the pharmaceutical compositions used with the methods or compounds described herein are known in the art and described, for example in Remington’s Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, PA), which is incorporated herein by reference. The terms “peptide,” “polypeptide,” and “protein” are used interchangeably herein, and refer to a compound comprised of amino acid residues covalently linked by peptide bonds. A protein or peptide must contain at least two amino acids, and no limitation is placed on the maximum number of amino acids that can comprise a protein’s or peptide’s sequence. Polypeptides include any peptide or protein comprising two or more amino acids joined to each other by peptide bonds. As used herein, the term refers to both short chains, which also commonly are referred to in the art as peptides, oligopeptides and oligomers, for example, - 27 - 53762388.1 Attorney Docket No.046483-7452WO1(03831) and to longer chains, which generally are referred to in the art as proteins, of which there are many types. “Polypeptides” include, for example, biologically active fragments, substantially homologous polypeptides, oligopeptides, homodimers, heterodimers, variants of polypeptides, modified polypeptides, derivatives, analogs, fusion proteins, among others. The polypeptides include natural peptides, recombinant peptides, synthetic peptides, or a combination thereof. The term “polymer conjugated lipid” refers to a molecule comprising both a lipid portion and a polymer portion. An example of a polymer conjugated lipid is a pegylated lipid. The term “pegylated lipid” refers to a molecule comprising both a lipid portion and a polyethylene glycol portion. Pegylated lipids are known in the art and include 1-(monomethoxy-polyethyleneglycol)-2,3-dimyristoylglycerol (PEG-s- DMG), DSPE-PEG- DBCO, DOPE-PEG-Azide, DSPE-PEG-Azide, DPPE-PEG-Azide, DSPE-PEG-Carboxy- NHS, DOPE-PEG-Carboxylic Acid, DSPE-PEG-Carboxylic acid and the like. The term “room temperature” as used herein refers to a temperature of about 15 °C to 28 °C. The term “solvent” as used herein refers to a liquid that can dissolve a solid, liquid, or gas. Non-limiting examples of solvents are silicones, organic compounds, water, alcohols, ionic liquids, and supercritical fluids. By the term “specifically binds,” as used herein with respect to an antibody, is meant an antibody which recognizes a specific antigen, but does not substantially recognize or bind other molecules in a sample. For example, an antibody that specifically binds to an antigen from one species may also bind to that antigen from one or more other species. But, such cross-species reactivity does not itself alter the classification of an antibody as specific. In another example, an antibody that specifically binds to an antigen may also bind to different allelic forms of the antigen. However, such cross reactivity does not itself alter the classification of an antibody as specific. In some instances, the terms “specific binding” or “specifically binding,” can be used in reference to the interaction of an antibody, a protein, or a peptide with a second chemical species, to mean that the interaction is dependent upon the presence of a particular structure (e.g., an antigenic determinant or epitope) on the chemical species; for example, an antibody recognizes and binds to a specific protein structure rather than to proteins generally. If an antibody is specific for epitope “A”, the presence of a molecule containing epitope A (or free, unlabeled A), in a reaction containing labeled “A” and the antibody, will reduce the amount of labeled A bound to the antibody. The term “substantially” as used herein refers to a majority of, or mostly, as in at least - 28 - 53762388.1 Attorney Docket No.046483-7452WO1(03831) about 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, 99.99%, or at least about 99.999% or more, or 100%. The term “substantially free of” as used herein can mean having none or having a trivial amount of, such that the amount of material present does not affect the material properties of the composition including the material, such that the composition is about 0 wt% to about 5 wt% of the material, or about 0 wt% to about 1 wt%, or about 5 wt% or less, or less than, equal to, or greater than about 4.5 wt%, 4, 3.5, 3, 2.5, 2, 1.5, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.01, or about 0.001 wt% or less. The term “substantially free of” can mean having a trivial amount of, such that a composition is about 0 wt% to about 5 wt% of the material, or about 0 wt% to about 1 wt%, or about 5 wt% or less, or less than, equal to, or greater than about 4.5 wt%, 4, 3.5, 3, 2.5, 2, 1.5, 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1, 0.01, or about 0.001 wt% or less, or about 0 wt%. The term “substituted” as used herein in conjunction with a molecule or an organic group as defined herein refers to the state in which one or more hydrogen atoms contained therein are replaced by one or more non-hydrogen atoms. The term “functional group” or “substituent” as used herein refers to a group that can be or is substituted onto a molecule or onto an organic group. Examples of substituents or functional groups include, but are not limited to, a halogen (e.g., F, Cl, Br, and I); an oxygen atom in groups such as hydroxy groups, alkoxy groups, aryloxy groups, aralkyloxy groups, oxo(carbonyl) groups, carboxyl groups including carboxylic acids, carboxylates, and carboxylate esters; a sulfur atom in groups such as thiol groups, alkyl and aryl sulfide groups, sulfoxide groups, sulfone groups, sulfonyl groups, and sulfonamide groups; a nitrogen atom in groups such as amines, hydroxyamines, nitriles, nitro groups, N-oxides, hydrazides, azides, and enamines; and other heteroatoms in various other groups. Non-limiting examples of substituents that can be bonded to a substituted carbon (or other) atom include F, Cl, Br, I, OR, OC(O)N(R)2, CN, NO, NO2, ONO2, azido, CF3, OCF3, R, O (oxo), S (thiono), C(O), S(O), methylenedioxy, ethylenedioxy, N(R)2, SR, SOR, SO2R, SO2N(R)2, SO3R, C(O)R, C(O)C(O)R, C(O)CH2C(O)R, C(S)R, C(O)OR, OC(O)R, C(O)N(R)2, OC(O)N(R)2, C(S)N(R)2, (CH2)0-2N(R)C(O)R, (CH2)0-2N(R)N(R)2, N(R)N(R)C(O)R, N(R)N(R)C(O)OR, N(R)N(R)CON(R)2, N(R)SO2R, N(R)SO2N(R)2, N(R)C(O)OR, N(R)C(O)R, N(R)C(S)R, N(R)C(O)N(R)2, N(R)C(S)N(R)2, N(COR)COR, N(OR)R, C(=NH)N(R)2, C(O)N(OR)R, and C(=NOR)R, wherein R can be hydrogen or a carbon-based moiety; for example, R can be hydrogen, (C1- C100) hydrocarbyl, alkyl, acyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, or heteroarylalkyl; or wherein two R groups bonded to a nitrogen atom or to adjacent nitrogen atoms can together with the nitrogen atom or atoms form a heterocyclyl. - 29 - 53762388.1 Attorney Docket No.046483-7452WO1(03831) A “therapeutic” treatment is a treatment administered to a subject who exhibits signs of pathology, for the purpose of diminishing or eliminating those signs. The term “therapeutic protein” as used herein refers to a protein or peptide which has a positive or advantageous effect on a condition or disease state of a subject when provided to the subject in a therapeutically effective amount. In one embodiment, a therapeutic protein or peptide has curative or palliative properties and may be administered to ameliorate, relieve, alleviate, reverse, delay onset of or lessen the severity of one or more symptoms of a disease or disorder. A therapeutic protein or peptide may have prophylactic properties and may be used to delay the onset of a disease or to lessen the severity of such disease or pathological condition. The term “therapeutic protein” includes entire proteins or peptides, and can also refer to therapeutically active fragments thereof. It can also include therapeutically active variants of a protein. Exemplary therapeutic proteins include, but are not limited to, an analgesic protein, an anti-inflammatory protein, an anti-proliferative protein, an proapoptotic protein, an anti-angiogenic protein, a cytotoxic protein, a cytostatic protein, a cytokine, a chemokine, a growth factor, a wound healing protein, a pharmaceutical protein, or a pro-drug activating protein. Therapeutic proteins may include growth factors (EGF, TGF-α, TGF- β, TNF, HGF, IGF, and IL-1-8, inter alia) cytokines, paratopes, Fabs (fragments, antigen binding), and antibodies. The terms “treat,” “treating” and “treatment,” as used herein, means reducing the frequency or severity with which symptoms of a disease or condition are experienced by a subject by virtue of administering an agent or compound to the subject. Lipids In one aspect, the present disclosure provides an ionizable lipid of Formula (I), or a salt, solvate, stereoisomer, or isotopologue thereof: , wherein: R1aand R1bare each ; R2a, R2b, R2c, R2d, R2e, R2f, R2g, selected from the - 30 - 53762388.1 Attorney Docket No.046483-7452WO1(03831) group consisting of H, optionally substituted C1-C12 alkyl, optionally substituted C2-C12 heteroalkyl, optionally substituted C3-C8cycloalkyl, optionally substituted C2-C8heterocycloalkyl, optionally substituted C2-C12 alkenyl, optionally substituted C2-C12 alkynyl, optionally substituted C7-C13aralkyl, optionally substituted C6-C10aryl, and optionally substituted C2-C10 heteroaryl; each occurrence of R3a, R3b, and R3cis independently selected from the group consisting of H, -(optionally substituted C1-C6 alkylenyl)-C(=O)OR4, -(optionally substituted C1-C6alkylenyl)-C(=O)N(R4)(R5), -(optionally substituted C1-C6alkylenyl)-C(=O)R4, - (optionally substituted C1-C6 alkylenyl)-(R4), -C(=O)OR4, -C(=O)N(R4)(R5), -C(=O)R4, and R4, wherein no more than one of each occurrence of R3a, R3b, and R3cis H; R4is selected from the group consisting of optionally substituted C1-C28alkyl, optionally substituted C2-C28 heteroalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C8heterocycloalkyl, optionally substituted C2-C28alkenyl, and optionally substituted C2-C28 alkynyl; R5is selected from the group consisting of H and optionally substituted C1-C6 alkyl; each occurrence of L1is independently selected from the group consisting of - (optionally substituted C1-C12 alkylenyl)-X-, -(optionally substituted C2-C12 alkenylenyl)-X-, -(optionally substituted C1-C12alkynylenyl)-X-, -(optionally substituted C1-C12heteroalkylenyl)-X-, -X-(optionally substituted C1-C12 alkylenyl)-, -X-(optionally substituted C2-C12alkenylenyl)-, -X-(optionally substituted C1-C12alkynylenyl)-, -X-(optionally substituted C1-C12 heteroalkylenyl)-, optionally substituted C3-C8 cycloalkylenyl, and optionally substituted C2-C8heterocyloalkylenyl; each occurrence of X, if present, is independently selected from the group consisting of a bond, -N(R3c)-, and -O-; and each occurrence of m is independently an integer selected from the group consisting of 1, 2, 3, and 4. In certain embodiments, at least one selected from the group consisting of R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2his H. In certain embodiments, at least two selected from the group consisting of R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2hare H. In certain embodiments, at least three selected from the group consisting of R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2hare H. In certain embodiments, at least four selected from the group consisting of R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2hare H. In certain embodiments, at least five selected from the group consisting of R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2hare H. In certain embodiments, at least - 31 - 53762388.1 Attorney Docket No.046483-7452WO1(03831) six selected from the group consisting of R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2hare H. In certain embodiments, at least seven selected from the group consisting of R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2hare H. In certain embodiments, each of R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2hare H. In certain embodiments, L1is -CH2-. In certain embodiments, L1is -(CH2)2-. In certain embodiments, L1is -(CH2)3-. In certain embodiments, L1is -(CH2)10-. In certain embodiments, L1is -(CH2)2O-. In certain embodiments, L1is -(CH2)3O-. In certain embodiments, L1is -CH2CH(OR5)CH2-. In certain embodiments, L1is -(CH2)2NR3c-. In certain embodiments, L1is . In certain embodiments, L1is . In certain embodiments, L1. For instances of L which are asymmetric (e.g., -(CH2)3O-) it is understood that the disclosure encompasses both possible orientations (e.g., - (CH2)3O- and -O(CH2)3-). In certain embodiments, the ionizable lipid of Formula (I) is: In certain embodiments, the ionizable lipid of Formula (I) In certain embodiments, the ionizable In certain - 32 - 53762388.1 Attorney Docket No.046483-7452WO1(03831) In the ionizable lipid of Formula (I) . In certain embodiments, CH2CH(OH)(optionally substituted C1-C28 alkyl). In certain embodiments, R3ais - CH2CH(OH)(optionally substituted C2-C28alkenyl). In certain embodiments, R3ais - CH2CH2C(=O)O(optionally substituted C1-C28 alkyl). In certain embodiments, R3ais - CH2CH2C(=O)NH(optionally substituted C1-C28alkyl). In certain embodiments, R3bis H. In certain embodiments, R3bis -CH2CH(OH)(optionally substituted C1-C28 alkyl). In certain embodiments, R3bis -CH2CH(OH)(optionally substituted C2-C28alkenyl). In certain embodiments, R3bis -CH2CH2C(=O)O(optionally substituted C1-C28 alkyl). In certain embodiments, R3bis -CH2CH2C(=O)NH(optionally substituted C1-C28 alkyl). In certain embodiments, R3cis H. In certain embodiments, R3cis -CH2CH(OH)(optionally substituted C1-C28 alkyl). In certain embodiments, R3cis -CH2CH(OH)(optionally substituted C2-C28 alkenyl). In certain embodiments, R3cis -CH2CH2C(=O)O(optionally substituted C1-C28- 33 - 53762388.1 Attorney Docket No.046483-7452WO1(03831) alkyl). In certain embodiments, R3cis -CH2CH2C(=O)NH(optionally substituted C1-C28 alkyl). In certain embodiments, R3ais -CH2CH(OH)(CH2)9CH3. In certain embodiments, R3ais -CH2CH(OH)(CH2)11CH3. In certain embodiments, R3ais -CH2CH(OH)(CH2)13CH3. In certain embodiments, R3bis -CH2CH(OH)(CH2)9CH3. In certain embodiments, R3bis - CH2CH(OH)(CH2)11CH3. In certain embodiments, R3bis -CH2CH(OH)(CH2)13CH3. In certain embodiments, R3cis -CH2CH(OH)(CH2)9CH3. In certain embodiments, R3cis - CH2CH(OH)(CH2)11CH3. In certain embodiments, R3cis -CH2CH(OH)(CH2)13CH3. In certain embodiments, each occurrence of optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted alkylenyl, optionally substituted heteroalkylenyl, optionally substituted cycloalkylenyl, and optionally substituted heterocycloalkylenyl, if present, is independently optionally substituted with at least one substituent selected from the group consisting of C1- C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, C1-C3 haloalkoxy, phenoxy, halogen, CN, NO2, OH, N(R’)(R’’), C(=O)R’, C(=O)OR’, OC(=O)OR’, C(=O)N(R’)(R’’), S(=O)2N(R’)(R’’), N(R’)C(=O)R’’, N(R’)S(=O)2R’’, C2-C8 heteroaryl, and phenyl optionally substituted with at least one halogen, wherein each occurrence of R’ and R’’ is independently selected from the group consisting of H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, benzyl, and phenyl. In certain embodiments, the ionizable lipid of Formula (I) is: HO hydroxytetradecyl)amino)ethyl)piperazin-1-yl)-2-ethoxypropyl)azanediyl)bis(tetradecan-2- ol) (C14-490). Ionizable Lipids and / or Cationic Lipids The scope of ionizable lipids contemplated for use in the present disclosure is not limited to ionizable lipids of Formula (I). In the lipid nanoparticles of the disclosure, the cationic lipid or ionizable lipid may comprise, e.g., one or more of the following: - 34 - 53762388.1 Attorney Docket No.046483-7452WO1(03831) (6Z,9Z,28Z,31Z)-heptatriaconta-6,9,28,31-tetraen-19-yl 4-(dimethylamino)butanoate (DLinMC3DMA), [(4-hydroxybutyl)azanediyl]di(hexane-6,1-diyl) bis(2-hexyldecanoate) (ALC-0315), heptadecan-9-yl 8-{(2-hydroxyethyl)[6-oxo-6- (undecyloxy)hexyl]amino}octanoate (SM-102), 1,1′-[[2-[4-[2-[[2-[bis(2- hydroxydodecyl)amino]ethyl](2-hydroxydodecyl)amino]ethyl]-1- piperazinyl]ethyl]imino]bis-2-dodecanol (C12-200), 1,2-dilinoleyloxy-N,N- dimethylaminopropane (DLinDMA), 1,2-dilinolenyloxy-N,N-dimethylaminopropane (DLenDMA), 2,2-dilinoleyl-4-(2-dimethylaminoethyl)-[1,3]-dioxolane (DLin-K-C2-DMA; “XTC2”), 2,2-dilinoleyl-4-(3- 45 dimethylaminopropyl)- 1,3]-dioxolane (D Lin-K-C3-D MA), 2,2-dilinoleyl-4-(4-dimethylaminobutyl)-[1,3]-dioxolane (DLin-K-C4-DMA), 2,2- dilinoleyl-5-dimethylaminomethyl-[1,3]-dioxane (DLin-K6-DMA), 2,2-dilinoleyl-4-N- methylpepiazino-[1,3]-dioxolane (DLin-K-MPZ), 2,2-dili-noleyl-4-dimethylaminomethyl- [1,3]-dioxolane (DLin-KDMA), 1,2-dilinoleylcarbamoyloxy-3-dimethylaminopropane (D Lin-C-DAP), 1,2-dilinoleyoxy-3-(dimethylaminoacetoxypropane (DLin-DAC), 1- 2dilinoleyoxy-3-morpholinopropane (DLin-MA), 1,2-dilinoleoyl-3-dimethylaminopropane (DLinDAP), 1,2-dilinoleylthio-3-dimethylaminopropane (DLin-2-DMAP), 1,2-dilinoleyloxy- 3-trimethylaminopropane chloride salt (DLin-TMA.Cl), 1,2-dilinoleoyl-3- trimethylaminopropane chloride salt (DLin-TAP.Cl), 1,2-dilinoleyloxy-3-(N- methylpiperazino)propane (D Lin-MPZ), 3-(N,N-dilinoleylamino)-1,2-propanediol (D LinAP), 3-(N,N-dioleylamino)-1,2-propanedio (DOAP), 1,2-dilinoleyloxo-3-(2-N,N- dimethylamino)ethoxypropane (D Lin-EG-D MA), N,N-dioleyl-N,N-dimethylanrmonium chloride (DODAC), 1,2-dioleyloxy-N,N-dimethylaminopropane (DODMA), 1,2- distearyloxy-N,N-dimethylaminopropane (DSD MA), N-(1-(2,3-dioleyloxy)propyl)-N,N,N- trimethylammonium chloride (DOTMA), N,N-distearyl-N,N-dimethylammonium bromide (DDAB), N-(1-(2,3-dioleoyloxy)propyl)-N,N, N-trimethylammonium chloride (DOTAP), 3- (N-(N’,N’dimethylaminoethane)-carbamoyl)cholesterol (DC-Chol), N-(l,2- dimyristyloxyprop-3-yl)-N,N-dimethyl-N-hydroxyethyl anrmonium bromide (DMRIE), 2,3- dioleyloxy-N-[2 (spermine-carboxamidoethyl]-N,N-dimethy 1-1- propanaminiumtrifluoroacetate (DOSPA), dioctadecylamidoglycyl spermine (DOGS), 3- dimethylamino-2-(cholest-5-en-3-beta-oxybutan-4-oxy)-1-(cis,cis-9,12- octadecadienoxy)propane (CLinDMA), 2-[5’-(cholest-5-en-3-beta-oxy)-3’-oxapentoxy)-3- dimethyl-1-(cis,cis-9’,1-2’-octadecadienoxy) propane (CpLinDMA), N,N-dimethyl-3,4- dioleyloxybenzylamine (DMOBA), 1,2-N,N’dioleylcarbamyl-3-dimethylaminopropane (DOcarbDAP), 1,2-N,N’-dilinoleylcarbamyl-3-dimethylaminopropane (DLincarbDAP), or - 35 - 53762388.1 Attorney Docket No.046483-7452WO1(03831) mixtures thereof. In certain embodiments, the cationic lipid is DLinDMA, DLin-K-C2-DMA (“XTC2”), or mixtures thereof. The ionizable lipids are not limited to those recited herein, and can further include ionizable lipids known to those skilled in the art, or described in PCT Application No. PCT / US2020 / 056255 and / or PCT Application No. PCT / US2020 / 056252, the disclosures of which are herein incorporated by reference in its entirety. The synthesis of cationic lipids such as DLin-K-C2-DMA (“XTC2”), DLin-K-C3- DMA, DLin-K-C4-DMA, DLin-K6-DMA, and DLin-K-MPZ, as well as additional cationic lipids, is described in U.S. Application Publication No. US 2011 / 0256175, the disclosure of which is herein incorporated by reference in its entirety for all purposes. The synthesis of cationic lipids such as DLin-K-DMA, DLin-CDAP, DLin-DAC, DLin-MA, DLinDAP, DLin-S-DMA, DLin-2-DMAP, DLin-TMA.Cl, DLin-TAP.Cl, DLin-MPZ, DLinAP, DOAP, and DLin-EG-DMA, as well as additional cationic lipids, is described in PCT Application No. PCT / US08 / 88676, filed December 31, 2008, the disclosure of which is herein incorporated by reference in its entirety for all purposes. The synthesis of cationic lipids such as CLinDMA, as well as additional cationic lipids, is described in U.S. Patent Publication No. US20060240554, the disclosure of which is herein incorporated by reference in its entirety for all purposes. Non-Cationic Lipid In the nucleic acid-lipid particles of the present disclosure, the non-cationic lipid may comprise, e.g., one or more anionic lipids and / or neutral lipids. In some embodiments, the non-cationic lipid comprises one of the following neutral lipid components: (1) cholesterol or a derivative thereof (2) a phospholipid; or (3) a mixture of a phospholipid and cholesterol or a derivative thereof. Examples of cholesterol derivatives include, but are not limited to, cholestanol, cholestanone, cholestenone, coprostanol, cholesteryl-2’-hydroxyethyl ether, cholesteryl-4’- hydroxybutyl ether, and mixtures thereof. The synthesis of cholesteryl-2’-hydroxyethyl ether is known to one skilled in the art and described in U.S. Patent Nos.8,058,069, 8,492,359, 8,822,668, 9,364,435, 9,504,651, and 11,141,378, all of which are hereby incorporated herein in their entireties for all purposes. Non-limiting examples of non-cationic lipids include phospholipids such as lecithin, phosphatidylethanolamine, lysolecithin, lysophosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, sphingomyelin, egg sphingomyelin (ESM), cephalin, cardiolipin, phosphatidic acid, cerebrosides, dicetylphosphate, distearoylphosphatidylcholine (DSPC), - 36 - 53762388.1 Attorney Docket No.046483-7452WO1(03831) dioleoylphosphatidylcholine (DOPC), dipalmitoylphosphatidylcholine (DPPC), dioleoylphosphatidylglycerol (DOPG), dipalmitoylphosphatidylglycerol (DPPG), ioleoylphosphatidylethanolamine (DOPE), palmitoyloleoylphosphatidylcholine (POPC), palmitoyloleoylphosphatidylethanolamine (POPE), palmitoyloleyolphosphatidylglycerol (POPG), dioleoylphosphatidylethanolamine 4-(N-maleimidomethyl)-cyclohexane-l- carboxylate DOPE-mal), dipalmitoylphosphatidylethanolamine (DPPE), dimyristoylphosphatidylethanolamine (DMPE), distearoylphosphatidylethanolamine (DSPE), monomethylphosphatidylethanolamine, dimethylphosphatidylethanolamine, dielaidoylphosphatidylethanolamine (DEPE), stearoyloleoylphosphatidylethanolamine (SOPE), lysophosphatidylcholine, dilinoleoylphosphatidylcholine, and mixtures thereof. Other diacylphosphatidylcholine and diacylphosphatidylethanolamine phospholipids can also be used. The acyl groups in these lipids can be, for example, acyl groups derived from fatty acids having C10-C24 carbon chains, e.g., lauroyl, myristoyl, palmitoyl, stearoyl, or oleoyl. Additional examples of non-cationic lipids include sterols such as cholesterol and derivatives thereof such as cholestanol, cholestanone, cholestenone, coprostanol, cholesteryl- 2’-hydroxyethyl ether, cholesteryl-4’-hydroxybutyl ether, and mixtures thereof. In certain embodiments, the phospholipid is DPPC, DSPC, or mixtures thereof. Conjugated Lipid In the nucleic acid-lipid particles of the present disclosure, the conjugated lipid that inhibits aggregation of particles may comprise, e.g., one or more of the following: a polyethyleneglycol (PEG) lipid conjugate, a polyamide (ATTA)-lipid conjugate, a cationic- polymer-lipid conjugates (CPLs), or mixtures thereof. In some embodiments, the nucleic acid-lipid particles comprise either a PEG-lipid conjugate or an ATTA-lipid conjugate. PEG is a linear, water-soluble polymer of ethylene PEG repeating units with two terminal hydroxyl groups. PEGs are classified by their molecular weights; for example, PEG 2000 has an average molecular weight of about 2,000 daltons, and PEG 5000 has an average molecular weight of about 5,000 daltons. PEGs are commercially available from Sigma Chemical Co. and other companies and include, for example, the following: monomethoxypolyethylene glycol (MePEGOH), monomethoxypolyethylene glycolsuccinate (MePEGS), monomethoxypolyethylene glycolsuccinimidyl succinate (MePEG-S-NHS), monomethoxypolyethylene glycolamine (MePEG-NH2), monomethoxypolyethylene glycoltresylate (MePEG-TRES), and monomethoxypolyethylene glycolimidazolylcarbonyl (MePEG-IM). Other PEGs such as those described in U.S. Patent Nos.6,774,180 and - 37 - 53762388.1 Attorney Docket No.046483-7452WO1(03831) 7,053,150 (e.g., mPEG (20 KDa) amine) are also useful for preparing the PEG-lipid conjugates of the present disclosure. The disclosures of these patents are herein incorporated by reference in their entirety for all purposes. In addition, monomethoxypolyethyleneglycolacetic acid (MePEG-CH2COOH) is particularly useful for preparing PEG-lipid conjugates including, e.g., PEG-DAA conjugates. In certain embodiments, the PEG-lipid conjugate or ATTA-lipid conjugate is used together with a CPL. The conjugated lipid that inhibits aggregation of particles may comprise a PEG-lipid including, e.g., a PEG-diacylglycerol (DAG), a PEG dialkyloxypropyl (DAA), a PEG-phospholipid, a PEG-ceramide (Cer), or mixtures thereof. The PEGDAA conjugate may be PEG-dilauryloxypropyl (C12), a PEG-dimyristyloxypropyl (C14), a PEG- dipalmityloxypropyl (C16), a PEG-distearyloxypropyl (C18), or mixtures thereof. Additional PEG-lipid conjugates suitable for use in the disclosure include, but are not limited to, mPEG2000-l,2-diO-alkyl-sn3-carbomoylglyceride (PEG-C-DOMG). The synthesis of PEG-C-DOMG is described in PCT Application No. PCT / US08 / 88676, filed December 31, 2008, the disclosure of which is herein incorporated by reference in its entirety for all purposes. Yet additional PEG-lipid conjugates suitable for use in the disclosure include, without limitation, l-[8’-(l,2-dimyristoyl-3-propanoxy)-carboxamido-3’,6’- dioxaoctanyl] carbamoyl-methyl-poly(ethylene glycol) (2 KPEG-DMG). The synthesis of 2 KPEG-DMG is described in U.S. Patent No.7,404,969, the disclosure of which is herein incorporated by reference in its entirety for all purposes. The PEG moiety of the PEG-lipid conjugates described herein may comprise an average molecular weight ranging from about 550 daltons to about 10,000 daltons. In certain instances, the PEG moiety has an average molecular weight of from about 750 daltons to about 5,000 daltons (e.g., from about 1,000 daltons to about 5,000 daltons, from about 1,500 daltons to about 3,000 daltons, from about 750 daltons to about 3,000 daltons, from about 750 daltons to about 2,000 daltons, etc.). In some embodiments, the PEG moiety has an average molecular weight of about 2,000 daltons or about 750 daltons. In addition to the foregoing, it will be readily apparent to those of skill in the art that other hydrophilic polymers can be used in place of PEG. Examples of suitable polymers that can be used in place of PEG include, but are not limited to, polyvinylpyrrolidone, polymethyloxazoline, polyethyloxazoline, polyhydroxypropyl methacrylamide, polymethacrylamide and polydimethylacrylamide, polylactic acid, polyglycolic acid, and derivatized celluloses such as hydroxymethylcellulose or hydroxyethylcellulose. In addition to the foregoing components, the particles (e.g., LNP) of the present - 38 - 53762388.1 Attorney Docket No.046483-7452WO1(03831) disclosure can further comprise cationic poly(ethylene glycol) (PEG) lipids or CPLs (e.g., Chen et al., Bioconj. Chem., 11:433-437 (2000)). Suitable SPLPs and SPLP-CPLs for use in the present disclosure, and methods of making and using SPLPs and SPLP-CPLs, are disclosed, e.g., in U.S. Patent No.6,852,334 and PCT Publication No. WO 00 / 62813, the disclosures of which are herein incorporated by reference in their entirety for all purposes. In certain instances, the conjugated lipid that inhibits aggregation of particles (e.g., PEG-lipid conjugate) may comprise from about 0.1 mol% to about 2 mol%, from about 0.5 mol% to about 2 mol%, from about 1 mol% to about 2 mol%, from about 0.6 mol% to about 1.9 mol%, from about 0.7 mol% to about 1.8 mol%, from about 0.8 mol% to about 1.7 mol%, from about 1 mol% to about 1.8 mol%, from about 1.2 mol% to about 1.8 mol%, from about 1.2 mol% to about 1.7 mol%, from about 1.3 mol% to about 1.6 mol%, from about 1.4 mol% to about 1.5 mol%, or about 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2 mol% (or any fraction thereof or range therein) of the total lipid present in the particle. In the lipid nanoparticles of the present disclosure, the active agent or therapeutic agent may be fully encapsulated within the lipid portion of the particle, thereby protecting the active agent or therapeutic agent from enzymatic degradation. In some embodiments, a nucleic acid-lipid particle comprising a nucleic acid such as a messenger RNA (i.e., mRNA) is fully encapsulated within the lipid portion of the particle, thereby protecting the nucleic acid from nuclease degradation. In certain instances, the nucleic acid in the nucleic acid-lipid particle is not substantially degraded after exposure of the particle to a nuclease at 37° C. for at least about 20, 30, 45, or 60 minutes. In certain other instances, the nucleic acid in the nucleic acid-lipid particle is not substantially degraded after incubation of the particle in serum at 37° C. for at least about 30, 45, or 60 minutes or at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, or 36 hours. In other embodiments, the active agent or therapeutic agent (e.g., nucleic acid such as siRNA) is complexed with the lipid portion of the particle. One of the benefits of the formulations of the present disclosure is that the lipid particle compositions are substantially non-toxic to mammals such as humans. Lipid Nanoparticles (LNPs) In one aspect, the present disclosure provides an immune cell targeted lipid nanoparticle (LNP). In certain embodiments, the LNP comprises at least one ionizable lipid. In certain embodiments, the LNP comprises at least one neutral lipid. In certain embodiments, the LNP comprises cholesterol and / or a modified derivative thereof. In certain embodiments, the LNP comprises at least one polymer conjugated lipid and / or modified - 39 - 53762388.1 Attorney Docket No.046483-7452WO1(03831) derivative thereof, and / or a modified derivative thereof. In certain embodiments, the LNP comprises a cell targeting domain specific to binding to a surface molecule of an hematopoietic stem cell, optionally wherein the cell targeting domain is covalently conjugated to at least one component of the LNP. In certain embodiments, the cell targeting domain is covalently conjugated to at least one component of the LNP. In certain, non-limiting, exemplary embodiments, the present disclosure provides a LNP. In certain embodiments, the LNP comprises (a) at least one ionizable lipid. In certain embodiments, the LNP comprises (b) at least one neutral lipid. In certain embodiments, the LNP comprises (c) at least one cholesterol compound and / or modified derivative thereof. In certain embodiments, the LNP comprises (d) at least one polymer conjugated lipid and at least one compound of Formula (II), or a salt, solvate, stereoisomer, or isotopologue thereof. In certain, non-limiting, exemplary embodiments, the present disclosure provides a LNP. In certain embodiments, the LNP comprises (a) at least one ionizable lipid of Formula (I), or a salt, solvate, stereoisomer, or isotopologue thereof. In certain embodiments, the LNP comprises (b) at least one neutral lipid. In certain embodiments, the LNP comprises (c) at least one cholesterol compound and / or modified derivative thereof. In certain embodiments, the LNP comprises (d) at least one polymer conjugated lipid. In certain embodiments, the LNP comprises (e) at least one cell targeting domain specific to binding to a surface molecule of an hematopoietic stem cell, optionally wherein the cell targeting domain is covalently conjugated to at least one component of the LNP. In certain, non-limiting, exemplary embodiments, the present disclosure provides a LNP. In certain embodiments, the LNP comprises (a) at least one ionizable lipid of Formula (I), or a salt, solvate, stereoisomer, or isotopologue thereof. In certain embodiments, the LNP comprises (b) at least one neutral lipid. In certain embodiments, the LNP comprises (c) at least one cholesterol compound and / or modified derivative thereof. In certain embodiments, the LNP comprises (d) at least one polymer conjugated lipid and at least one compound of Formula (II), or a salt, solvate, stereoisomer, or isotopologue thereof. In certain embodiments, the at least one ionizable lipid comprises an ionizable lipid of Formula (I), or a salt, solvate, stereoisomer, or isotopologue thereof: , wherein: - 40 - 53762388.1 Attorney Docket No.046483-7452WO1(03831) R1aand R1bare each independently ; R2a, R2b, R2c, R2d, R2e, R2f, R2g, and selected from the group consisting of H, optionally optionally substituted C2-C12 heteroalkyl, optionally substituted C3-C8cycloalkyl, optionally substituted C2-C8heterocycloalkyl, optionally substituted C2-C12 alkenyl, optionally substituted C2-C12 alkynyl, optionally substituted C7-C13aralkyl, optionally substituted C6-C10aryl, and optionally substituted C2-C10 heteroaryl; each occurrence of R3a, R3b, and R3cis independently selected from the group consisting of H, -(optionally substituted C1-C6 alkylenyl)-C(=O)OR4, -(optionally substituted C1-C6alkylenyl)-C(=O)N(R4)(R5), -(optionally substituted C1-C6alkylenyl)-C(=O)R4, - (optionally substituted C1-C6 alkylenyl)-(R4), -C(=O)OR4, -C(=O)N(R4)(R5), -C(=O)R4, and R4, wherein no more than one of each occurrence of R3a, R3b, and R3cis H; R4is selected from the group consisting of optionally substituted C1-C28alkyl, optionally substituted C2-C28 heteroalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C8heterocycloalkyl, optionally substituted C2-C28alkenyl, and optionally substituted C2-C28 alkynyl; R5is selected from the group consisting of H and optionally substituted C1-C6alkyl; Each occurrence of L1is independently selected from the group consisting of - (optionally substituted C1-C12 alkylenyl)-X-, -(optionally substituted C2-C12 alkenylenyl)-X-, -(optionally substituted C1-C12alkynylenyl)-X-, -(optionally substituted C1-C12heteroalkylenyl)-X-, -X-(optionally substituted C1-C12 alkylenyl)-, -X-(optionally substituted C2-C12alkenylenyl)-, -X-(optionally substituted C1-C12alkynylenyl)-, -X-(optionally substituted C1-C12 heteroalkylenyl)-, optionally substituted C3-C8 cycloalkylenyl, and optionally substituted C2-C8heterocyloalkylenyl; each occurrence of X, if present, is independently selected from the group consisting of a bond, -N(R3c)-, and -O-; and each occurrence of m is independently an integer selected from the group consisting of 1, 2, 3, and 4. In certain embodiments, at least one selected from the group consisting of R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2his H. In certain embodiments, at least two selected from the group consisting of R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2hare H. In certain embodiments, at - 41 - 53762388.1 Attorney Docket No.046483-7452WO1(03831) least three selected from the group consisting of R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2hare H. In certain embodiments, at least four selected from the group consisting of R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2hare H. In certain embodiments, at least five selected from the group consisting of R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2hare H. In certain embodiments, at least six selected of R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2hare H. In certain embodiments, at least seven selected from the group consisting of R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2hare H. In certain embodiments, each of R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2hare H. In certain embodiments, L1is -CH2-. In certain embodiments, L1is -(CH2)2-. In certain embodiments, L1is -(CH2)3-. In certain embodiments, L1is -(CH2)10-. In certain embodiments, L1is -(CH2)2O-. In certain embodiments, L1is -(CH2)3O-. In certain embodiments, L1is -CH2CH(OR5)CH2-. In certain embodiments, L1is -(CH2)2NR3c-. In certain embodiments, L1is . In certain embodiments, L1. In certain embodiments, L1. For instances of L which are asymmetric (e.g., -(CH2)3O-) it is understood that the disclosure encompasses both possible orientations (e.g., - (CH2)3O- and -O(CH2)3-). In certain embodiments, the ionizable lipid of Formula (I) is: In certain embodiments, the ionizable lipid of Formula (I) In certain embodiments, the ionizable In certain - 42 - 53762388.1 Attorney Docket No.046483-7452WO1(03831) In certain In the ionizable lipid of Formula (I) . In certain embodiments, CH2CH(OH)(optionally substituted C1-C28 alkyl). In certain embodiments, R3ais - CH2CH(OH)(optionally substituted C2-C28alkenyl). In certain embodiments, R3ais - CH2CH2C(=O)O(optionally substituted C1-C28 alkyl). In certain embodiments, R3ais - CH2CH2C(=O)NH(optionally substituted C1-C28alkyl). In certain embodiments, R3bis H. In certain embodiments, R3bis -CH2CH(OH)(optionally substituted C1-C28 alkyl). In certain embodiments, R3bis -CH2CH(OH)(optionally substituted C2-C28alkenyl). In certain - 43 - 53762388.1 Attorney Docket No.046483-7452WO1(03831) embodiments, R3bis -CH2CH2C(=O)O(optionally substituted C1-C28 alkyl). In certain embodiments, R3bis -CH2CH2C(=O)NH(optionally substituted C1-C28alkyl). In certain embodiments, R3cis H. In certain embodiments, R3cis -CH2CH(OH)(optionally substituted C1-C28alkyl). In certain embodiments, R3cis -CH2CH(OH)(optionally substituted C2-C28alkenyl). In certain embodiments, R3cis -CH2CH2C(=O)O(optionally substituted C1-C28 alkyl). In certain embodiments, R3cis -CH2CH2C(=O)NH(optionally substituted C1-C28alkyl). In certain embodiments, R3ais -CH2CH(OH)(CH2)9CH3. In certain embodiments, R3ais -CH2CH(OH)(CH2)11CH3. In certain embodiments, R3ais -CH2CH(OH)(CH2)13CH3. In certain embodiments, R3bis -CH2CH(OH)(CH2)9CH3. In certain embodiments, R3bis - CH2CH(OH)(CH2)11CH3. In certain embodiments, R3bis -CH2CH(OH)(CH2)13CH3. In certain embodiments, R3cis -CH2CH(OH)(CH2)9CH3. In certain embodiments, R3cis - CH2CH(OH)(CH2)11CH3. In certain embodiments, R3cis -CH2CH(OH)(CH2)13CH3. In certain embodiments, each occurrence of optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted alkylenyl, optionally substituted heteroalkylenyl, optionally substituted cycloalkylenyl, and optionally substituted heterocycloalkylenyl, if present, is independently optionally substituted with at least one substituent selected from the group consisting of C1- C6alkyl, C3-C8cycloalkyl, C1-C6haloalkyl, C1-C3haloalkoxy, phenoxy, halogen, CN, NO2, OH, N(R’)(R’’), C(=O)R’, C(=O)OR’, OC(=O)OR’, C(=O)N(R’)(R’’), S(=O)2N(R’)(R’’), N(R’)C(=O)R’’, N(R’)S(=O)2R’’, C2-C8heteroaryl, and phenyl optionally substituted with at least one halogen, wherein each occurrence of R’ and R’’ is independently selected from the group consisting of H, C1-C6alkyl, C3-C8cycloalkyl, C1-C6haloalkyl, benzyl, and phenyl. In certain embodiments, the ionizable lipid of Formula (I) is: HO hydroxytetradecyl)amino)ethyl)piperazin-1-yl)-2-ethoxypropyl)azanediyl)bis(tetradecan-2- ol) (C14-490). - 44 - 53762388.1 Attorney Docket No.046483-7452WO1(03831) In certain embodiments, the at least one ionizable lipid comprises about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or about 99 mol% of the LNP. In certain embodiments, the at least one ionizable lipid comprises less than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or about 99 mol% of the LNP. In certain embodiments, the at least one ionizable lipid comprises more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or about 99 mol% of the LNP. In certain embodiments, the at least one ionizable lipid comprises about 45 mol% of the LNP. In certain embodiments, the neutral lipid comprises dioleoylphosphatidylethanolamine (DOPE) and distearoylphosphatidylcholine (DSPC). In certain embodiments, the neutral lipid is dioleoylphosphatidylethanolamine (DOPE). In certain embodiments, the neutral lipid is dioleoylphosphatidylethanolamine (DOPE). In certain embodiments, the at least one neutral lipid comprises about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, or about 45 mol% of the LNP. In certain embodiments, the at least one neutral lipid comprises less than about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, or about 45 mol% of the LNP. In certain embodiments, the at least one neutral lipid comprises more than about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, or about 45 mol% of the LNP. In certain embodiments, the at least one neutral lipid comprises about 15 mol% of the LNP. In certain embodiments, the LNP comprises about 15 mol% DOPE. In certain embodiments, the cholesterol and / or modified derivative thereof comprises - 45 - 53762388.1 Attorney Docket No.046483-7452WO1(03831) about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, or about 60 mol% of the LNP. In certain embodiments, the cholesterol and / or modified derivative thereof comprises less than about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, or about 60 mol% of the LNP. In certain embodiments, the cholesterol and / or modified derivative thereof comprises more than about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, or about 60 mol% of the LNP. In certain embodiments, the cholesterol and / or modified derivative thereof is cholesterol. In certain embodiments, the cholesterol comprises about 40 mol% of the LNP. In certain embodiments, the at least one polymer conjugated lipid and / or modified derivative thereof comprises about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.2, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.2, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.2, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.2, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.2, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 10.1, 10.2, 10.2, 10.4, 10.5, 10.6, 10.7, 10.8, 10.9, 11.0, 11.1, 11.2, 11.2, 11.4, 11.5, 11.6, 11.7, 11.8, 11.9, 12.0, 12.1, 12.2, 12.3, 12.4, or about 12.5 mol% of the LNP. In certain embodiments, the at least one polymer conjugated lipid and / or modified derivative thereof comprises less than about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.2, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.2, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.2, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.2, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.2, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 10.1, 10.2, 10.2, 10.4, 10.5, 10.6, 10.7, 10.8, 10.9, 11.0, 11.1, 11.2, 11.2, 11.4, 11.5, 11.6, 11.7, 11.8, 11.9, 12.0, 12.1, 12.2, 12.3, 12.4, or about 12.5 mol% of the LNP. In certain embodiments, the at least one polymer conjugated lipid and / or modified derivative thereof comprises more than about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.2, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.2, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.2, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.2, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.2, 9.4, 9.5, 9.6, 9.7, - 46 - 53762388.1 Attorney Docket No.046483-7452WO1(03831) 9.8, 9.9, 10.0, 10.1, 10.2, 10.2, 10.4, 10.5, 10.6, 10.7, 10.8, 10.9, 11.0, 11.1, 11.2, 11.2, 11.4, 11.5, 11.6, 11.7, 11.8, 11.9, 12.0, 12.1, 12.2, 12.3, 12.4, or about 12.5 mol% of the LNP. In certain embodiments, the at least one polymer conjugated lipid and / or modified derivative thereof comprises about 1.5 mol% of the LNP. In certain embodiments, the at least one polymer conjugated lipid and / or modified derivative thereof comprises a polyethylene glycol (PEG) conjugated lipid and / or modified derivative thereof. In certain embodiments, the at least one polyethylene glycol (PEG) conjugated lipid and / or modified derivative thereof comprises C14-PEG2000. In certain embodiments, C14-PEG2000 comprises (1,2-dimyristoyl-sn-glycero-3- phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000]: . of the PEG-conjugated lipid. A non-limiting example of covalent linkage to PEG chain of the PEG-conjugated lipid to the PEG chain may comprise bond. In certain embodiments, the surface molecule of the hematopoietic stem cell is a CD45 receptor. In certain embodiments, the cell targeting domain specific to binding a surface molecule of the hematopoietic stem cell is an antibody against CD45 (αCD45), or a fragment thereof. In certain embodiments, the component to which the cell targeting domain is conjugated is the polymer conjugated lipid and / or modified derivative thereof and / or modified derivative thereof. In certain embodiments, the targeting domain is covalently conjugated to the polymer conjugated lipid and / or modified derivative thereof and / or modified derivative thereof. In certain embodiments, the covalent conjugation comprises a covalent bond forming reaction selected from the group consisting of a [1,4]-conjugate addition (i.e., Michael addition), [4+2] cycloaddition, [3+2] dipolar cycloaddition, nucleophilic addition, transition - 47 - 53762388.1 Attorney Docket No.046483-7452WO1(03831) metal-catalyzed cross-coupling reaction, carbonyl condensation reaction, and reductive amination. In certain embodiments, the covalent conjugation reaction comprises a [1,4]- conjugate addition reaction (i.e., Michael addition). In certain embodiments, the [1,4]-conjugate addition occurs between a PEG- polyethylene glycol (PEG) conjugated lipid and / or modified derivative thereof which is further conjugated to a maleimide moiety and a cysteine thiol of a polypeptide. In certain embodiments, the cystine thiol of the polypeptide is derived from a reduced disulfide bridge of an antibody against CD45, or a fragment thereof. Alternative non-limiting examples of complementary functional groups for conjugation of the lipid-conjugate and targeting domain include: (a) a nucleophile and electrophile (e.g., SN1or SN2reaction of an hydroxyl and benzyl chloride or an amine and a carboxylic acid or derivative thereof); (b) an azide and an alkyne (i.e., [3+2] cycloaddition or “click” reaction); and (c) a diene and a dienophile (e.g., substituted butadiene and substituted maleimide) via a Diels-Alder [4+2] cycloaddition, inter alia. It is appreciated that any of a number covalent bond forming reactions (e.g., SN2, condensation, Diels-Alder reaction (i.e., [4+2] cycloaddition), [3+2] dipolar cycloaddition, and transition metal catalyzed cross-coupling, inter alia) may be employed to prepare the conjugated compositions of the present disclosure. It is understood that, given a particular bond forming reaction (e.g., SN2 reaction), one skilled in the art would readily recognize the requisite functional groups suitable for each component (i.e., conjugated lipid and targeting domain) necessary to achieve conjugation. Additionally, one skilled in the art of organic synthesis would be apprised of the necessary additional reagents and / or catalyst necessary to achieve covalent bond formation. In certain embodiments, the LNP has a molar ratio of PEG-polyethylene glycol (PEG) conjugated lipid and / or modified derivative thereof and PEG-polyethylene glycol (PEG) conjugated lipid and / or modified derivative thereof further conjugated to a maleimide moiety selected from the group consisting of about 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, and 1:10. In certain embodiments, the LNP has a molar ratio of PEG-polyethylene glycol (PEG) conjugated lipid and / or modified derivative thereof and PEG-polyethylene glycol (PEG) conjugated lipid and / or modified derivative thereof further conjugated to a maleimide moiety of about 5:1. In certain embodiments, the LNP has a molar ratio of polymer conjugated lipid and - 48 - 53762388.1 Attorney Docket No.046483-7452WO1(03831) modified derivative of the conjugated lipid further conjugated to a maleimide moiety selected from the group consisting of about 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, and 1:10. In certain embodiments, the modified derivative of the polymer conjugated lipid is a compound of Formula (II), or a salt, solvate, stereoisomer, or isotopologue thereof: , wherein: R5aand R5bare consisting of - C(=O)(optionally substituted C1-C28 alkyl), -C(=O)(optionally substituted C2-C28 alkenyl), - C(=O)(optionally substituted C2-C28alkynyl), optionally substituted C1-C28alkyl, optionally substituted C2-C28 alkenyl, and optionally substituted C2-C28 alkynyl; Z is a monovalent cation; L2comprises n units , o units , wherein each a C-O or Dct is a cell targeting domain comprising an antibody against CD45, wherein is C-S bond; R6aand R6bare each independently selected from the group consisting of H and C1-C6alkyl; n, o, and p are each independently 1, 2, 3, 4, or 5; q is an integer ranging from 1 to 100; and r and s are each independently an integer ranging from 1 to 10. In certain embodiments, R5ais C(=O)(C5-C20 alkyl). In certain embodiments, R5ais C(=O)(CH2)16CH3. In certain embodiments, R5bis C(=O)(C5-C20alkyl). In certain embodiments, R5bis C(=O)(CH2)16CH3. In certain embodiments, Z is NH4+. In certain . In certain - 49 - 53762388.1 Attorney Docket No.046483-7452WO1(03831) . In the compound of , of formula (II) have a molar ratio of about 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, and 1:10. In certain embodiments, the LNP has a molar ratio of (a):(b):(c):(d) of about 40:30:25:2.5. In certain embodiments, the LNP has a molar ratio of (a):(b):(c):(d) of about 41:30.8:25.6:2.5. In certain embodiments, (d) comprises the polymer conjugated lipid and the compound of formula (II) having a ratio of about 2.1:0.4. In certain embodiments, the LNP further comprises at least one cargo selected from the group consisting of a nucleic acid molecule and a therapeutic agent. In certain embodiments, the therapeutic agent is at least one selected from the group consisting of a small molecule, a protein, and an antibody. In certain embodiments, the LNP comprises a nucleic acid molecule. In certain embodiments, the nucleic acid molecule is a DNA molecule or an RNA molecule. In certain embodiments, the nucleic acid molecule is selected from the group consisting of cDNA, mRNA, miRNA, siRNA, modified RNA, antagomir, antisense molecule, and a targeted nucleic acid, or any combination thereof. In certain embodiments, the nucleic acid molecule encodes a chimeric antigen receptor (CAR). In certain embodiments, the CAR is specific for binding to a surface antigen of a pathogenic cell. In certain embodiments, the nucleic acid molecule encodes mRNA. In certain embodiments, the nucleic acid molecule encodes sgRNA. In certain embodiments, the nucleic acid molecule encodes mRNA and sgRNA. In certain embodiments, the mRNA encodes a therapeutic protein. In certain embodiments, the therapeutic protein is a CRISPR-associated protein. In certain embodiments, the CRISPR-associated protein is CRISPR-associated protein 9 (Cas9). In certain embodiments, the therapeutic agent is a CRISPR-associated protein. In certain embodiments, the CRISPR-associated protein is CRISPR-associated protein 9 (Cas9). - 50 - 53762388.1 Attorney Docket No.046483-7452WO1(03831) LNP Cargo Anti-Cancer Agents In one embodiment, the at least one additional agent is an anti-cancer agent. Any suitable anti-cancer agent may be used in the compositions and methods of the present disclosure. The selection of a suitable anti-cancer agent may depend upon, among other things, the type of cancer to be treated and the nanoparticle compositions of the present disclosure. In certain embodiments, the anti-cancer agent may be effective for treating one or more of pancreatic cancer, esophageal cancer, rectal cancer, colon cancer, prostate cancer, kidney cancer, liver cancer, breast cancer, ovarian cancer, and stomach cancer. Examples of anti-cancer agents include, but are not limited to, chemotherapeutic agents, antiproliferative agents, anti-tumor agents, checkpoint inhibitors, and anti-angiogenic agents. For example, in one embodiment, the anti-cancer agent is gemcitabine, doxorubicin, 5-Fu, tyrosine kinase inhibitors, sorafenib, trametinib, rapamycin, fulvestrant, ezalutamide, or paclitaxel. Chemotherapeutic agents include cytotoxic agents (e.g., 5-fluorouracil, cisplatin, carboplatin, methotrexate, daunorubicin, doxorubicin, vincristine, vinblastine, oxorubicin, carmustine (BCNU), lomustine (CCNU), cytarabine USP, cyclophosphamide, estramucine phosphate sodium, altretamine, hydroxyurea, ifosfamide, procarbazine, mitomycin, busulfan, cyclophosphamide, mitoxantrone, carboplatin, cisplatin, interferon alfa-2a recombinant, paclitaxel, teniposide, and streptozoci), cytotoxic alkylating agents (e.g., busulfan, chlorambucil, cyclophosphamide, melphalan, or ethylesulfonic acid), alkylating agents (e.g., asaley, AZQ, BCNU, busulfan, bisulphan, carboxyphthalatoplatinum, CBDCA, CCNU, CHIP, chlorambucil, chlorozotocin, cis-platinum, clomesone, cyanomorpholinodoxorubicin, cyclodisone, cyclophosphamide, dianhydrogalactitol, fluorodopan, hepsulfam, hycanthone, iphosphamide, melphalan, methyl CCNU, mitomycin C, mitozolamide, nitrogen mustard, PCNU, piperazine, piperazinedione, pipobroman, porfiromycin, spirohydantoin mustard, streptozotocin, teroxirone, tetraplatin, thiotepa, triethylenemelamine, uracil nitrogen mustard, and Yoshi-864), antimitotic agents (e.g., allocolchicine, Halichondrin M, colchicine, colchicine derivatives, dolastatin 10, maytansine, rhizoxin, paclitaxel derivatives, paclitaxel, thiocolchicine, trityl cysteine, vinblastine sulfate, and vincristine sulfate), plant alkaloids (e.g., actinomycin D, bleomycin, L-asparaginase, idarubicin, vinblastine sulfate, vincristine sulfate, mitramycin, mitomycin, daunorubicin, VP-16-213, VM-26, navelbine and taxotere), biologicals (e.g., alpha interferon, BCG, G-CSF, GM-CSF, and interleukin-2), topoisomerase I inhibitors (e.g., camptothecin, camptothecin derivatives, and morpholinodoxorubicin), - 51 - 53762388.1 Attorney Docket No.046483-7452WO1(03831) topoisomerase II inhibitors (e.g., mitoxantron, amonafide, m-AMSA, anthrapyrazole derivatives, pyrazoloacridine, bisantrene HCL, daunorubicin, deoxydoxorubicin, menogaril, N,N-dibenzyl daunomycin, oxanthrazole, rubidazone, VM-26 and VP-16), and synthetics (e.g., hydroxyurea, procarbazine, o,p’-DDD, dacarbazine, CCNU, BCNU, cis- diamminedichloroplatimun, mitoxantrone, CBDCA, levamisole, hexamethylmelamine, all- trans retinoic acid, gliadel and porfimer sodium). Antiproliferative agents are compounds that decrease the proliferation of cells. Antiproliferative agents include alkylating agents, antimetabolites, enzymes, biological response modifiers, miscellaneous agents, hormones and antagonists, androgen inhibitors (e.g., flutamide and leuprolide acetate), antiestrogens (e.g., tamoxifen citrate and analogs thereof, toremifene, droloxifene and roloxifene), Additional examples of specific antiproliferative agents include, but are not limited to levamisole, gallium nitrate, granisetron, sargramostim strontium-89 chloride, filgrastim, pilocarpine, dexrazoxane, and ondansetron. The inhibitors of the invention can be administered alone or in combination with other anti-tumor agents, including cytotoxic / antineoplastic agents and anti-angiogenic agents. Cytotoxic / anti-neoplastic agents are defined as agents which attack and kill cancer cells. Some cytotoxic / anti-neoplastic agents are alkylating agents, which alkylate the genetic material in tumor cells, e.g., cis-platin, cyclophosphamide, nitrogen mustard, trimethylene thiophosphoramide, carmustine, busulfan, chlorambucil, belustine, uracil mustard, chlomaphazin, and dacabazine. Other cytotoxic / anti-neoplastic agents are antimetabolites for tumor cells, e.g., cytosine arabinoside, fluorouracil, methotrexate, mercaptopuirine, azathioprime, and procarbazine. Other cytotoxic / anti-neoplastic agents are antibiotics, e.g., doxorubicin, bleomycin, dactinomycin, daunorubicin, mithramycin, mitomycin, mytomycin C, and daunomycin. There are numerous liposomal formulations commercially available for these compounds. Still other cytotoxic / anti-neoplastic agents are mitotic inhibitors (vinca alkaloids). These include vincristine, vinblastine and etoposide. Miscellaneous cytotoxic / anti- neoplastic agents include taxol and its derivatives, L-asparaginase, anti-tumor antibodies, dacarbazine, azacytidine, amsacrine, melphalan, VM-26, ifosfamide, mitoxantrone, and vindesine. Anti-angiogenic agents are well known to those of skill in the art. Suitable anti- angiogenic agents for use in the methods and compositions of the present disclosure include anti-VEGF antibodies, including humanized and chimeric antibodies, anti-VEGF aptamers and antisense oligonucleotides. Other known inhibitors of angiogenesis include angiostatin, endostatin, interferons, interleukin 1 (including alpha and beta) interleukin 12, retinoic acid, - 52 - 53762388.1 Attorney Docket No.046483-7452WO1(03831) and tissue inhibitors of metalloproteinase-1 and -2. (TIMP-1 and -2). Small molecules, including topoisomerases such as razoxane, a topoisomerase II inhibitor with anti-angiogenic activity, can also be used. Other anti-cancer agents that can be used in combination with the disclosed compounds include, but are not limited to: acivicin; aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine; ambomycin; ametantrone acetate; aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan; cactinomycin; calusterone; caracemide; carbetimer; carboplatin; carmustine; carubicin hydrochloride; carzelesin; cedefingol; chlorambucil; cirolemycin; cisplatin; cladribine; crisnatol mesylate; cyclophosphamide; cytarabine; dacarbazine; dactinomycin; daunorubicin hydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguanine mesylate; diaziquone; docetaxel; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate; dromostanolone propionate; duazomycin; edatrexate; eflornithine hydrochloride; elsamitrucin; enloplatin; enpromate; epipropidine; epirubicin hydrochloride; erbulozole; esorubicin hydrochloride; estramustine; estramustine phosphate sodium; etanidazole; etoposide; etoposide phosphate; etoprine; fadrozole hydrochloride; fazarabine; fenretinide; floxuridine; fludarabine phosphate; fluorouracil; fluorocitabine; fosquidone; fostriecin sodium; gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide; ilmofosine; interleukin II (including recombinant interleukin II, or rIL2), interferon alfa-2a; interferon alfa-2b; interferon alfa-n1; interferon alfa-n3; interferon beta-I a; interferon gamma-I b; iproplatin; irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolide acetate; liarozole hydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride; masoprocol; maytansine; mechlorethamine hydrochloride; megestrol acetate; melengestrol acetate; melphalan; menogaril; mercaptopurine; methotrexate; methotrexate sodium; metoprine; meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazole; nogalamycin; ormaplatin; oxisuran; paclitaxel; pegaspargase; peliomycin; pentamustine; peplomycin sulfate; perfosfamide; pipobroman; piposulfan; piroxantrone hydrochloride; plicamycin; plomestane; porfimer sodium; porfiromycin; prednimustine; procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazofurin; riboprine; rogletimide; safingol; safingol hydrochloride; semustine; simtrazene; sparfosate sodium; sparsomycin; spirogermanium hydrochloride; spiromustine; spiroplatin; streptonigrin; - 53 - 53762388.1 Attorney Docket No.046483-7452WO1(03831) streptozocin; sulofenur; talisomycin; tecogalan sodium; tegafur; teloxantrone hydrochloride; temoporfin; teniposide; teroxirone; testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin; tirapazamine; toremifene citrate; trestolone acetate; triciribine phosphate; trimetrexate; trimetrexate glucuronate; triptorelin; tubulozole hydrochloride; uracil mustard; uredepa; vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate; vinglycinate sulfate; vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate; vinzolidine sulfate; vorozole; zeniplatin; zinostatin; zorubicin hydrochloride. Other anti-cancer drugs include, but are not limited to: 20-epi-1,25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti- dorsalizing morphogenetic protein-1; antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine; baccatin III derivatives; balanol; batimastat; BCR / ABL antagonists; benzochlorins; benzoylstaurosporine; beta lactam derivatives; beta-alethine; betaclamycin B; betulinic acid; bFGF inhibitor; bicalutamide; bisantrene; bisaziridinylspermine; bisnafide; bistratene A; bizelesin; breflate; bropirimine; budotitane; buthionine sulfoximine; calcipotriol; calphostin C; camptothecin derivatives; canarypox IL-2; capecitabine; carboxamide-amino-triazole; carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor; carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropin B; cetrorelix; chlorins; chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine; clomifene analogues; clotrimazole; collismycin A; collismycin B; combretastatin A4; combretastatin analogue; conagenin; crambescidin 816; crisnatol; cryptophycin 8; cryptophycin A derivatives; curacin A; cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin; dexamethasone; dexifosfamide; dexrazoxane; dexverapamil; diaziquone; didemnin B; didox; diethylnorspermine; dihydro-5-azacytidine; dihydrotaxol, 9-; dioxamycin; diphenyl spiromustine; docetaxel; docosanol; dolasetron; doxifluridine; droloxifene; dronabinol; duocarmycin SA; ebselen; ecomustine; edelfosine; edrecolomab; eflornithine; elemene; emitefur; epirubicin; epristeride; estramustine analogue; estrogen agonists; estrogen antagonists; etanidazole; etoposide phosphate; exemestane; fadrozole; - 54 - 53762388.1 Attorney Docket No.046483-7452WO1(03831) fazarabine; fenretinide; filgrastim; finasteride; flavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunorunicin hydrochloride; forfenimex; formestane; fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix; gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam; heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene; idramantone; ilmofosine; ilomastat; imidazoacridones; imiquimod; immunostimulant peptides; insulin-like growth factor-1 receptor inhibitor; interferon agonists; interferons; interleukins; iobenguane; iododoxorubicin; ipomeanol, 4-; iroplact; irsogladine; isobengazole; isohomohalicondrin B; itasetron; jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide; leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemia inhibiting factor; leukocyte alpha interferon; leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole; linear polyamine analogue; lipophilic disaccharide peptide; lipophilic platinum compounds; lissoclinamide 7; lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine; lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides; maitansine; mannostatin A; marimastat; masoprocol; maspin; matrilysin inhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone; meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone; miltefosine; mirimostim; mismatched double stranded RNA; mitoguazone; mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast growth factor-saporin; mitoxantrone; mofarotene; molgramostim; monoclonal antibody, human chorionic gonadotrophin; monophosphoryl lipid A+myobacterium cell wall sk; mopidamol; multiple drug resistance gene inhibitor; multiple tumor suppressor 1-based therapy; mustard anticancer agent; mycaperoxide B; mycobacterial cell wall extract; myriaporone; N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip; naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin; nemorubicin; neridronic acid; neutral endopeptidase; nilutamide; nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn; O6-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone; ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin; osaterone; oxaliplatin; oxaunomycin; paclitaxel; paclitaxel analogues; paclitaxel derivatives; palauamine; palmitoylrhizoxin; pamidronic acid; panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase; peldesine; pentosan polysulfate sodium; pentostatin; pentrozole; perflubron; perfosfamide; perillyl alcohol; phenazinomycin; phenylacetate; phosphatase inhibitors; picibanil; pilocarpine hydrochloride; pirarubicin; piritrexim; placetin A; placetin B; plasminogen activator inhibitor; platinum complex; platinum compounds; platinum- triamine complex; porfimer sodium; porfiromycin; prednisone; propyl bis-acridone; - 55 - 53762388.1 Attorney Docket No.046483-7452WO1(03831) prostaglandin J2; proteasome inhibitors; protein A-based immune modulator; protein kinase C inhibitor; protein kinase C inhibitors, microalgal; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine; pyridoxylated hemoglobin polyoxyethylene conjugate; raf antagonists; raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors; ras inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin; ribozymes; RII retinamide; rogletimide; rohitukine; romurtide; roquinimex; rubiginone B1; ruboxyl; safingol; saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics; semustine; senescence derived inhibitor 1; sense oligonucleotides; signal transduction inhibitors; signal transduction modulators; single chain antigen binding protein; sizofuran; sobuzoxane; sodium borocaptate; sodium phenylacetate; solverol; somatomedin binding protein; sonermin; sparfosic acid; spicamycin D; spiromustine; splenopentin; spongistatin 1; squalamine; stem cell inhibitor; stem-cell division inhibitors; stipiamide; stromelysin inhibitors; sulfinosine; superactive vasoactive intestinal peptide antagonist; suradista; suramin; swainsonine; synthetic glycosaminoglycans; tallimustine; tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium; tegafur; tellurapyrylium; telomerase inhibitors; temoporfin; temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine; thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetic; thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroid stimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocene bichloride; topsentin; toremifene; totipotent stem cell factor; translation inhibitors; tretinoin; triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenital sinus-derived growth inhibitory factor; urokinase receptor antagonists; vapreotide; variolin B; vector system, erythrocyte gene therapy; velaresol; veramine; verdins; verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; and zinostatin stimalamer. In one embodiment, the anti- cancer drug is 5-fluorouracil, taxol, or leucovorin. In some embodiments, the anti-cancer agent may be a prodrug form of an anti-cancer agent. As used herein, the term “prodrug form” and its derivatives is used to refer to a drug that has been chemically modified to add and / or remove one or more substituents in such a manner that, upon introduction of the prodrug form into a subject, such a modification may be reversed by naturally occurring processes, thus reproducing the drug. The use of a prodrug form of an anti-cancer agent in the compositions, among other things, may increase the concentration of the anti-cancer agent in the compositions of the present disclosure. In certain embodiments, an anti-cancer agent may be chemically modified with an alkyl or acyl group - 56 - 53762388.1 Attorney Docket No.046483-7452WO1(03831) or some form of lipid. The selection of such a chemical modification, including the substituent(s) to add and / or remove to create the prodrug, may depend upon a number of factors including, but not limited to, the particular drug and the desired properties of the prodrug. One of ordinary skill in the art, with the benefit of this disclosure, will recognize suitable chemical modifications. Small molecule therapeutic agents In various embodiments, the agent is a therapeutic agent. In various embodiments, the therapeutic agent is a small molecule. When the therapeutic agent is a small molecule, a small molecule may be obtained using standard methods known to the skilled artisan. Such methods include chemical organic synthesis or biological means. Biological means include purification from a biological source, recombinant synthesis and in vitro translation systems, using methods well known in the art. In certain embodiments, a small molecule therapeutic agents comprises an organic molecule, inorganic molecule, biomolecule, synthetic molecule, and the like. Combinatorial libraries of molecularly diverse chemical compounds potentially useful in treating a variety of diseases and conditions are well known in the art, as are method of making the libraries. The method may use a variety of techniques well-known to the skilled artisan including solid phase synthesis, solution methods, parallel synthesis of single compounds, synthesis of chemical mixtures, rigid core structures, flexible linear sequences, deconvolution strategies, tagging techniques, and generating unbiased molecular landscapes for lead discovery vs. biased structures for lead development. In some embodiments of the invention, the therapeutic agent is synthesized and / or identified using combinatorial techniques. In a general method for small library synthesis, an activated core molecule is condensed with a number of building blocks, resulting in a combinatorial library of covalently linked, core-building block ensembles. The shape and rigidity of the core determines the orientation of the building blocks in shape space. The libraries can be biased by changing the core, linkage, or building blocks to target a characterized biological structure (“focused libraries”) or synthesized with less structural bias using flexible cores. In some embodiments of the invention, the therapeutic agent is synthesized via small library synthesis. The small molecule and small molecule compounds described herein may be present as salts even if salts are not depicted, and it is understood that the invention embraces all salts and solvates of the therapeutic agents depicted here, as well as the non-salt and non-solvate - 57 - 53762388.1 Attorney Docket No.046483-7452WO1(03831) form of the therapeutic agents, as is well understood by the skilled artisan. In some embodiments, the salts of the therapeutic agents of the invention are pharmaceutically acceptable salts. Where tautomeric forms may be present for any of the therapeutic agents described herein, each and every tautomeric form is intended to be included in the present invention, even though only one or some of the tautomeric forms may be explicitly depicted. For example, when a 2-hydroxypyridyl moiety is depicted, the corresponding 2-pyridone tautomer is also intended. The invention also includes any or all of the stereochemical forms, including any enantiomeric or diastereomeric forms of the therapeutic agents described. The recitation of the structure or name herein is intended to embrace all possible stereoisomers of therapeutic agents depicted. All forms of the therapeutic agents are also embraced by the invention, such as crystalline or non-crystalline forms of the therapeutic agent. Compositions comprising a therapeutic agents of the invention are also intended, such as a composition of substantially pure therapeutic agent, including a specific stereochemical form thereof, or a composition comprising mixtures of therapeutic agents of the invention in any ratio, including two or more stereochemical forms, such as in a racemic or non-racemic mixture. The invention also includes any or all active analog or derivative, such as a prodrug, of any therapeutic agent described herein. In certain embodiments, the therapeutic agent is a prodrug. In certain embodiments, the small molecules described herein are candidates for derivatization. As such, in certain instances, the analogs of the small molecules described herein that have modulated potency, selectivity, and solubility are included herein and provide useful leads for drug discovery and drug development. Thus, in certain instances, during optimization new analogs are designed considering issues of drug delivery, metabolism, novelty, and safety. In some instances, small molecule therapeutic agents described herein are derivatives or analogs of known therapeutic agents, as is well known in the art of combinatorial and medicinal chemistry. The analogs or derivatives can be prepared by adding and / or substituting functional groups at various locations. As such, the small molecules described herein can be converted into derivatives / analogs using well known chemical synthesis procedures. For example, all of the hydrogen atoms or substituents can be selectively modified to generate new analogs. Also, the linking atoms or groups can be modified into longer or shorter linkers with carbon backbones or hetero atoms. Also, the ring groups can be changed so as to have a different number of atoms in the ring and / or to include hetero atoms. - 58 - 53762388.1 Attorney Docket No.046483-7452WO1(03831) Moreover, aromatics can be converted to cyclic rings, and vice versa. For example, the rings may be from 5-7 atoms, and may be carbocyclic or heterocyclic. As used herein, the term “analog,” “analogue,” or “derivative” is meant to refer to a chemical compound or molecule made from a parent compound or molecule by one or more chemical reactions. As such, an analog can be a structure having a structure similar to that of the small molecule therapeutic agents described herein or can be based on a scaffold of a small molecule therapeutic agents described herein, but differing from it in respect to certain components or structural makeup, which may have a similar or opposite action metabolically. An analog or derivative of any of a small molecule inhibitor in accordance with the present invention can be used to treat a disease or disorder. In certain embodiments, the small molecule therapeutic agents described herein can independently be derivatized, or analogs prepared therefrom, by modifying hydrogen groups independently from each other into other substituents. That is, each atom on each molecule can be independently modified with respect to the other atoms on the same molecule. Any traditional modification for producing a derivative / analog can be used. For example, the atoms and substituents can be independently comprised of hydrogen, an alkyl, aliphatic, straight chain aliphatic, aliphatic having a chain hetero atom, branched aliphatic, substituted aliphatic, cyclic aliphatic, heterocyclic aliphatic having one or more hetero atoms, aromatic, heteroaromatic, polyaromatic, polyamino acids, peptides, polypeptides, combinations thereof, halogens, halo-substituted aliphatics, and the like. Additionally, any ring group on a compound can be derivatized to increase and / or decrease ring size as well as change the backbone atoms to carbon atoms or hetero atoms. Nucleic Acids In certain embodiments, the invention includes an ionizable LNP molecule formulated for targeted in vivo T cell delivery comprising or encapsulating one or more nucleic acid molecule. In certain embodiments, the nucleic acid molecule is a mRNA molecule. In certain embodiments, the mRNA molecule encodes a CAR. In certain embodiments, the nucleoside- modified mRNA molecule encodes a CAR. In certain embodiments, the invention includes a nucleoside-modified mRNA molecule encoding an adjuvant. The nucleotide sequences encoding an CAR, as described herein, can alternatively comprise sequence variations with respect to the original nucleotide sequences, for example, substitutions, insertions and / or deletions of one or more nucleotides, with the condition that the resulting polynucleotide encodes a polypeptide according to the invention. Therefore, the - 59 - 53762388.1 Attorney Docket No.046483-7452WO1(03831) scope of the present invention includes nucleotide sequences that are substantially homologous to the nucleotide sequences recited herein and encode an antigen or antigen binding molecule or adjuvant of interest. Further, the scope of the invention includes nucleotide sequences that encode amino acid sequences that are substantially homologous to the amino acid sequences recited herein and preserve the immunogenic function of the original amino acid sequence. As used herein, an amino acid sequence is “substantially homologous” to any of the amino acid sequences described herein when its amino acid sequence has a degree of identity with respect to the amino acid sequence of at least 60%, advantageously of at least 70%, preferably of at least 85%, and more preferably of at least 95%. The identity between two amino acid sequences is preferably determined by using the BLASTN algorithm (BLAST Manual, Altschul, S., et al., NCBI NLM NIH Bethesda, Md.20894, Altschul, S., et al., J. Mol. Biol.215: 403-410 (1990)). In certain embodiments, the invention relates to a construct, comprising a nucleotide sequence encoding a CAR. In certain embodiments, the construct comprises a plurality of nucleotide sequences encoding a plurality of antigens. For example, in certain embodiments, the construct encodes 1 or more, 2 or more, 5 or more, 10 or more, 15 or more, or 20 or more antigens. In certain embodiments, the invention relates to a construct, comprising a nucleotide sequence encoding an adjuvant. In certain embodiments, the construct comprises a first nucleotide sequence encoding a CAR and a second nucleotide sequence encoding an adjuvant. In certain embodiments, the composition comprises a plurality of constructs, each construct encoding one or more antigens. In certain embodiments, the composition comprises 1 or more, 2 or more, 5 or more, 10 or more, 15 or more, or 20 or more constructs. In certain embodiments, the composition comprises a first construct, comprising a nucleotide sequence encoding a CAR; and a second construct, comprising a nucleotide sequence encoding an adjuvant. In another particular embodiment, the construct is operatively bound to a translational control element. The construct can incorporate an operatively bound regulatory sequence for the expression of the nucleotide sequence of the invention, thus forming an expression cassette. Polypeptide therapeutic agents In other related aspects, the therapeutic agent includes an isolated peptide that - 60 - 53762388.1 Attorney Docket No.046483-7452WO1(03831) modulates a target. For example, In certain embodiments, the peptide of the invention inhibits or activates a target directly by binding to the target thereby modulating the normal functional activity of the target. In certain embodiments, the peptide of the invention modulates the target by competing with endogenous proteins. In certain embodiments, the peptide of the invention modulates the activity of the target by acting as a transdominant negative mutant. The variants of the polypeptide therapeutic agents may be (i) one in which one or more of the amino acid residues are substituted with a conserved or non-conserved amino acid residue (preferably a conserved amino acid residue) and such substituted amino acid residue may or may not be one encoded by the genetic code, (ii) one in which there are one or more modified amino acid residues, e.g., residues that are modified by the attachment of substituent groups, (iii) one in which the polypeptide is an alternative splice variant of the polypeptide of the present invention, (iv) fragments of the polypeptides and / or (v) one in which the polypeptide is fused with another polypeptide, such as a leader or secretory sequence or a sequence which is employed for purification (for example, His-tag) or for detection (for example, Sv5 epitope tag). The fragments include polypeptides generated via proteolytic cleavage (including multi-site proteolysis) of an original sequence. Variants may be post-translationally, or chemically modified. Such variants are deemed to be within the scope of those skilled in the art from the teaching herein. CAR agents In certain embodiments, the mRNA molecule of the invention encodes a chimeric antigen receptor (CAR). In certain embodiments, the CAR comprises an antigen binding domain. In certain embodiments, the antigen binding domain is a targeting domain, wherein the targeting domain directs the T cell expressing the CAR to a specific cell or tissue of interest. For example, In certain embodiments, the targeting domain comprises an antibody, antibody fragment, or peptide that specifically binds to an expressed on a pathogenic organism or a tumor cell thereby directing the T cell expressing the CAR to a cell or tissue expressing the antigen. In certain embodiments, the invention relates to an immune cell targeted LNP comprising an agent, wherein the agent comprises a nucleic acid sequence encoding a chimeric antigen receptor (CAR). In certain embodiments, agent comprises an mRNA molecule encoding a CAR. In certain embodiments, the agent comprises a modified nucleoside mRNA molecule encoding a CAR. In various embodiments, the CAR can be a “first generation,” “second generation,” - 61 - 53762388.1 Attorney Docket No.046483-7452WO1(03831) “third generation,” “fourth generation” or “fifth generation” CAR (see, for example, Sadelain et al., Cancer Discov.3(4):388-398 (2013); Jensen et al., Immunol. Rev.257:127-133 (2014); Sharpe et al., Dis. Model Mech.8(4):337-350 (2015); Brentjens et al., Clin. Cancer Res. 13:5426-5435 (2007); Gade et al., Cancer Res.65:9080-9088 (2005); Maher et al., Nat. Biotechnol.20:70-75 (2002); Kershaw et al., J. Immunol.173:2143-2150 (2004); Sadelain et al., Curr. Opin. Immunol. (2009); Hollyman et al., J. Immunother.32:169-180 (2009)). “First generation” CARs for use in the invention comprise an antigen binding domain, for example, a single-chain variable fragment (scFv), fused to a transmembrane domain, which is fused to a cytoplasmic / intracellular domain of the T cell receptor chain. “First generation” CARs typically have the intracellular domain from the CD3ζ-chain, which is the primary transmitter of signals from endogenous T cell receptors (TCRs). “First generation” CARs can provide de novo antigen recognition and cause activation of both CD4+ and CD8+ T cells through their CD3ζ chain signaling domain in a single fusion molecule, independent of HLA-mediated antigen presentation. “Second-generation” CARs for use in the invention comprise an antigen binding domain, for example, a single-chain variable fragment (scFv), fused to an intracellular signaling domain capable of activating T cells and a co-stimulatory domain designed to augment T cell potency and persistence (Sadelain et al., Cancer Discov.3:388-398 (2013)). CAR design can therefore combine antigen recognition with signal transduction, two functions that are physiologically borne by two separate complexes, the TCR heterodimer and the CD3 complex. “Second generation” CARs include an intracellular domain from various co-stimulatory molecules, for example, CD28, 4-1BB, ICOS, OX40, and the like, in the cytoplasmic tail of the CAR to provide additional signals to the cell. “Second generation” CARs provide both co-stimulation, for example, by CD28 or 4- 1BB domains, and activation, for example, by a CD3ζ signaling domain. Preclinical studies have indicated that “Second Generation” CARs can improve the anti-tumor activity of T cells. For example, robust efficacy of “Second Generation” CAR modified T cells was demonstrated in clinical trials targeting the CD19 molecule in patients with chronic lymphoblastic leukemia (CLL) and acute lymphoblastic leukemia (ALL) (Davila et al., Oncoimmunol.1(9):1577-1583 (2012)). “Third generation” CARs provide multiple co-stimulation, for example, by comprising both CD28 and 4-1BB domains, and activation, for example, by comprising a CD3ζ activation domain. “Fourth generation” CARs provide co-stimulation, for example, by CD28 or 4-1BB - 62 - 53762388.1 Attorney Docket No.046483-7452WO1(03831) domains, and activation, for example, by a CD3ζ signaling domain in addition to a constitutive or inducible chemokine component. “Fifth generation” CARs provide co-stimulation, for example, by CD28 or 4-1BB domains, and activation, for example, by a CD3ζ signaling domain, a constitutive or inducible chemokine component, and an intracellular domain of a cytokine receptor, for example, IL-2Rβ. In various embodiments, the CAR can be included in a multivalent CAR system, for example, a DualCAR or “TandemCAR” system. Multivalent CAR systems include systems or cells comprising multiple CARs and systems or cells comprising bivalent / bispecific CARs targeting more than one antigen. In the embodiments disclosed herein, the CARs generally comprise an antigen binding domain, a transmembrane domain and an intracellular domain, as described above. In a particular non-limiting embodiment, the antigen-binding domain is an scFv specific for binding to a surface antigen of a target cell of interest (e.g., a pathogen or tumor cell.) Combinations In certain embodiments, the composition of the present invention comprises a combination of agents described herein. In certain embodiments, a composition comprising a combination of agents described herein has an additive effect, wherein the overall effect of the combination is approximately equal to the sum of the effects of each individual agent. In other embodiments, a composition comprising a combination of agents described herein has a synergistic effect, wherein the overall effect of the combination is greater than the sum of the effects of each individual agent. A composition comprising a combination of agents comprises individual agents in any suitable ratio. For example, In certain embodiments, the composition comprises a 1:1 ratio of two individual agents. However, the combination is not limited to any particular ratio. Rather any ratio that is shown to be effective is encompassed. Methods In one aspect, the present disclosure provides a method of treating, preventing, and / or ameliorating a hematopoietic stem cell (HSC) based disease or disorder in a subject. In certain embodiments, the method comprises administering to the subject at least one LNP of the disclosure. In certain embodiments, the LNP is formulated as a pharmaceutical composition. - 63 - 53762388.1 Attorney Docket No.046483-7452WO1(03831) In certain embodiments, the hematopoietic stem cell-based disease and / or disorder is at least one selected from the group consisting of cancer, cardiac failure, neural disorders, hemoglobinopathies, auto-immune diseases, immunodeficiency, and a metabolic or genetic disorder. In certain embodiments, the subject is a mammal. In certain embodiments, the mammal is a human. In certain embodiments, the human is a fetus. In certain embodiments, the administration comprises in utero administration. Pharmaceutical Compositions In another aspect, the present disclosure provides a pharmaceutical composition comprising the lipid nanoparticle (LNP) of the present disclosure and at least one pharmaceutically acceptable carrier. In certain embodiments, the composition further comprises at least one adjuvant. In certain embodiments, the composition is a vaccine. Such a pharmaceutical composition may consist of at least one composition of the invention, in a form suitable for administration to a subject, or the pharmaceutical composition may comprise at least one composition, and one or more pharmaceutically acceptable carriers, one or more additional ingredients, or any combinations of these. At least one composition of the invention may be present in the pharmaceutical composition in the form of a physiologically acceptable salt, such as in combination with a physiologically acceptable cation or anion, as is well known in the art. In certain embodiments, the pharmaceutical compositions useful for practicing the method of the invention may be administered to deliver a dose of between 1 ng / kg / day and 100 mg / kg / day. In other embodiments, the pharmaceutical compositions useful for practicing the invention may be administered to deliver a dose of between 1 ng / kg / day and 1,000 mg / kg / day. The relative amounts of the active ingredient, the pharmaceutically acceptable carrier, and any additional ingredients in a pharmaceutical composition of the invention will vary, depending upon the identity, size, and condition of the subject treated and further depending upon the route by which the composition is to be administered. By way of example, the composition may comprise between 0.1% and 100% (w / w) active ingredient. Pharmaceutical compositions that are useful in the methods of the invention may be suitably developed for nasal, inhalational, oral, rectal, vaginal, pleural, peritoneal, parenteral, topical, transdermal, pulmonary, intranasal, buccal, ophthalmic, epidural, intrathecal, intravenous, or another route of administration. A composition useful within the methods of - 64 - 53762388.1 Attorney Docket No.046483-7452WO1(03831) the invention may be directly administered to the brain, the brainstem, or any other part of the central nervous system of a mammal or bird. Other contemplated formulations include projected nanoparticles, microspheres, liposomal preparations, coated particles, polymer conjugates, resealed erythrocytes containing the active ingredient, and immunologically- based formulations. In certain embodiments, the compositions of the invention are part of a pharmaceutical matrix, which allows for manipulation of insoluble materials and improvement of the bioavailability thereof, development of controlled or sustained release products, and generation of homogeneous compositions. By way of example, a pharmaceutical matrix may be prepared using hot melt extrusion, solid solutions, solid dispersions, size reduction technologies, molecular complexes (e.g., cyclodextrins, and others), microparticulate, and particle and formulation coating processes. Amorphous or crystalline phases may be used in such processes. The route(s) of administration will be readily apparent to the skilled artisan and will depend upon any number of factors including the type and severity of the disease being treated, the type and age of the veterinary or human patient being treated, and the like. The formulations of the pharmaceutical compositions described herein may be prepared by any method known or hereafter developed in the art of pharmacology and pharmaceutics. In general, such preparatory methods include the step of bringing the active ingredient into association with a carrier or one or more other accessory ingredients, and then, if necessary or desirable, shaping or packaging the product into a desired single-dose or multi-dose unit. As used herein, a “unit dose” is a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient that would be administered to a subject or a convenient fraction of such a dosage such as, for example, one-half or one- third of such a dosage. The unit dosage form may be for a single daily dose or one of multiple daily doses (e.g., about 1 to 4 or more times per day). When multiple daily doses are used, the unit dosage form may be the same or different for each dose. Although the descriptions of pharmaceutical compositions provided herein are principally directed to pharmaceutical compositions suitable for ethical administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions - 65 - 53762388.1 Attorney Docket No.046483-7452WO1(03831) suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and perform such modification with merely ordinary, if any, experimentation. Subjects to which administration of the pharmaceutical compositions of the invention is contemplated include, but are not limited to, humans and other primates, mammals including commercially relevant mammals such as cattle, pigs, horses, sheep, cats, and dogs. In certain embodiments, the compositions of the invention are formulated using one or more pharmaceutically acceptable excipients or carriers. In certain embodiments, the pharmaceutical compositions of the invention comprise a therapeutically effective amount of at least one compound of the invention and a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers, which are useful, include, but are not limited to, glycerol, water, saline, ethanol, recombinant human albumin (e.g., RECOMBUMIN®), solubilized gelatins (e.g., GELOFUSINE®), and other pharmaceutically acceptable salt solutions such as phosphates and salts of organic acids. Examples of these and other pharmaceutically acceptable carriers are described in Remington’s Pharmaceutical Sciences (1991, Mack Publication Co., New Jersey). The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), recombinant human albumin, solubilized gelatins, suitable mixtures thereof, and vegetable oils. The proper fluidity may 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 may be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, isotonic agents, for example, sugars, sodium chloride, or polyalcohols such as mannitol and sorbitol, are included in the composition. Prolonged absorption of the injectable compositions may be brought about by including in the composition an agent that delays absorption, for example, aluminum monostearate or gelatin. Formulations may be employed in admixtures with conventional excipients, i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for oral, parenteral, nasal, inhalational, intravenous, subcutaneous, transdermal enteral, or any other suitable mode of administration, known to the art. The pharmaceutical preparations may be sterilized and if desired mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure buffers, - 66 - 53762388.1 Attorney Docket No.046483-7452WO1(03831) coloring, flavoring, and / or fragrance-conferring substances and the like. They may also be combined where desired with other active agents, e.g., other analgesic, anxiolytics or hypnotic agents. As used herein, “additional ingredients” include, but are not limited to, one or more ingredients that may be used as a pharmaceutical carrier. The composition of the invention may comprise a preservative from about 0.005% to 2.0% by total weight of the composition. The preservative is used to prevent spoilage in the case of exposure to contaminants in the environment. Examples of preservatives useful in accordance with the invention include but are not limited to those selected from the group consisting of benzyl alcohol, sorbic acid, parabens, imidurea and any combinations thereof. One such preservative is a combination of about 0.5% to 2.0% benzyl alcohol and 0.05-0.5% sorbic acid. The composition may include an antioxidant and a chelating agent that inhibit the degradation of the compound. Antioxidants for some compounds are BHT, BHA, alpha- tocopherol and ascorbic acid in the exemplary range of about 0.01% to 0.3%, or BHT in the range of 0.03% to 0.1% by weight by total weight of the composition. The chelating agent may be present in an amount of from 0.01% to 0.5% by weight by total weight of the composition. Exemplary chelating agents include edetate salts (e.g. disodium edetate) and citric acid in the weight range of about 0.01% to 0.20%, or in the range of 0.02% to 0.10% by weight by total weight of the composition. The chelating agent is useful for chelating metal ions in the composition that may be detrimental to the shelf life of the formulation. While BHT and disodium edetate are exemplary antioxidant and chelating agent, respectively, for some compounds, other suitable and equivalent antioxidants and chelating agents may be substituted therefore as would be known to those skilled in the art. Liquid suspensions may be prepared using conventional methods to achieve suspension of the active ingredient in an aqueous or oily vehicle. Aqueous vehicles include, for example, water, and isotonic saline. Oily vehicles include, for example, almond oil, oily esters, ethyl alcohol, vegetable oils such as arachis, olive, sesame, or coconut oil, fractionated vegetable oils, and mineral oils such as liquid paraffin. Liquid suspensions may further comprise one or more additional ingredients including, but not limited to, suspending agents, dispersing or wetting agents, emulsifying agents, demulcents, preservatives, buffers, salts, flavorings, coloring agents, and sweetening agents. Oily suspensions may further comprise a thickening agent. Known suspending agents include, but are not limited to, sorbitol syrup, hydrogenated edible fats, sodium alginate, polyvinylpyrrolidone, gum tragacanth, gum acacia, and cellulose derivatives such as sodium carboxymethylcellulose, methylcellulose, - 67 - 53762388.1 Attorney Docket No.046483-7452WO1(03831) hydroxypropylmethyl cellulose. Known dispersing or wetting agents include, but are not limited to, naturally-occurring phosphatides such as lecithin, condensation products of an alkylene oxide with a fatty acid, with a long chain aliphatic alcohol, with a partial ester derived from a fatty acid and a hexitol, or with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene stearate, heptadecaethyleneoxycetanol, polyoxyethylene sorbitol monooleate, and polyoxyethylene sorbitan monooleate, respectively). Known emulsifying agents include, but are not limited to, lecithin, acacia, and ionic or non-ionic surfactants. Known preservatives include, but are not limited to, methyl, ethyl, or n-propyl para-hydroxybenzoates, ascorbic acid, and sorbic acid. Known sweetening agents include, for example, glycerol, propylene glycol, sorbitol, sucrose, and saccharin. Liquid solutions of the active ingredient in aqueous or oily solvents may be prepared in substantially the same manner as liquid suspensions, the primary difference being that the active ingredient is dissolved, rather than suspended in the solvent. As used herein, an “oily” liquid is one which comprises a carbon-containing liquid molecule and which exhibits a less polar character than water. Liquid solutions of the pharmaceutical composition of the invention may comprise each of the components described with regard to liquid suspensions, it being understood that suspending agents will not necessarily aid dissolution of the active ingredient in the solvent. Aqueous solvents include, for example, water, and isotonic saline. Oily solvents include, for example, almond oil, oily esters, ethyl alcohol, vegetable oils such as arachis, olive, sesame, or coconut oil, fractionated vegetable oils, and mineral oils such as liquid paraffin. A pharmaceutical composition of the invention may also be prepared, packaged, or sold in the form of oil-in-water emulsion or a water-in-oil emulsion. The oily phase may be a vegetable oil such as olive or arachis oil, a mineral oil such as liquid paraffin, or a combination of these. Such compositions may further comprise one or more emulsifying agents such as naturally occurring gums such as gum acacia or gum tragacanth, naturally- occurring phosphatides such as soybean or lecithin phosphatide, esters or partial esters derived from combinations of fatty acids and hexitol anhydrides such as sorbitan monooleate, and condensation products of such partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate. These emulsions may also contain additional ingredients including, for example, sweetening or flavoring agents. Methods for impregnating or coating a material with a chemical composition are known in the art, and include, but are not limited to methods of depositing or binding a chemical composition onto a surface, methods of incorporating a chemical composition into - 68 - 53762388.1 Attorney Docket No.046483-7452WO1(03831) the structure of a material during the synthesis of the material (i.e., such as with a physiologically degradable material), and methods of absorbing an aqueous or oily solution or suspension into an absorbent material, with or without subsequent drying. Methods for mixing components include physical milling, the use of pellets in solid and suspension formulations and mixing in a transdermal patch, as known to those skilled in the art. Administration / Dosing The regimen of administration may affect what constitutes an effective amount. The therapeutic formulations may be administered to the patient either prior to or after the onset of a disease or disorder. Further, several divided dosages, as well as staggered dosages may be administered daily or sequentially, or the dose may be continuously infused, or may be a bolus injection. Further, the dosages of the therapeutic formulations may be proportionally increased or decreased as indicated by the exigencies of the therapeutic or prophylactic situation. Administration of the compositions of the present disclosure to a patient, such as a mammal, such as a human, may be carried out using known procedures, at dosages and for periods of time effective to treat a disease or disorder contemplated herein. An effective amount of therapeutic (i.e., composition) necessary to achieve a therapeutic effect may vary according to factors such as the activity of the particular therapeutic employed; the time of administration; the rate of excretion of the composition; the duration of the treatment; other drugs, compounds or materials used in combination with the composition; the state of the disease or disorder, age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well-known in the medical arts. Dosage regimens may be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation. A non-limiting example of an effective dose range for a therapeutic composition of the disclosure is from about 0.01 mg / kg to 100 mg / kg of body weight / per day of active agent (i.e., nucleic acid). One of ordinary skill in the art would be able to study the relevant factors and make the determination regarding the effective amount of the therapeutic composition without undue experimentation. The composition may be administered to an animal as frequently as several times daily, or it may be administered less frequently, such as once a day, once a week, once every two weeks, once a month, or even less frequently, such as once every several months or even once a year or less. It is understood that the amount of composition dosed per day may be - 69 - 53762388.1 Attorney Docket No.046483-7452WO1(03831) administered, in non-limiting examples, every day, every other day, every 2 days, every 3 days, every 4 days, or every 5 days. For example, with every other day administration, a 5 mg per day dose may be initiated on Monday with a first subsequent 5 mg per day dose administered on Wednesday, a second subsequent 5 mg per day dose administered on Friday, and so on. The frequency of the dose is readily apparent to the skilled artisan and depends upon a number of factors, such as, but not limited to, type and severity of the disease being treated, and type and age of the animal. Actual dosage levels of the active ingredients in the pharmaceutical compositions of this disclosure may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient. A medical doctor, e.g., physician or veterinarian, having ordinary skill in the art may readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the compounds of the disclosure employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. In particular embodiments, it is especially advantageous to formulate the compound 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 composition to produce the desired therapeutic effect in association with the required pharmaceutical vehicle. The dosage unit forms of the disclosure are dictated by and directly dependent on (a) the unique characteristics of the therapeutic composition and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding / formulating such a therapeutic composition for the treatment of a disease or disorder in a patient. In certain embodiments, the compositions of the disclosure are administered to the patient in dosages that range from one to five times per day or more. In other embodiments, the compositions of the disclosure are administered to the patient in range of dosages that include, but are not limited to, once every day, every two days, every three days to once a week, and once every two weeks. It will be readily apparent to one skilled in the art that the frequency of administration of the various combination compositions of the disclosure will vary from subject to subject depending on many factors including, but not limited to, age, disease or disorder to be treated, gender, overall health, and other factors. Thus, the - 70 - 53762388.1 Attorney Docket No.046483-7452WO1(03831) disclosure should not be construed to be limited to any particular dosage regime and the precise dosage and composition to be administered to any patient will be determined by the attending physician taking all other factors about the patient into account. The amount of active agent of the composition(s) of the disclosure for administration may be in the range of from about 1 µg to about 7,500 mg, about 20 µg to about 7,000 mg, about 40 µg to about 6,500 mg, about 80 µ g to about 6,000 mg, about 100 µ g to about 5,500 mg, about 200 µ g to about 5,000 mg, about 400 µ g to about 4,000 mg, about 800 µ g to about 3,000 mg, about 1 mg to about 2,500 mg, about 2 mg to about 2,000 mg, about 5 mg to about 1,000 mg, about 10 mg to about 750 mg, about 20 mg to about 600 mg, about 30 mg to about 500 mg, about 40 mg to about 400 mg, about 50 mg to about 300 mg, about 60 mg to about 250 mg, about 70 mg to about 200 mg, about 80 mg to about 150 mg, and any and all whole or partial increments there-in-between. In some embodiments, the dose of active agent (i.e., nucleic acid) present in the composition of the disclosure is from about 0.5 µg and about 5,000 mg. In some embodiments, a dose of active agent present in the composition of the disclosure used in compositions described herein is less than about 5,000 mg, or less than about 4,000 mg, or less than about 3,000 mg, or less than about 2,000 mg, or less than about 1,000 mg, or less than about 800 mg, or less than about 600 mg, or less than about 500 mg, or less than about 200 mg, or less than about 50 mg. Similarly, in some embodiments, a dose of a second compound as described herein is less than about 1,000 mg, or less than about 800 mg, or less than about 600 mg, or less than about 500 mg, or less than about 400 mg, or less than about 300 mg, or less than about 200 mg, or less than about 100 mg, or less than about 50 mg, or less than about 40 mg, or less than about 30 mg, or less than about 25 mg, or less than about 20 mg, or less than about 15 mg, or less than about 10 mg, or less than about 5 mg, or less than about 2 mg, or less than about 1 mg, or less than about 0.5 mg, and any and all whole or partial increments thereof. In certain embodiments, the present disclosure is directed to a packaged pharmaceutical composition comprising a container holding a therapeutically effective amount of the composition of the disclosure, alone or in combination with a second pharmaceutical agent; and instructions for using the compound to treat, prevent, or reduce one or more symptoms of a disease or disorder in a patient. The term “container” includes any receptacle for holding the pharmaceutical composition or for managing stability or water uptake. For example, in certain embodiments, the container is the packaging that contains the pharmaceutical composition, such as liquid - 71 - 53762388.1 Attorney Docket No.046483-7452WO1(03831) (solution and suspension), semisolid, lyophilized solid, solution and powder or lyophilized formulation present in dual chambers. In other embodiments, the container is not the packaging that contains the pharmaceutical composition, i.e., the container is a receptacle, such as a box or vial that contains the packaged pharmaceutical composition or unpackaged pharmaceutical composition and the instructions for use of the pharmaceutical composition. Moreover, packaging techniques are well known in the art. It should be understood that the instructions for use of the pharmaceutical composition may be contained on the packaging containing the pharmaceutical composition, and as such the instructions form an increased functional relationship to the packaged product. However, it should be understood that the instructions may contain information pertaining to the compound’s ability to perform its intended function, e.g., treating, preventing, or reducing a disease or disorder in a patient. Administration Routes of administration of any of the compositions of the disclosure include inhalational, oral, nasal, rectal, parenteral, sublingual, transdermal, transmucosal (e.g., sublingual, lingual, (trans)buccal, (trans)urethral, vaginal (e.g., trans- and perivaginally), (intra)nasal, and (trans)rectal), intravesical, intrapulmonary, intraduodenal, intragastrical, intrathecal, epidural, intrapleural, intraperitoneal, subcutaneous, intramuscular, intradermal, intra-arterial, intravenous, intrabronchial, inhalation, and topical administration. Suitable compositions and dosage forms include, for example, tablets, capsules, caplets, pills, gel caps, troches, emulsions, dispersions, suspensions, solutions, syrups, granules, beads, transdermal patches, gels, powders, pellets, magmas, lozenges, creams, pastes, plasters, lotions, discs, suppositories, liquid sprays for nasal or oral administration, dry powder or aerosolized formulations for inhalation, compositions and formulations for intravesical administration and the like. It should be understood that the formulations and compositions that would be useful in the present disclosure are not limited to the particular formulations and compositions that are described herein. Parenteral Administration As used herein, “parenteral administration” of a pharmaceutical composition includes any route of administration characterized by physical breaching of a tissue of a subject and administration of the pharmaceutical composition through the breach in the tissue. Parenteral administration thus includes, but is not limited to, administration of a pharmaceutical composition by injection of the composition, by application of the composition through a - 72 - 53762388.1 Attorney Docket No.046483-7452WO1(03831) surgical incision, by application of the composition through a tissue-penetrating non-surgical wound, and the like. In particular, parenteral administration is contemplated to include, but is not limited to, subcutaneous, intravenous, intraperitoneal, intramuscular, intrasternal injection, and kidney dialytic infusion techniques. Formulations of a pharmaceutical composition suitable for parenteral administration comprise the active ingredient combined with a pharmaceutically acceptable carrier, such as sterile water or sterile isotonic saline. Such formulations may be prepared, packaged, or sold in a form suitable for bolus administration or for continuous administration. Injectable formulations may be prepared, packaged, or sold in unit dosage form, such as in ampules or in multidose containers containing a preservative. Injectable formulations may also be prepared, packaged, or sold in devices such as patient-controlled analgesia (PCA) devices. Formulations for parenteral administration include, but are not limited to, suspensions, solutions, emulsions in oily or aqueous vehicles, pastes, and implantable sustained-release or biodegradable formulations. Such formulations may further comprise one or more additional ingredients including, but not limited to, suspending, stabilizing, or dispersing agents. In certain embodiments of a formulation for parenteral administration, the active ingredient is provided in dry (i.e., powder or granular) form for reconstitution with a suitable vehicle (e.g., sterile pyrogen-free water) prior to parenteral administration of the reconstituted composition. The pharmaceutical compositions may be prepared, packaged, or sold in the form of a sterile injectable aqueous or oily suspension or solution. This suspension or solution may be formulated according to the known art, and may comprise, in addition to the active ingredient, additional ingredients such as the dispersing agents, wetting agents, or suspending agents described herein. Such sterile injectable formulations may be prepared using a non- toxic parenterally acceptable diluent or solvent, such as water or 1,3-butanediol, for example. Other acceptable diluents and solvents include, but are not limited to, Ringer’s solution, isotonic sodium chloride solution, and fixed oils such as synthetic mono- or di-glycerides. Other parentally-administrable formulations which are useful include those which comprise the active ingredient in microcrystalline form in a recombinant human albumin, a fluidized gelatin, in a liposomal preparation, or as a component of a biodegradable polymer system. Compositions for sustained release or implantation may comprise pharmaceutically acceptable polymeric or hydrophobic materials such as an emulsion, an ion exchange resin, a sparingly soluble polymer, or a sparingly soluble salt. EXAMPLES - 73 - 53762388.1 Attorney Docket No.046483-7452WO1(03831) Various embodiments of the present application can be better understood by reference to the following Examples which are offered by way of illustration. The scope of the present application is not limited to the Examples given herein. Example 1: Baseline LNP-mediated transfection of mouse HSCs in utero LNPs are conventionally formulated with four organic components: an ionizable lipid for nucleic acid loading and endosomal escape of nucleic acid cargo, phospholipid for bilayer stability, cholesterol for membrane rigidity, and lipid-anchored polyethylene glycol (PEG) for reduced aggregation and increased circulation time. A major advantage of LNPs for gene delivery applications is their modularity. Organic excipients can be interchanged to produce LNPs with distinct physiochemical properties, passively shifting biodistribution towards specific organs or cell types. Alternatively, target-specific ligands can be included during LNP formulation to actively influence tissue tropism. Described herein, in part, are methods to maximize LNP transfection of HSCs in vivo. In a prior study, potent ionizable lipids (e.g., C14-490) were identified for transfection of the mouse fetal liver following in utero IV injection at gestational day (E) 16. Given that murine fetal hematopoiesis begins to shift away from the liver by E16, this experiment was repeated at an earlier gestational timepoint to optimize baseline HSC transfection while maintaining technical feasibility. R26mT / mGfetuses (dual-fluorescent floxed reporter mouse model) were injected at E13.5 with C14-490 LNPs encapsulating Cre mRNA at a dose of 1 mg / kg mRNA.60 h later, fetal tissues were harvested, demonstrating strong transfection of the whole fetus and fetal liver. While 50% of fetal hepatocytes were transfected, only 2% of fetal HSCs were transfected, demonstrating that passive biodistribution alone is insufficient for robust LNP delivery to HSCs. Example 2: Design and characterization of anti-CD45 LNPs To enhance LNP-mediated transfection of HSCs, an active targeting approach was utilized, leveraging the CD45 receptor (CD45R), a type 1 transmembrane protein tyrosine phosphatase expressed on the surface of all HSCs (FIGs.1B-1C). To specifically engage the CD45R, CD45 antibody F(ab’)2 fragments were conjugated to the surface of C14-490 LNPs composed of a 5:1 ratio of PEG to PEG-maleimide via a thiol-maleimide reaction (targeted LNPs). C14-490 LNPs possessing PEG-maleimide moieties but without CD45 antibody functionalization (untargeted LNPs) served as controls. For initial studies, both targeted and untargeted LNPs were formulated to encapsulate GFP reporter mRNA. Targeted LNPs - 74 - 53762388.1 Attorney Docket No.046483-7452WO1(03831) displayed a ~20 nm increase in average diameter relative to untargeted LNPs (FIG.1D) without aggregation (FIG.1E) and with excellent mRNA encapsulation efficiency (FIG.1F). The impact of CD45 antibody functionalization to LNPs was tested in vitro in an immortalized human T cell line (Jurkats). Importantly, 100% of untreated Jurkats constitutively express the CD45R on their surface. Jurkats were treated with either targeted or untargeted LNPs encapsulating GFP mRNA and assessed for resultant GFP fluorescence via flow cytometry after 24 h. Targeted LNPs facilitated an 8-fold improvement in functional mRNA delivery to Jurkats relative to untargeted LNPs (FIG.2A) without in vitro cytotoxicity (FIG.2B). Enhancement in mRNA delivery was shown to be dose-dependent with a limited effect at a low dose of mRNA but a pronounced and saturating effect at higher doses of mRNA (FIG.2C). Targeted LNPs formulated with a 5:1 ratio of PEG to PEG- maleimide maximized mRNA delivery to Jurkats relative to lower (7:1 ratio) and higher ratios (3:1) of the linker group. Moreover, targeted LNPs enhanced mRNA delivery to primary human cord blood cells and CD34+ progenitor cells derived from human fetal liver. These results validated the active targeting strategy, demonstrating that LNP functionalization to CD45 antibodies improves transfection of cells possessing the cognate receptor. Next, the specificity of enhanced mRNA delivery to CD45 antibody functionalization was determined. Targeted LNPs conjugated to IgG isotype control antibody fragments (IgG LNPs) were generated using the same method. IgG LNPs facilitated a similar level of transfection to untargeted LNPs in Jurkats (FIG.2D) despite having similar physiochemical properties to targeted LNPs. To determine if CD45-CD45R interactions facilitated improvement in mRNA delivery, Jurkats were pre-treated with free CD45 antibody prior to untargeted or targeted LNP treatment. As the dose of CD45 antibody pre-treatment increased, the effect of CD45 functionalization to LNPs diminished (FIG.2E). A similar experiment was conducted with pre-treatment of IgG isotype control antibody, yet a corresponding reduction in targeted LNP transfection efficacy was not observed (FIG.2F). When cells that do not express CD45R (HepG2) were treated with untargeted or targeted LNPs, there was no increase in cell transfection with the addition of CD45 targeting moieties to the LNP surface (Fig.2G). Finally, unbiased mass spectrometry-based proteomics was used to identify the plasma proteins that bind the surface of untargeted or targeted LNPs ex vivo. It was found that among the 859 distinct proteins adsorbed to the surface of both untargeted and targeted LNPs, 94% of these proteins were not differentially abundant between groups (FIG.2H). The role of the LNP protein corona was then investigated in - 75 - 53762388.1 Attorney Docket No.046483-7452WO1(03831) Jurkats treated with untargeted or targeted LNPs pre-incubated in either plasma or PBS. Although pre-incubation in plasma resulted in a minor improvement in mRNA delivery for both untargeted and targeted LNPs, CD45 functionalization played a greater role in mediating cell transfection in both groups (FIG.2I). Taken together, these results supported that targeted LNPs utilize a CD45R-specific mechanism to improve transfection of hematopoietic-lineage cells in vitro. Example 3: Targeted LNPs enhance mRNA delivery to HSCs in utero Next, the safety and efficacy of targeted LNPs was tested in vivo. R26mT / mGfetuses were injected at E13.5 with untargeted or targeted LNPs encapsulating Cre mRNA at a dose of 1 mg / kg mRNA. After 60 h, fetal livers were harvested and processed for fetal hepatocytes and fetal HSCs. Both untargeted and targeted LNPs facilitated transfection of ~50% of fetal hepatocytes (FIG.3A). While only 4% of fetal HSCs were transfected after untargeted LNP administration, 30% of fetal HSCs were transfected after targeted LNP administration (FIG. 3A). Transfection of CD45+ cells in the fetus by targeted LNPs was confirmed on histology (FIG.3B). Interestingly, when a similar experiment was conducted in adult R26mT / mGmice, both untargeted and targeted LNPs robustly transfected to liver but failed to produce discernable genome modulation in adult bone marrow HSCs (FIG.3C). These results imply that transfection of HSCs via this strategy requires both active targeting to HSCs and a fetal microenvironment that possesses an accessible and abundant population of these cells. The durability of genome modulation via this approach was subsequently assessed in vivo. Of note, Cre recombinase-mediated excision of the LoxP flanked tdTomato cassette in R26mT / mGmice results in permanent expression of green fluorescence protein in transfected cells and their progeny. Thus, R26mT / mGfetuses were injected at E13.5 with untargeted or targeted LNPs encapsulating Cre mRNA at a dose of 1 mg / kg mRNA and harvested adult liver, bone marrow, and peripheral blood after four months. In concordance with the results at 60 h, both untargeted and targeted LNPs facilitated long-term transfection in 50% of hepatocytes (FIG.3C). Targeted LNPs mediated long-term genome modulation in 20% of bone marrow HSCs compared to only 4% of bone marrow HSCs in animals treated with untargeted LNPs (FIG.3D). Genome modification of hematopoietic lineage cells, including T cells, B cell, monocytes, granulocytes, and erythrocytes, in experimental animals corresponded directly to progenitor HSC transfection in both LNP treatment groups (FIG. 3E). Therefore, not only are targeted LNPs able to facilitate potent and long-term genome modulation in HSCs relative to untargeted LNPs, but these LNP-mediated edits are passed - 76 - 53762388.1 Attorney Docket No.046483-7452WO1(03831) down proportionally to cell progeny within the peripheral blood. As expected, long-term genome modification was not observed in a similar cohort of R26mT / mGmice treated as adults with either untargeted or targeted LNPs (FIG.3F). Given the high ethical standards for fetal intervention, the safety of this delivery strategy was characterized in vivo. First, in the long-term cohort of R26mT / mGmice injected at E13.5, survival to birth was equivalent between PBS-, untargeted LNP-, and targeted LNP- treated fetuses (FIG.3G). Next, liver enzyme and cytokine levels were assessed 24 h after in utero IV administration of either PBS, untargeted LNPs, or targeted LNPs in wild-type mice. Measured AST, ALT, and alkaline phosphatase levels were found to be similar in targeted LNP-treated mice relative to PBS-treated controls (FIGs.3I-3J). Further analysis of fetal blood revealed that 24 out of 25 cytokines measured were not significantly elevated in LNP- treated mice relative to PBS-treated controls (FIG.3K). GM-CSF (a regulator of macrophage production) was found to be increased in both LNP treatment groups, as previously observed following LNP administration. However, levels of this acute phase cytokine returned to normal in LNP-treated mice after 48 h. Although additional studies are warranted to fully characterize the safety of targeted LNPs, the limited toxicity observed confirmed the potential suitability of this platform for downstream fetal HSC gene editing applications. Example 4: Secondary transplant confirms targeted LNP-mediated transfection of mouse HSCs The gold standard definition of an HSC is a cell that when transferred into an irradiated recipient will have the ability to reestablish blood cell production long-term in the recipient. To definitively confirm that targeted LNPs transfect multipotent and self-renewing mouse HSCs, a secondary transplant study was conducted using R26mT / mGand wild-type Balb / c mice (FIG.4A). R26mT / mGmice were injected at E13.5 with targeted LNPs encapsulating Cre mRNA at a dose of 1 mg / kg prior to bone marrow harvest after 4 months (donors). A separate cohort of adult Balb / c mice underwent total body irradiation to eliminate the native hematopoietic niche (recipients). Donor whole bone marrow, at an initial transfection rate of 20%, was then transplanted into recipient mice via IV injection, and recipients were followed for 4 months via peripheral blood draws before terminal bone marrow harvest. Of note, adult Balb / c recipient mice had no prior exposure to LNP treatment, and thus any observed green fluorescence could be attributed to secondary transplant from donor mice. Analysis of peripheral blood 1 month after secondary transplant revealed that 20% of - 77 - 53762388.1 Attorney Docket No.046483-7452WO1(03831) hematopoietic lineage cells in recipient mice expressed green fluorescence, matching the initial transfection efficiency of transplanted cells (FIG.4B). Moreover, this transfection level was maintained over the course of 4 months (FIG.4B), and 100% of mice survived to terminal harvest.4 months after secondary transplant, it was observed that ~20% of hematopoietic lineage cells, including T cells, B cell, monocytes, granulocytes, and erythrocytes, expressed green fluorescence (FIG.4C). A high percentage of recipient bone marrow HSCs were found to express green fluorescence relative to transplanted donor whole bone marrow (FIG.4D), perhaps indicating a survival advantage of genome modified HSCs in this model. These results provide strong evidence that targeted LNPs facilitate durable and definitive in vivo genome modulation in mouse HSCs. Example 5: Design of experiments reveals optimal LNP formulation for delivery of gene editing cargo Co-delivery of Cas9 mRNA and single guide RNA (sgRNA) is a promising strategy for therapeutic genome editing in a wide range of cells, including HSCs. However, LNP co- encapsulation and delivery of large mRNA cargos such as these remains a significant engineering challenge. One strategy to maximize LNP-mediated mRNA delivery involves optimization of organic excipient molar ratios, which can be evaluated high-throughput using orthogonal design of experiments (DOE). Thus, principles of DOE were used to design and formulate sequential libraries of C14-490 LNPs encapsulating Cas9 mRNA and EGFP sgRNA with varied excipient molar ratios (FIG.5A). The first library of C14-490 LNPs (Library A) was characterized for standard physiochemical parameters, including size, PDI, and encapsulation efficiency (Table 1). The 16 LNPs in Library A and the initial LNP formulation (A0) were then screened in HepG2 cells constitutively expressing EGFP (HepG2-GFP). Gene editing in this in vitro model was quantified via knockout of EGFP expression. Relative to A0 LNPs, 3 LNPs (A1, A11, A14) facilitated greater gene editing (FIG.5B). It was also observed that LNP-mediated gene editing increased with increasing molar fraction of ionizable lipid and decreasing molar fraction of phospholipid, cholesterol, and PEG within C14-490 LNP formulations. Table 1. Formulations of certain compositions of Library A LNP C14-490 DOPE (mol%) Cholesterol PEG-lipid (mol%) - 78 - 53762388.1 Attorney Docket No.046483-7452WO1(03831) A2 35 16 38.5 1.5 A3 42.5 20 42.5 2 A4 50 24 465 25 - 490 LNPs (Library B), which was characterized and screened in the same in vitro model. Relative to A0 LNPs, 7 LNPs (B1, B2, B3, B4, B5, B7, B9) facilitated significantly greater gene editing (FIG.5C). The top-performing LNP formulation (B5) enhanced gene editing by 2.5-fold, resulting in gene disruption in approximately 30% of HepG2-GFP cells at a low dose. Given an intended application for hematopoietic disorders, B5 LNPs and A0 LNPs were then evaluated for gene editing efficacy in an EGFP-positive hematopoietic lineage cell line (Jurkats-GFP). B5 LNPs enhanced gene editing in Jurkats-GFP relative to A0 LNPs (FIG.5D). Upon injection in utero in wild-type mice, B5 LNPs facilitated 3-fold greater insertions and deletions (indels) at the indented locus within the fetal liver compared to the standard A0 LNP formulation (FIG.5E). Thus, the B5 formulation for C14-490 LNPs was used as the basis for subsequent in utero gene editing studies. Table 2. Formulations of certain compositions of Library B LNP C14-490 DOPE (mol%) Cholesterol PEG-lipid (mol%) (mol%) (mol%) Example 6: STEM LNPs facilitate in utero gene editing of mouse HSCs To demonstrate the proof-of-concept utility of the engineered platform for in vivo HSC gene editing therapies, C14-490 LNPs were formulated to encapsulate Cas9 mRNA and sgRNA specific for the TTR gene at a therapeutic locus using optimized B5 formulation parameters and surface conjugation to CD45 antibody F(ab’)2 fragments, referred to herein as Systematically-optimized Targeted Editing Machinery LNPs (STEM LNPs). STEM LNPs, untargeted B5 LNPs, or PBS were administered IV to E13.5 C57BL / 6 fetuses at a dose of 1 mg / kg total mRNA. After 5 days, mice were sacrificed, and HSCs were isolated from harvested fetal liver or bone marrow via FACS. Next-generation sequencing demonstrated efficient editing (~7%) at the intended locus in genomic DNA isolated from the fetal liver of mice treated with either untargeted B5 - 79 - 53762388.1 Attorney Docket No.046483-7452WO1(03831) LNPs or STEM LNPs (FIG.5F). In contrast, 4-fold higher levels of gene editing were observed at the intended locus in fetal liver HSCs (FIG.5G) isolated from mice treated with STEM LNPs (~9%) relative to those from mice treated with untargeted LNPs (~2%). This relative improvement in gene editing was maintained in fetal HSCs that had already migrated into the bone marrow niche. Together, these results support the efficacy of the engineered STEM LNP platform in mediating gene editing of HSCs in utero. Enumerated Embodiments The following exemplary embodiments are provided, the numbering of which is not to be construed as designating levels of importance: Embodiment 1 provides a hematopoietic stem cell targeted lipid nanoparticle (LNP) comprising: (a) at least one ionizable lipid; (b) at least one neutral lipid; (c) cholesterol and / or a modified derivative thereof; (d) at least one polymer conjugated lipid and / or a modified derivative thereof; and (e) a cell targeting domain specific to binding to a surface molecule of an hematopoietic stem cell, optionally wherein the cell targeting domain is covalently conjugated to at least one component of the LNP. Embodiment 2 provides the LNP of Embodiment 1, wherein the at least one ionizable lipid is a compound of Formula (I), or a salt, solvate, stereoisomer, or isotopologue thereof: , wherein: R1aand R1bare each independently ; R2a, R2b, R2c, R2d, R2e, R2f, R2g, and independently selected from the group consisting of H, optionally substituted C1-C12 alkyl, optionally substituted C2-C12 heteroalkyl, optionally substituted C3-C8cycloalkyl, optionally substituted C2-C8heterocycloalkyl, optionally substituted C2-C12 alkenyl, optionally substituted C2-C12 alkynyl, optionally substituted C6-C10aryl, and optionally substituted C2-C10heteroaryl; - 80 - 53762388.1 Attorney Docket No.046483-7452WO1(03831) each occurrence of R3aand R3bis independently selected from the group consisting of H, optionally substituted C1-C28alkyl, optionally substituted C2-C28heteroalkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C8 heterocycloalkyl, optionally substituted C2-C28alkenyl, and optionally substituted C2-C28alkynyl; each occurrence of L1is independently selected from the group consisting of a bond, optionally substituted C1-C12 alkylenyl, optionally substituted C2-C12 alkenylenyl, optionally substituted C1-C12alkynylenyl, optionally substituted C1-C12heteroalkylenyl, optionally substituted C3-C8 cycloalkylenyl, and optionally substituted C2-C8 heterocyloalkylenyl; and m is an integer selected from the group consisting of 1, 2, 3, and 4. Embodiment 3 provides the LNP of Embodiment 2, wherein at least one of the following applies: (a) at least one selected from the group consisting of R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2his H; (b) at least two selected from the group consisting of R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2hare H; (c) at least three selected from the group consisting of R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2hare H; (d) at least four selected from the group consisting of R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2hare H; (e) at least five selected from the group consisting of R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2hare H; (f) at least six selected from the group consisting of R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2hare H; (g) at least seven selected from the group consisting of R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2hare H; and (h) each of R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2hare H. Embodiment 4 provides the LNP of Embodiment 2 or 3, wherein R3aand R3bare each independently selected from the group consisting of H and -CH2CH(OH)(optionally substituted C1-C20alkylenyl)CH3. Embodiment 5 provides the LNP of any one of Embodiments 2-4, wherein R3aand R3bare each independently selected from the group consisting of H, - CH2CH(OH)(CH2)9CH3, -CH2CH(OH)(CH2)10CH3, -CH2CH(OH)(CH2)11CH3, - - 81 - 53762388.1 Attorney Docket No.046483-7452WO1(03831) CH2CH(OH)(CH2)12CH3, and -CH2CH(OH)(CH2)13CH3. Embodiment 6 provides the LNP of any one of Embodiments 2-5, wherein each occurrence of L1is independently selected from the group consisting of a bond, -(CH2)1-10-, - , group consisting of H, optionally substituted C1-C28 alkyl, optionally substituted C2-C28 heteroalkyl, optionally substituted C3-C8cycloalkyl, optionally substituted C2-C8heterocycloalkyl, optionally substituted C2-C28 alkenyl, and optionally substituted C2-C28 alkynyl; and each occurrence of -CH2- is independently optionally substituted with at least one selected from the group consisting of C1-C12 alkyl, C1-C12 alkoxy, C1-C12 haloalkyl, C2-C12 heteroalkyl, and halogen. Embodiment 7 provides the LNP of any one of Embodiments 2-6, wherein each occurrence of optionally substituted alkyl, optionally substituted alkylenyl, optionally substituted heteroalkyl, optionally substituted heteroalkylenyl, optionally substituted cycloalkyl, optionally substituted cycloalkylenyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylenyl, optionally substituted alkenyl, optionally substituted alkenylenyl, optionally substituted alkynyl, optionally substituted aryl, and optionally substituted heteroaryl, if present, is independently optionally substituted with at least one substituent selected from the group consisting of C1-C6alkyl, C3-C8cycloalkyl, C1- C6 haloalkyl, C1-C3 haloalkoxy, phenoxy, halogen, CN, NO2, OH, N(R’)(R’’), C(=O)R’, C(=O)OR’, OC(=O)OR’, C(=O)N(R’)(R’’), S(=O)2N(R’)(R’’), N(R’)C(=O)R’’, N(R’)S(=O)2R’’, C2-C8heteroaryl, and phenyl optionally substituted with at least one halogen, wherein each occurrence of R’ and R’’ is independently selected from the group consisting of H, C1-C6alkyl, C3-C8cycloalkyl, C1-C6haloalkyl, benzyl, and phenyl. Embodiment 8 provides the LNP of any one of Embodiments 2-7, wherein R1aand R1bare each independently selected from the group consisting of: , - 82 - 53762388.1 Attorney Docket No.046483-7452WO1(03831) , one ionizable lipid of Formula (I) is selected from the group consisting of: - 83 - 53762388.1 Attorney Docket No.046483-7452WO1(03831) R4is independently selected from the group consisting of H, -CH2CH(OH)(CH2)9CH3, -CH2CH(OH)(CH2)10CH3, - CH2CH(OH)(CH2)11CH3, -CH2CH(OH)(CH2)12CH3, and -CH2CH(OH)(CH2)13CH3. Embodiment 10 provides the LNP of any one of Embodiments 1-9, wherein the at least one ionizable lipid comprises: HO hydroxytetradecyl)amino)ethyl)piperazin-1-yl)-2-ethoxypropyl)azanediyl)bis(tetradecan-2- ol) (C14-490). Embodiment 11 provides the LNP of any one of Embodiments 1-10, wherein the at least one ionizable lipid comprises about 10 mol% to about 70 mol% of the LNP. Embodiment 12 provides the LNP of any one of Embodiments 1-11, wherein the at least one ionizable lipid comprises about 45 mol% of the LNP. Embodiment 13 provides the LNP of any one of Embodiments 1-12, wherein the at least one neutral lipid comprises at least one selected from the group consisting of dioleoylphosphatidylethanolamine (DOPE), distearoylphosphatidylcholine (DSPC), and dioleoylphosphatidylcholine (DOPC). Embodiment 14 provides the LNP of any one of Embodiments 1-13, wherein the at least one neutral lipid comprises about 5 mol% to about 45 mol% of the LNP. Embodiment 15 provides the LNP of any one of Embodiments 1-14, wherein the at - 84 - 53762388.1 Attorney Docket No.046483-7452WO1(03831) least one neutral lipid comprises about 15 mol% of the LNP. Embodiment 16 provides the LNP of any one of Embodiments 1-15, wherein the cholesterol and / or modified derivative thereof comprises about 5 mol% to about 60 mol% of the LNP. Embodiment 17 provides the LNP of any one of Embodiments 1-16, wherein the cholesterol lipid and / or modified derivative thereof comprises about 40 mol% of the LNP. Embodiment 18 provides the LNP of any one of Embodiments 1-17, wherein the at least one polymer conjugated lipid and / or modified derivative thereof comprises about 0.5 mol% to about 12.5 mol% of the LNP. Embodiment 19 provides the LNP of any one of Embodiments 1-18, wherein the at least one polymer conjugated lipid and / or modified derivative thereof comprises about 1.5 mol% of the LNP. Embodiment 20 provides the LNP of any one of Embodiments 1-19, wherein the at least one polymer conjugated lipid and / or modified derivative thereof comprises a polyethylene glycol (PEG) conjugated lipid. Embodiment 21 provides the LNP of any one of Embodiments 1-20, wherein the PEG-conjugated lipid comprises 1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine-N- [methoxy(polyethylene glycol)-2000] (C14PEG2000). Embodiment 22 provides the LNP of any one of Embodiments 1-21, wherein the surface molecule of the hematopoietic stem cell is a CD45 receptor. Embodiment 23 provides the LNP of any one of Embodiments 1-22, wherein the cell targeting domain specific to binding a surface molecule of the hematopoietic stem cell is an antibody against CD45 (αCD45), or a fragment thereof. Embodiment 24 provides the LNP of any one of Embodiments 1-23, wherein the component to which the hematopoietic stem cell targeting domain is covalently conjugated is the modified derivative of the polymer conjugated lipid. Embodiment 25 provides the LNP of Embodiment 24, wherein the covalent conjugation comprises a covalent bond forming reaction selected from the group consisting of a [1,4]-conjugate addition (i.e., Michael addition), [4+2] cycloaddition, [3+2] dipolar cycloaddition, nucleophilic addition, transition metal-catalyzed cross-coupling reaction, carbonyl condensation reaction, and reductive amination. Embodiment 26 provides the LNP of Embodiment 25, wherein the covalent conjugation reaction comprises a [1,4]-conjugate addition reaction (i.e., Michael addition). Embodiment 27 provides the LNP of Embodiment 25 or 26, wherein the [1,4]- - 85 - 53762388.1 Attorney Docket No.046483-7452WO1(03831) conjugate addition occurs between the modified derivative of the polymer conjugated lipid which is further conjugated to a maleimide moiety and a cysteine thiol of a polypeptide. Embodiment 28 provides the LNP of Embodiment 27, wherein the cystine thiol of the polypeptide is derived from a reduced disulfide bridge of the antibody against CD45 (αCD45), or a fragment thereof. Embodiment 29 provides the LNP of Embodiment 27 or 28, wherein the LNP has a molar ratio of polymer conjugated lipid and modified derivative of the conjugated lipid further conjugated to a maleimide moiety selected from the group consisting of about 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, and 1:10, optionally wherein the molar ratio of polymer conjugated lipid and modified derivative of the conjugated lipid further conjugated to a maleimide moiety is about 5:1. Embodiment 30 provides the LNP of any one of Embodiments 1-24, wherein the modified derivative of the polymer conjugated lipid is a compound of Formula (II), or a salt, solvate, stereoisomer, or isotopologue thereof: , wherein: R5aand R5bare each independently selected form the group consisting of - C(=O)(optionally substituted C1-C28 alkyl), -C(=O)(optionally substituted C2-C28 alkenyl), - C(=O)(optionally substituted C2-C28 alkynyl), optionally substituted C1-C28 alkyl, optionally substituted C2-C28 alkenyl, and optionally substituted C2-C28 alkynyl; Z is a monovalent cation; L2comprises n units , o units , and p units of , wherein each a C-O or Dctis a cell targeting domain comprising an antibody against CD45, wherein is C-S bond; R6aand R6bare each independently selected from the group consisting of H and C1-C6 alkyl; n, o, and p are each independently 1, 2, 3, 4, or 5; q is an integer ranging from 1 to 100; and - 86 - 53762388.1 Attorney Docket No.046483-7452WO1(03831) r and s are each independently an integer ranging from 1 to 10. Embodiment 31 provides the LNP of Embodiment 30, wherein R5aand R5bare each independently C(=O)(C5-C20 alkyl), optionally wherein R5aand R5bare each independently C(=O)(CH2)16CH3. Embodiment 32 provides the LNP of Embodiment 30 or 31, wherein Z is NH4+. Embodiment 33 provides the LNP of any one of Embodiments 30-32, wherein L2is . the LNP of any one of Embodiments 30-33, wherein the . 30-34, wherein Dct comprises an antibody of CD45 (αCD45). Embodiment 36 provides the LNP of any one of Embodiments 31-35, wherein (d) comprises the polymer conjugated lipid and the compound of formula (II), wherein the polymer conjugated lipid and the compound of formula (II) have a molar ratio of about 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, and 1:10, optionally wherein the molar ratio of polymer conjugated lipid and modified derivative of the conjugated lipid further conjugated to a maleimide moiety is about 5:1. Embodiment 37 provides the LNP of any one of Embodiments 31-36, wherein the LNP has a molar ratio of (a) : (b) : (c) : (d) of about 45:15:40:1.5, optionally wherein (d) comprises the polymer conjugated lipid and the compound of formula (II) having a ratio of about 5:1. Embodiment 38 provides the LNP of any one of Embodiments 1-37, wherein the LNP further comprises at least one cargo selected from the group consisting of a nucleic acid molecule and a therapeutic agent. Embodiment 39 provides the LNP of Embodiment 38, wherein the therapeutic agent is at least one selected from the group consisting of a small molecule, a protein, and an antibody. Embodiment 40 provides the LNP of Embodiment 39, wherein the LNP comprises a - 87 - 53762388.1 Attorney Docket No.046483-7452WO1(03831) nucleic acid molecule. Embodiment 41 provides the LNP of Embodiment 40, wherein the nucleic acid molecule is a DNA molecule or an RNA molecule. Embodiment 42 provides the LNP of Embodiment 40 or 41, wherein the nucleic acid molecule is selected from the group consisting of cDNA, mRNA, miRNA, siRNA, modified RNA, antagomir, antisense molecule, and a targeted nucleic acid, or any combination thereof. Embodiment 43 provides the LNP of any one of Embodiments 40-42, wherein the nucleic acid molecule encodes a chimeric antigen receptor (CAR). Embodiment 44 provides the LNP of Embodiment 43, wherein the CAR is specific for binding to a surface antigen of a pathogenic cell. Embodiment 45 provides the LNP of any one of Embodiments 40-44, wherein the nucleic acid molecule encodes at least one selected from the group consisting of mRNA and sgRNA. Embodiment 46 provides the LNP of Embodiment 45, wherein the mRNA encodes a therapeutic protein, optionally wherein the therapeutic protein is a CRISPR-associated protein, and optionally wherein the CRISPR-associated protein is CRISPR-associated protein 9 (Cas9). Embodiment 47 provides the LNP of Embodiment 39 or 40, wherein the therapeutic agent is a CRISPR-associated protein, optionally wherein the CRISPR-associated protein is CRISPR-associated protein 9 (Cas9). Embodiment 48 provides a pharmaceutical composition comprising the lipid nanoparticle (LNP) of any one of Embodiments 1-47 and at least one pharmaceutically acceptable carrier. Embodiment 49 provides a method of treating, preventing, and / or ameliorating a hematopoietic stem cell-based disease and / or disorder in a subject, the method comprising administering to the subject the lipid nanoparticle (LNP) of any one of Embodiments 1-47 and / or the pharmaceutical composition of Embodiment 48. Embodiment 50 provides the method of Embodiment 49, wherein the hematopoietic stem cell-based disease and / or disorder is at least one selected from the group consisting of cancer, cardiac failure, neural disorders, hemoglobinopathies, auto-immune diseases, immunodeficiency, multiple sclerosis, and a metabolic or genetic disorder. Embodiment 51 provides a method of treating, preventing, and / or ameliorating a monogenic blood disease and / or disorder in a subject, the method comprising administering to the subject the lipid nanoparticle (LNP) of any one of Embodiments 1-47 and / or the - 88 - 53762388.1 Attorney Docket No.046483-7452WO1(03831) pharmaceutical composition of Embodiment 48. Embodiment 52 provides the method of Embodiment 51, wherein the monogenic blood disease and / or disorders comprises sickle cell disease or α / β thalassemia. Embodiment 53 provides a method of treating, preventing, and / or ameliorating a metabolic and / or genetic abnormality in a subject, the method comprising administering to the subject the lipid nanoparticle (LNP) of any one of Embodiments 1-47 and / or the pharmaceutical composition of Embodiment 48. Embodiment 54 provides the method of any one of Embodiments 49-53, wherein the subject is a mammal. Embodiment 55 provides the method of Embodiment 54, wherein the mammal is a human. Embodiment 56 provides the method of Embodiment 55, wherein the human is a fetus. Embodiment 57 provides the method of any one of Embodiments 49-56, wherein the administration comprises in utero administration. The terms and expressions employed herein are used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the embodiments of the present application. Thus, it should be understood that although the present application describes specific embodiments and optional features, modification and variation of the compositions, methods, and concepts herein disclosed may be resorted to by those of ordinary skill in the art, and that such modifications and variations are considered to be within the scope of embodiments of the present application. - 89 - 53762388.1

Claims

Attorney Docket No.046483-7452WO1(03831) CLAIMS What is claimed is:

1. A hematopoietic stem cell targeted lipid nanoparticle (LNP) comprising: (a) at least one ionizable lipid; (b) at least one neutral lipid; (c) cholesterol and / or a modified derivative thereof; (d) at least one polymer conjugated lipid and / or a modified derivative thereof; and (e) a cell targeting domain specific to binding to a surface molecule of an hematopoietic stem cell, optionally wherein the cell targeting domain is covalently conjugated to at least one component of the LNP.

2. The LNP of claim 1, wherein the at least one ionizable lipid is a compound of Formula (I), or a salt, solvate, stereoisomer, or isotopologue thereof: , wherein:R1aand R1bare each independently ; R2a, R2b, R2c, R2d, R2e, R2f, R2g, andindependently selected from the group consisting of H, optionally substituted C1-C12 alkyl, optionally substituted C2-C12 heteroalkyl, optionally substituted C3-C8cycloalkyl, optionally substituted C2-C8heterocycloalkyl, optionally substituted C2-C12 alkenyl, optionally substituted C2-C12 alkynyl, optionally substituted C6-C10aryl, and optionally substituted C2-C10heteroaryl; each occurrence of R3aand R3bis independently selected from the group consisting of H, optionally substituted C1-C28 alkyl, optionally substituted C2-C28 heteroalkyl, optionally substituted C3-C8cycloalkyl, optionally substituted C2-C8heterocycloalkyl, optionally substituted C2-C28 alkenyl, and optionally substituted C2-C28 alkynyl; each occurrence of L1is independently selected from the group consisting of a bond, optionally substituted C1-C12alkylenyl, optionally substituted C2-C12alkenylenyl, - 90 - 53762388.1Attorney Docket No.046483-7452WO1(03831) optionally substituted C1-C12 alkynylenyl, optionally substituted C1-C12 heteroalkylenyl, optionally substituted C3-C8cycloalkylenyl, and optionally substituted C2-C8heterocyloalkylenyl; and m is an integer selected from the group consisting of 1, 2, 3, and 4.

3. The LNP of claim 2, wherein at least one of the following applies: (a) at least one selected from the group consisting of R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2his H; (b) at least two selected from the group consisting of R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2hare H; (c) at least three selected from the group consisting of R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2hare H; (d) at least four selected from the group consisting of R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2hare H; (e) at least five selected from the group consisting of R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2hare H; (f) at least six selected from the group consisting of R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2hare H; (g) at least seven selected from the group consisting of R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2hare H; and (h) each of R2a, R2b, R2c, R2d, R2e, R2f, R2g, and R2hare H.

4. The LNP of claim 2 or 3, wherein R3aand R3bare each independently selected from the group consisting of H and -CH2CH(OH)(optionally substituted C1-C20 alkylenyl)CH3.

5. The LNP of any one of claims 2-4, wherein R3aand R3bare each independently selected from the group consisting of H, -CH2CH(OH)(CH2)9CH3, -CH2CH(OH)(CH2)10CH3, -CH2CH(OH)(CH2)11CH3, -CH2CH(OH)(CH2)12CH3, and -CH2CH(OH)(CH2)13CH3.

6. The LNP of any one of claims 2-5, wherein each occurrence of L1is independently selected from the group consisting of a bond, -(CH2)1-10-, -(CH2)1-3NR4-, -(CH2)1-3O-, ,- 91 - 53762388.1Attorney Docket No.046483-7452WO1(03831) wherein: each occurrence of R4is independently selected from the group consisting of H, optionally substituted C1-C28 alkyl, optionally substituted C2-C28 heteroalkyl, optionally substituted C3-C8cycloalkyl, optionally substituted C2-C8heterocycloalkyl, optionally substituted C2-C28 alkenyl, and optionally substituted C2-C28 alkynyl; and each occurrence of -CH2- is independently optionally substituted with at least one selected from the group consisting of C1-C12 alkyl, C1-C12 alkoxy, C1-C12 haloalkyl, C2-C12 heteroalkyl, and halogen.

7. The LNP of any one of claims 2-6, wherein each occurrence of optionally substituted alkyl, optionally substituted alkylenyl, optionally substituted heteroalkyl, optionally substituted heteroalkylenyl, optionally substituted cycloalkyl, optionally substituted cycloalkylenyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylenyl, optionally substituted alkenyl, optionally substituted alkenylenyl, optionally substituted alkynyl, optionally substituted aryl, and optionally substituted heteroaryl, if present, is independently optionally substituted with at least one substituent selected from the group consisting of C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, C1-C3 haloalkoxy, phenoxy, halogen, CN, NO2, OH, N(R’)(R’’), C(=O)R’, C(=O)OR’, OC(=O)OR’, C(=O)N(R’)(R’’), S(=O)2N(R’)(R’’), N(R’)C(=O)R’’, N(R’)S(=O)2R’’, C2-C8heteroaryl, and phenyl optionally substituted with at least one halogen, wherein each occurrence of R’ and R’’ is independently selected from the group consisting of H, C1-C6alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, benzyl, and phenyl.

8. The LNP of any one of claims 2-7, wherein R1aand R1bare each independently selected from the group consisting of: , ,- 92 - 53762388.1Attorney Docket No.046483-7452WO1(03831) ,(I) is selected from the group consisting of:- 93 - 53762388.1Attorney Docket No.046483-7452WO1(03831) , and R4is independently selected from the group- -CH2CH(OH)(CH2)10CH3, - CH2CH(OH)(CH2)11CH3, -CH2CH(OH)(CH2)12CH3, and -CH2CH(OH)(CH2)13CH3.

10. The LNP of any one of claims 1-9, wherein the at least one ionizable lipid comprises: HO OHhydroxytetradecyl)amino)ethyl)piperazin-1-yl)-2-ethoxypropyl)azanediyl)bis(tetradecan-2- ol) (C14-490).

11. The LNP of any one of claims 1-10, wherein the at least one ionizable lipid comprises about 10 mol% to about 70 mol% of the LNP.

12. The LNP of any one of claims 1-11, wherein the at least one ionizable lipid comprises about 45 mol% of the LNP.

13. The LNP of any one of claims 1-12, wherein the at least one neutral lipid comprises at least one selected from the group consisting of dioleoylphosphatidylethanolamine (DOPE), distearoylphosphatidylcholine (DSPC), and dioleoylphosphatidylcholine (DOPC).

14. The LNP of any one of claims 1-13, wherein the at least one neutral lipid comprises about 5 mol% to about 45 mol% of the LNP.

15. The LNP of any one of claims 1-14, wherein the at least one neutral lipid comprises about 15 mol% of the LNP. - 94 - 53762388.1Attorney Docket No.046483-7452WO1(03831) 16. The LNP of any one of claims 1-15, wherein the cholesterol and / or modified derivative thereof comprises about 5 mol% to about 60 mol% of the LNP.

17. The LNP of any one of claims 1-16, wherein the cholesterol lipid and / or modified derivative thereof comprises about 40 mol% of the LNP.

18. The LNP of any one of claims 1-17, wherein the at least one polymer conjugated lipid and / or modified derivative thereof comprises about 0.5 mol% to about 12.5 mol% of the LNP.

19. The LNP of any one of claims 1-18, wherein the at least one polymer conjugated lipid and / or modified derivative thereof comprises about 1.5 mol% of the LNP.

20. The LNP of any one of claims 1-19, wherein the at least one polymer conjugated lipid and / or modified derivative thereof comprises a polyethylene glycol (PEG) conjugated lipid.

21. The LNP of any one of claims 1-20, wherein the PEG-conjugated lipid comprises 1,2- dimyristoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (C14PEG2000).

22. The LNP of any one of claims 1-21, wherein the surface molecule of the hematopoietic stem cell is a CD45 receptor.

23. The LNP of any one of claims 1-22, wherein the cell targeting domain specific to binding a surface molecule of the hematopoietic stem cell is an antibody against CD45 (αCD45), or a fragment thereof.

24. The LNP of any one of claims 1-23, wherein the component to which the hematopoietic stem cell targeting domain is covalently conjugated is the modified derivative of the polymer conjugated lipid.

25. The LNP of claim 24, wherein the covalent conjugation comprises a covalent bond forming reaction selected from the group consisting of a [1,4]-conjugate addition (i.e., - 95 - 53762388.1Attorney Docket No.046483-7452WO1(03831) Michael addition), [4+2] cycloaddition, [3+2] dipolar cycloaddition, nucleophilic addition, transition metal-catalyzed cross-coupling reaction, carbonyl condensation reaction, and reductive amination.

26. The LNP of claim 25, wherein the covalent conjugation reaction comprises a [1,4]- conjugate addition reaction (i.e., Michael addition).

27. The LNP of claim 25 or 26, wherein the [1,4]-conjugate addition occurs between the modified derivative of the polymer conjugated lipid which is further conjugated to a maleimide moiety and a cysteine thiol of a polypeptide.

28. The LNP of claim 27, wherein the cystine thiol of the polypeptide is derived from a reduced disulfide bridge of the antibody against CD45 (αCD45), or a fragment thereof.

29. The LNP of claim 27 or 28, wherein the LNP has a molar ratio of polymer conjugated lipid and modified derivative of the conjugated lipid further conjugated to a maleimide moiety selected from the group consisting of about 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, and 1:10, optionally wherein the molar ratio of polymer conjugated lipid and modified derivative of the conjugated lipid further conjugated to a maleimide moiety is about 5:

1.

30. The LNP of any one of claims 1-24, wherein the modified derivative of the polymer conjugated lipid is a compound of Formula (II), or a salt, solvate, stereoisomer, or isotopologue thereof: , wherein:R5aand R5bare each independently selected form the group consisting of - C(=O)(optionally substituted C1-C28 alkyl), -C(=O)(optionally substituted C2-C28 alkenyl), - C(=O)(optionally substituted C2-C28alkynyl), optionally substituted C1-C28alkyl, optionally substituted C2-C28 alkenyl, and optionally substituted C2-C28 alkynyl; Z is a monovalent cation; - 96 - 53762388.1Attorney Docket No.046483-7452WO1(03831) L2comprises n units of , o units of , and p units of , wherein each a C-O orDctis a cell targeting domain comprising an antibody against CD45, wherein is C-S bond; R6aand R6bare each independently selected from the group consisting of H and C1-C6 alkyl; n, o, and p are each independently 1, 2, 3, 4, or 5; q is an integer ranging from 1 to 100; and r and s are each independently an integer ranging from 1 to 10.

31. The LNP of claim 30, wherein R5aand R5bare each independently C(=O)(C5-C20alkyl), optionally wherein R5aand R5bare each independently C(=O)(CH2)16CH3.

32. The LNP of claim 30 or 31, wherein Z is NH4+.

33. The LNP of any one of claims 30-32, wherein L2.

34. The LNP of any one of claims 30-33, wherein the compound of formula (II) is: .

35. The LNP of any one of claims 30-34, wherein Dct comprises an antibody of CD45 (αCD45).

36. The LNP of any one of claims 31-35, wherein (d) comprises the polymer conjugated lipid and the compound of formula (II), wherein the polymer conjugated lipid and the compound of formula (II) have a molar ratio of about 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, and 1:10, optionally wherein the molar ratio of - 97 - 53762388.1Attorney Docket No.046483-7452WO1(03831) polymer conjugated lipid and modified derivative of the conjugated lipid further conjugated to a maleimide moiety is about 5:

1.

37. The LNP of any one of claims 31-36, wherein the LNP has a molar ratio of (a) : (b) : (c) : (d) of about 45:15:40:1.5, optionally wherein (d) comprises the polymer conjugated lipid and the compound of formula (II) having a ratio of about 5:

1.

38. The LNP of any one of claims 1-37, wherein the LNP further comprises at least one cargo selected from the group consisting of a nucleic acid molecule and a therapeutic agent.

39. The LNP of claim 38, wherein the therapeutic agent is at least one selected from the group consisting of a small molecule, a protein, and an antibody.

40. The LNP of claim 39, wherein the LNP comprises a nucleic acid molecule.

41. The LNP of claim 40, wherein the nucleic acid molecule is a DNA molecule or an RNA molecule.

42. The LNP of claim 40 or 41, wherein the nucleic acid molecule is selected from the group consisting of cDNA, mRNA, miRNA, siRNA, modified RNA, antagomir, antisense molecule, and a targeted nucleic acid, or any combination thereof.

43. The LNP of any one of claims 40-42, wherein the nucleic acid molecule encodes a chimeric antigen receptor (CAR).

44. The LNP of claim 43, wherein the CAR is specific for binding to a surface antigen of a pathogenic cell.

45. The LNP of any one of claims 40-44, wherein the nucleic acid molecule encodes at least one selected from the group consisting of mRNA and sgRNA.

46. The LNP of claim 45, wherein the mRNA encodes a therapeutic protein, optionally wherein the therapeutic protein is a CRISPR-associated protein, and optionally wherein the CRISPR-associated protein is CRISPR-associated protein 9 (Cas9). - 98 - 53762388.1Attorney Docket No.046483-7452WO1(03831) 47. The LNP of claim 39 or 40, wherein the therapeutic agent is a CRISPR-associated protein, optionally wherein the CRISPR-associated protein is CRISPR-associated protein 9 (Cas9).

48. A pharmaceutical composition comprising the lipid nanoparticle (LNP) of any one of claims 1-47 and at least one pharmaceutically acceptable carrier.

49. A method of treating, preventing, and / or ameliorating a hematopoietic stem cell-based disease and / or disorder in a subject, the method comprising administering to the subject the lipid nanoparticle (LNP) of any one of claims 1-47 and / or the pharmaceutical composition of claim 48.

50. The method of claim 49, wherein the hematopoietic stem cell-based disease and / or disorder is at least one selected from the group consisting of cancer, cardiac failure, neural disorders, hemoglobinopathies, auto-immune diseases, immunodeficiency, multiple sclerosis, and a metabolic or genetic disorder.

51. A method of treating, preventing, and / or ameliorating a monogenic blood disease and / or disorder in a subject, the method comprising administering to the subject the lipid nanoparticle (LNP) of any one of claims 1-47 and / or the pharmaceutical composition of claim 48.

52. The method of claim 51, wherein the monogenic blood disease and / or disorders comprises sickle cell disease or α / β thalassemia.

53. A method of treating, preventing, and / or ameliorating a metabolic and / or genetic abnormality in a subject, the method comprising administering to the subject the lipid nanoparticle (LNP) of any one of claims 1-47 and / or the pharmaceutical composition of claim 48.

54. The method of any one of claims 49-53, wherein the subject is a mammal.

55. The method of claim 54, wherein the mammal is a human. - 99 - 53762388.1Attorney Docket No.046483-7452WO1(03831) 56. The method of claim 55, wherein the human is a fetus.

57. The method of any one of claims 49-56, wherein the administration comprises in utero administration. - 100 - 53762388.1