Cationic lipid compounds for use in lipid nanoparticles

Abstract

The present disclosure provides cationic lipid compounds having the following Structure (I): where G 1 , G 2 , R 1 , R 2 , R 3a , R 3b , R 3c , R 3d , R 4a , R 4b , R 4c , R 4d , L 1 , L 2 , and L 3 are as defined herein. The present disclosure also discloses pharmaceutically acceptable salts or stereoisomers thereof. Also provided by the present disclosure are uses of the compounds as a component of lipid nanoparticle formulations for delivery of a therapeutic agent, compositions comprising the compounds and methods for their use and preparation are also provided.

Description

[0001] CATIONIC LIPID COMPOUNDS FOR USE IN LIPID NANOPARTICLES BACKGROUND Technical Field The present disclosure generally relates to novel cationic lipids that can be used in combination with other lipid components, such as neutral lipids, cholesterol, and polymer conjugated lipids, to form lipid nanoparticles with oligonucleotides, to facilitate the intracellular delivery of therapeutic nucleic acids (e.g., oligonucleotides, messenger RNA) both in vitro and in vivo. Description of the Related Art There are many challenges associated with the delivery of nucleic acids to affect a desired response in a biological system. Nucleic acid-based therapeutics have enormous potential but there remains a need for more effective delivery of nucleic acids to appropriate sites within a cell or organism to realize this potential. Therapeutic nucleic acids include, e.g., messenger RNA (mRNA), antisense oligonucleotides, ribozymes, DNAzymes, plasmids, immune stimulating nucleic acids, antagomir, antimir, mimic, supermir, and aptamers. Some nucleic acids, such as mRNA or plasmids, can be used to effect expression of specific cellular products as would be useful in the treatment of, for example, diseases related to a deficiency of a protein or enzyme. The therapeutic applications of translatable nucleotide delivery are extremely broad as constructs can be synthesized to produce any chosen protein sequence, whether indigenous to the system. The expression products of the nucleic acid can augment existing levels of protein, replace missing or non-functional versions of a protein, or introduce a new protein and associated functionality in a cell or organism. Some nucleic acids, such as miRNA inhibitors, can be used to effect expression of specific cellular products that are regulated by miRNA as would be useful in the treatment of, for example, diseases related to deficiency of protein or enzyme. The therapeutic applications of miRNA inhibition are extremely broad as constructs can be synthesized to inhibit one or more miRNA that would in turn regulate the expression of mRNA products. The inhibition of endogenous miRNA can augment its downstream target endogenous protein expression and restore proper function in a cell or organism as a means to treat disease associated to a specific miRNA or a group of miRNA. Other nucleic acids can down-regulate intracellular levels of specific mRNA and, as a result, down-regulate the synthesis of the corresponding proteins through processes such as RNA interference (RNAi) or complementary binding of antisense RNA. The therapeutic applications of antisense oligonucleotide and RNAi are also extremely broad, since oligonucleotide constructs can be synthesized with any nucleotide sequence directed against a target mRNA. Targets may include mRNAs from normal cells, mRNAs associated with disease-states, such as cancer, and mRNAs of infectious agents, such as viruses. To date, antisense oligonucleotide constructs have shown the ability to specifically down-regulate target proteins through degradation of the cognate mRNA in both in vitro and in vivo models. In addition, antisense oligonucleotide constructs are currently being evaluated in clinical studies. However, two problems currently face using oligonucleotides in therapeutic contexts. First, free RNAs are susceptible to nuclease digestion in plasma. Second, free RNAs have limited ability to gain access to the intracellular compartment where the relevant translation machinery resides. Lipid nanoparticles formed from lipid components, such as cationic lipids, neutral lipids, cholesterol, PEG, PEGylated lipids, and oligonucleotides have been used to block degradation of the RNAs in plasma and facilitate the cellular uptake of the oligonucleotides. There remains a need for improved cationic lipids and lipid nanoparticles for the delivery of oligonucleotides. Preferably, these lipid nanoparticles would provide optimal drug to lipid ratios, protect the nucleic acid from degradation and clearance in serum, be suitable for systemic delivery, and provide intracellular delivery of the nucleic acid. In addition, these lipid-nucleic acid particles should be well-tolerated and provide an adequate therapeutic index, such that patient treatment at an effective dose of the nucleic acid is not associated with unacceptable toxicity and / or risk to the patient. The present disclosure provides these and related advantages. BRIEF SUMMARY In brief, the present disclosure provides lipid compounds, including pharmaceutically acceptable salts and stereoisomers thereof, which can be used alone or in combination with other lipid components such as neutral lipids, charged lipids, steroids (including for example, all sterols) and / or their analogs, and / or polymer conjugated lipids to form lipid nanoparticles for the delivery of therapeutic agents. In some instances, the lipid nanoparticles are used to deliver nucleic acids such as antisense and / or messenger RNA. Methods for use of such lipid nanoparticles for treatment of various diseases or conditions, such as those caused by infectious entities and / or insufficiency of a protein, are also provided. One embodiment provides a compound having the following Structure (I): where G1, G2, R1, R2, R3a, R3b, R3c, R3d, R4a, R4b, R4c, R4d, L1, L2, and L3are as defined herein. Pharmaceutical compositions comprising compounds of the present disclosure (e.g., compounds of Structure (I)) and a therapeutic agent are also provided. In some embodiments, the pharmaceutical compositions further comprise one or more components selected from neutral lipids, charged lipids, steroids, and polymer conjugated lipids. Such compositions are useful for formation of lipid nanoparticles for the delivery of the therapeutic agent. In other embodiments, the present disclosure provides a method for administering a therapeutic agent to a patient in need thereof, the method comprising preparing a composition of lipid nanoparticles comprising compounds of the present disclosure (e.g., compounds of Structure (I)) and a therapeutic agent and delivering the composition to the patient. Such methods are useful for inducing expression of a protein in a subject, for example for expressing an antigen for purposes of vaccination or a gene editing protein. These and other aspects of the disclosure will be apparent upon reference to the following detailed description. DETAILED DESCRIPTION In the following description, certain specific details are set forth to provide a thorough understanding of various embodiments of the disclosure. However, one skilled in the art will understand that the embodiments of the disclosure may be practiced without these details. The present disclosure is based, in part, upon the discovery of novel cationic lipids that provide advantages when used in lipid nanoparticles (LNPs) for the in vivo delivery of an active or therapeutic agent such as a nucleic acid into a cell of a mammal. Some embodiments of the present disclosure provide nucleic acid-lipid nanoparticle compositions comprising one or more of the novel cationic lipids described herein that provide increased activity of the therapeutic agent, such as a nucleic acid, and improved tolerability of the compositions in vivo, resulting in a significant increase in the therapeutic index as compared to nucleic acid-lipid nanoparticle compositions previously described. In some embodiments, the present disclosure provides novel cationic lipids that enable the formation of improved LNPs for the in vitro and in vivo delivery of mRNA and / or other oligonucleotides. In some embodiments, these improved LNPs are useful for expression of protein encoded by mRNA. In other embodiments, these improved LNPs are useful for upregulation of endogenous protein expression by delivering miRNA inhibitors targeting one specific miRNA or a group of miRNA regulating one target mRNA or several mRNA. In other embodiments, these improved LNPs are useful for down-regulating (e.g., silencing) the protein levels and / or mRNA levels of target genes. In some other embodiments, the LNPs are also useful for delivery of mRNA and plasmids for expression of transgenes. In yet other embodiments, the LNPs are useful for inducing a pharmacological effect resulting from expression of a protein, e.g., increased production of red blood cells through the delivery of a suitable erythropoietin mRNA, or protection against infection through delivery of mRNA encoding for a suitable antibody. The LNPs and compositions comprising the LNPs of the present disclosure may be used for a variety of purposes, including the delivery of encapsulated or associated (e.g., complexed) therapeutic agents such as nucleic acids to cells, both in vitro and in vivo. Accordingly, embodiments of the present disclosure provide methods of treating or preventing diseases or disorders in a subject in need thereof by contacting the subject with a LNP that encapsulates or is associated with a suitable therapeutic agent, wherein the LNP comprises one or more of the novel cationic lipids described herein. As described herein, embodiments of the LNPs of the present disclosure are particularly useful for the delivery of nucleic acids, including, e.g., mRNA, antisense oligonucleotide, plasmid DNA, microRNA (miRNA), miRNA inhibitors (antagomirs / antimirs), messenger-RNA- interfering complementary RNA (micRNA), DNA, multivalent RNA, dicer substrate RNA, complementary DNA (cDNA), etc. Therefore, the LNPs and compositions comprising the LNPs of the present disclosure may be used to induce expression of a desired protein both in vitro and in vivo by contacting cells with a LNP comprising one or more novel cationic lipids described herein, wherein the LNP encapsulates or is associated with a nucleic acid that is expressed to produce the desired protein (e.g., a messenger RNA or plasmid encoding the desired protein). Alternatively, the LNPs and compositions comprising the LNPs of the present disclosure may be used to decrease the expression of target genes and proteins both in vitro and in vivo by contacting cells with a LNP comprising one or more novel cationic lipids described herein, wherein the LNP encapsulates or is associated with a nucleic acid that reduces target gene expression (e.g., an antisense oligonucleotide or small interfering RNA (siRNA)). The LNPs and compositions comprising the LNPs of the present disclosure may also be used for co-delivery of different nucleic acids (e.g., mRNA and plasmid DNA) separately or in combination, such as may be useful to provide an effect requiring colocalization of different nucleic acids (e.g., mRNA encoding for a suitable gene modifying enzyme and DNA segment(s) for incorporation into the host genome). Nucleic acids for use with this disclosure may be prepared according to any available technique. For mRNA, the primary methodology of preparation is, but not limited to, enzymatic synthesis (also termed in vitro transcription) which currently represents the most efficient method to produce long sequence-specific mRNA. In vitro transcription describes a process of template- directed synthesis of RNA molecules from an engineered DNA template comprised of an upstream bacteriophage promoter sequence (e.g., including but not limited to that from the T7, T3, and SP6 coliphage) linked to a downstream sequence encoding the gene of interest. Template DNA can be prepared for in vitro transcription from a number of sources with appropriate techniques which are well known in the art including, but not limited to, plasmid DNA and polymerase chain reaction amplification (see Linpinsel, J.L. and Conn, G.L., General protocols for preparation of plasmid DNA template and Bowman, J.C., Azizi, B., Lenz, T.K., Ray, P., and Williams, L.D. in RNA in vitro transcription and RNA purification by denaturing PAGE in Recombinant and in vitro RNA syntheses Methods v.941 Conn G.L. (ed), New York, N.Y. Humana Press, 2012). Transcription of the RNA occurs in vitro using the linearized DNA template in the presence of the corresponding RNA polymerase and adenosine, guanosine, uridine, and cytidine ribonucleoside triphosphates (rNTPs) under conditions that support polymerase activity while minimizing potential degradation of the resultant mRNA transcripts. In vitro transcription can be performed using a variety of commercially available kits including, but not limited to RiboMax Large Scale RNA Production System (Promega), MegaScript Transcription kits (Life Technologies) as well as with commercially available reagents including RNA polymerases and rNTPs. The methodology for in vitro transcription of mRNA is well known in the art. (see, e.g., Losick, R., 1972, In vitro transcription, Ann Rev Biochem v.41409-46; Kamakaka, R. T. and Kraus, W. L. 2001. In Vitro Transcription. Current Protocols in Cell Biology. 2:11.6:11.6.1– 11.6.17; Beckert, B. And Masquida, B., (2010) Synthesis of RNA by In Vitro Transcription in RNA in Methods in Molecular Biology v.703 (Neilson, H. Ed), New York, N.Y. Humana Press, 2010; Brunelle, J.L. and Green, R., 2013, Chapter Five – In vitro transcription from plasmid or PCR-amplified DNA, Methods in Enzymology v. 530, 101-114; all of which are incorporated herein by reference). The desired in vitro transcribed mRNA is then purified from the undesired components of the transcription or associated reactions (including unincorporated rNTPs, protein enzyme, salts, short RNA oligos etc.). Techniques for the isolation of the mRNA transcripts are well known in the art. Well known procedures include phenol / chloroform extraction or precipitation with either alcohol (ethanol, isopropanol) in the presence of monovalent cations or lithium chloride. Additional, non-limiting examples of purification procedures which can be used include size exclusion chromatography (Lukavsky, P.J. and Puglisi, J.D., 2004, Large-scale preparation and purification of polyacrylamide-free RNA oligonucleotides, RNA v.10, 889-893), silica-based affinity chromatography and polyacrylamide gel electrophoresis (Bowman, J.C., Azizi, B., Lenz, T.K., Ray, P., and Williams, L.D. in RNA in vitro transcription and RNA purification by denaturing PAGE in Recombinant and in vitro RNA syntheses Methods v. 941 Conn G.L. (ed), New York, N.Y. Humana Press, 2012 ). Purification can be performed using a variety of commercially available kits including, but not limited to SV Total Isolation System (Promega) and In Vitro Transcription Cleanup and Concentration Kit (Norgen Biotek). Furthermore, while reverse transcription can yield large quantities of mRNA, the products can contain several aberrant RNA impurities associated with undesired polymerase activity which may need to be removed from the full-length mRNA preparation. These include short RNAs that result from abortive transcription initiation as well as double-stranded RNA (dsRNA) generated by RNA-dependent RNA polymerase activity, RNA-primed transcription from RNA templates and self-complementary 3'-extension. It has been demonstrated that these contaminants with dsRNA structures can lead to undesired immunostimulatory activity through interaction with various innate immune sensors in eukaryotic cells that function to recognize specific nucleic acid structures and induce potent immune responses. This in turn, can dramatically reduce mRNA translation since protein synthesis is reduced during the innate cellular immune response. Therefore, additional techniques to remove these dsRNA contaminants have been developed and are known in the art including but not limited to scaleable HPLC purification (see, e.g., Kariko, K., Muramatsu, H., Ludwig, J. And Weissman, D., 2011, Generating the optimal mRNA for therapy: HPLC purification eliminates immune activation and improves translation of nucleoside- modified, protein-encoding mRNA, Nucl Acid Res, v. 39 e142; Weissman, D., Pardi, N., Muramatsu, H., and Kariko, K., HPLC Purification of in vitro transcribed long RNA in Synthetic Messenger RNA and Cell Metabolism Modulation in Methods in Molecular Biology v.969 (Rabinovich, P.H. Ed), 2013). HPLC purified mRNA has been reported to be translated at much greater levels, particularly in primary cells and in vivo. A significant variety of modifications have been described in the art which are used to alter specific properties of in vitro transcribed mRNA and improve its utility. These include but are not limited to modifications to the 5'- and 3'-termini of the mRNA. Endogenous eukaryotic mRNA typically contains a cap structure on the 5′-end of a mature molecule which plays an important role in mediating binding of the mRNA Cap Binding Protein (CBP), which is in turn responsible for enhancing mRNA stability in the cell and efficiency of mRNA translation. Therefore, highest levels of protein expression are achieved with capped mRNA transcripts. The 5′-cap contains a 5′- 5′-triphosphate linkage between the 5′-most nucleotide and guanine nucleotide. The conjugated guanine nucleotide is methylated at the N7 position. Additional modifications include methylation of the ultimate and penultimate most 5′-nucleotides on the 2′-hydroxyl group. Multiple distinct cap structures can be used to generate the 5′-cap of in vitro transcribed synthetic mRNA. 5'-capping of synthetic mRNA can be performed co-transcriptionally with chemical cap analogs (i.e., capping during in vitro transcription). For example, the Anti-Reverse Cap Analog (ARCA) cap contains a 5′-5′-triphosphate guanine-guanine linkage where one guanine contains an N7 methyl group as well as a 3′-O-methyl group. However, up to 20% of transcripts remain uncapped during this co-transcriptional process and the synthetic cap analog is not identical to the 5′-cap structure of an authentic cellular mRNA, potentially reducing translatability and cellular stability. Alternatively, synthetic mRNA molecules may also be enzymatically capped post-transcriptionally. These may generate a more authentic 5′-cap structure that more closely mimics, either structurally or functionally, the endogenous 5'-cap which have enhanced binding of cap binding proteins, increased half-life, reduced susceptibility to 5′ endonucleases and / or reduced 5′ de-capping. Numerous synthetic 5'-cap analogs have been developed and are known in the art to enhance mRNA stability and translatability (see, e.g., Grudzien-Nogalska, E., Kowalska, J., Su, W., Kuhn, A.N., Slepenkov, S.V., Darynkiewicz, E., Sahin, U., Jemielity, J., and Rhoads, R.E., Synthetic mRNAs with superior translation and stability properties in Synthetic Messenger RNA and Cell Metabolism Modulation in Methods in Molecular Biology v.969 (Rabinovich, P.H. Ed), 2013). On the 3'-terminus, a long chain of adenine nucleotides (poly-A tail) is normally added to mRNA molecules during RNA processing. Immediately after transcription, the 3′ end of the transcript is cleaved to free a 3′ hydroxyl to which poly-A polymerase adds a chain of adenine nucleotides to the RNA in a process called polyadenylation. The poly-A tail has been extensively shown to enhance both translational efficiency and stability of mRNA (see Bernstein, P. and Ross, J., 1989, Poly (A), poly (A) binding protein and the regulation of mRNA stability, Trends Bio Sci v.14373-377; Guhaniyogi, J. And Brewer, G., 2001, Regulation of mRNA stability in mammalian cells, Gene, v. 265, 11-23; Dreyfus, M. And Regnier, P., 2002, The poly (A) tail of mRNAs: Bodyguard in eukaryotes, scavenger in bacteria, Cell, v.111, 611-613). Poly (A) tailing of in vitro transcribed mRNA can be achieved using various approaches including, but not limited to, cloning of a poly (T) tract into the DNA template or by post- transcriptional addition using Poly (A) polymerase. The first case allows in vitro transcription of mRNA with poly (A) tails of defined length, depending on the size of the poly (T) tract, but requires additional manipulation of the template. The latter case involves the enzymatic addition of a poly (A) tail to in vitro transcribed mRNA using poly (A) polymerase which catalyzes the incorporation of adenine residues onto the 3'-termini of RNA, requiring no additional manipulation of the DNA template, but results in mRNA with poly(A) tails of heterogenous length.5'-capping and 3'-poly (A) tailing can be performed using a variety of commercially available kits including, but not limited to Poly (A) Polymerase Tailing kit (EpiCenter), mMESSAGE mMACHINE T7 Ultra kit and Poly (A) Tailing kit (Life Technologies) as well as with commercially available reagents, various ARCA caps, Poly (A) polymerase, etc. In addition to 5'-cap and 3'-poly adenylation, other modifications of the in vitro transcripts have been reported to provide benefits as related to efficiency of translation and stability. It is well known in the art that pathogenic DNA and RNA can be recognized by a variety of sensors within eukaryotes and trigger potent innate immune responses. The ability to discriminate between pathogenic and self-DNA and RNA has been shown to be based, at least in part, on structure and nucleoside modifications since most nucleic acids from natural sources contain modified nucleosides. In contrast, in vitro synthesized RNA lacks these modifications, thus rendering it immunostimulatory which in turn can inhibit effective mRNA translation as outlined above. The introduction of modified nucleosides into in vitro transcribed mRNA can be used to prevent recognition and activation of RNA sensors, thus mitigating this undesired immunostimulatory activity and enhancing translation capacity (see, e.g., Kariko, K. And Weissman, D. 2007, Naturally occurring nucleoside modifications suppress the immunostimulatory activity of RNA: implication for therapeutic RNA development, Curr Opin Drug Discov Devel, v.10 523-532; Pardi, N., Muramatsu, H., Weissman, D., Kariko, K., In vitro transcription of long RNA containing modified nucleosides in Synthetic Messenger RNA and Cell Metabolism Modulation in Methods in Molecular Biology v.969 (Rabinovich, P.H. Ed), 2013); Kariko, K., Muramatsu, H., Welsh, F.A., Ludwig, J., Kato, H., Akira, S., Weissman, D., 2008, Incorporation of Pseudouridine Into mRNA Yields Superior Nonimmunogenic Vector With Increased Translational Capacity and Biological Stability, Mol Ther v.16, 1833-1840. The modified nucleosides and nucleotides used in the synthesis of modified RNAs can be prepared monitored and utilized using general methods and procedures known in the art. A large variety of nucleoside modifications are available that may be incorporated alone or in combination with other modified nucleosides to some extent into the in vitro transcribed mRNA (see, e.g., US Publication No.2012 / 0251618). In vitro synthesis of nucleoside-modified mRNA has been reported to have reduced ability to activate immune sensors with a concomitant enhanced translational capacity. Other components of mRNA which can be modified to provide benefit in terms of translatability and stability include the 5′- and 3'-untranslated regions (UTR). Optimization of the UTRs (favorable 5'- and 3'-UTRs can be obtained from cellular or viral RNAs), either both or independently, have been shown to increase mRNA stability and translational efficiency of in vitro transcribed mRNA (see, e.g., Pardi, N., Muramatsu, H., Weissman, D., Kariko, K., In vitro transcription of long RNA containing modified nucleosides in Synthetic Messenger RNA and Cell Metabolism Modulation in Methods in Molecular Biology v.969 (Rabinovich, P.H. Ed), 2013). In addition to mRNA, other nucleic acid payloads may be used for this disclosure. For oligonucleotides, methods of preparation include but are not limited to chemical synthesis and enzymatic, chemical cleavage of a longer precursor, in vitro transcription as described above, etc. Methods of synthesizing DNA and RNA nucleotides are widely used and well known in the art (see, e.g., Gait, M. J. (ed.)Oligonucleotide synthesis: a practical approach, Oxford [Oxfordshire], Washington, D.C.: IRL Press, 1984; and Herdewijn, P. (ed.) Oligonucleotide synthesis: methods and applications, Methods in Molecular Biology, v. 288 (Clifton, N.J.) Totowa, N.J.: Humana Press, 2005; both of which are incorporated herein by reference). For plasmid DNA, preparation for use with this disclosure commonly utilizes but is not limited to expansion and isolation of the plasmid DNA in vitro in a liquid culture of bacteria containing the plasmid of interest. The presence of a gene in the plasmid of interest that encodes resistance to a particular antibiotic (penicillin, kanamycin, etc.) allows those bacteria containing the plasmid of interest to selective grow in antibiotic-containing cultures. Methods of isolating plasmid DNA are widely used and well known in the art (see, e.g., Heilig, J., Elbing, K. L. and Brent, R (2001) Large-Scale Preparation of Plasmid DNA. Current Protocols in Molecular Biology. 41:II:1.7:1.7.1–1.7.16; Rozkov, A., Larsson, B., Gillström, S., Björnestedt, R. and Schmidt, S. R. (2008), Large-scale production of endotoxin-free plasmids for transient expression in mammalian cell culture. Biotechnol. Bioeng., 99: 557–566; and US Patent No. 6,197,553). Plasmid isolation can be performed using a variety of commercially available kits including, but not limited to Plasmid Plus (Qiagen), GenJET plasmid MaxiPrep (Thermo) and PureYield MaxiPrep (Promega) kits as well as with commercially available reagents. Various exemplary embodiments of the cationic lipids of the present disclosure, lipid nanoparticles and compositions comprising the same, and their use to deliver active or therapeutic agents such as nucleic acids to modulate gene and protein expression, are described in further detail below. As used herein, the following terms have the meanings ascribed to them unless specified otherwise. Unless the context requires otherwise, throughout the present specification and claims, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open and inclusive sense, that is, as “including, but not limited to.” Reference throughout this specification to “one embodiment” or “an embodiment” means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment of the present disclosure. Thus, the appearances of the phrases “in one embodiment” or “in an embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this disclosure belongs. As used in the specification and claims, the singular form “a,” “an,” and “the” include plural references unless the context clearly dictates otherwise. The phrase “induce expression of a desired protein” refers to the ability of a nucleic acid to increase expression of the desired protein. To examine the extent of protein expression, a test sample (e.g., a sample of cells in culture expressing the desired protein) or a test mammal (e.g., a mammal such as a human or an animal model such as a rodent (e.g., mouse) or a non-human primate (e.g., monkey) model) is contacted with a nucleic acid (e.g., nucleic acid in combination with a lipid of the present disclosure). Expression of the desired protein in the test sample or test animal is compared to expression of the desired protein in a control sample (e.g., a sample of cells in culture expressing the desired protein) or a control mammal (e.g., a mammal such as a human or an animal model such as a rodent (e.g., mouse) or non-human primate (e.g., monkey) model) that is not contacted with or administered the nucleic acid. When the desired protein is present in a control sample or a control mammal, the expression of a desired protein in a control sample or a control mammal may be assigned a value of 1.0. In some embodiments, inducing expression of a desired protein is achieved when the ratio of desired protein expression in the test sample or the test mammal to the level of desired protein expression in the control sample or the control mammal is greater than 1, for example, about 1.1, 1.5, 2.0.5.0 or 10.0. When a desired protein is not present in a control sample or a control mammal, inducing expression of a desired protein is achieved when any measurable level of the desired protein in the test sample or the test mammal is detected. One of ordinary skill in the art will understand appropriate assays to determine the level of protein expression in a sample, for example dot blots, northern blots, in situ hybridization, ELISA, immunoprecipitation, enzyme function, and phenotypic assays, or assays based on reporter proteins that can produce fluorescence or luminescence under appropriate conditions. The term “nucleic acid” as used herein refers to a polymer containing at least two deoxyribonucleotides and / or ribonucleotides in either single- or double-stranded form and includes DNA, RNA, and hybrids thereof. DNA may be in the form of antisense molecules, plasmid DNA, cDNA, PCR products, or vectors. RNA may be in the form of small hairpin RNA (shRNA), messenger RNA (mRNA), antisense RNA, miRNA, micRNA, multivalent RNA, dicer substrate RNA or 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, single nucleotide polymorphisms, 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)). “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 alkylhalides. The term “gene” refers to a nucleic acid (e.g., DNA or RNA) sequence that comprises partial length or entire length coding sequences necessary to produce a polypeptide or precursor polypeptide. The term “lipid” refers to a group of organic compounds that include, but are not limited to, esters of fatty acids and are generally characterized by being poorly soluble in water, but soluble in many organic solvents. A “steroid” is a compound the carbon skeleton: Non-limiting examples of steroids include cholesterol, and the like. A “cationic lipid” refers to a lipid capable of being positively charged. Exemplary cationic lipids include one or more amine group(s) which bear the positive charge. Preferred cationic lipids are ionizable such that they can exist in a positively charged or neutral form depending on pH. The ionization of the cationic lipid affects the surface charge of the lipid nanoparticle under different pH conditions. This charge state can influence plasma protein absorption, blood clearance and tissue distribution (Semple, S.C., et al., Adv. Drug Deliv Rev 32:3-17 (1998)) as well as the ability to form endosomolytic non-bilayer structures (Hafez, I.M., et al., Gene Ther 8:1188-1196 (2001)) critical to the intracellular delivery of nucleic acids. The term “lipid nanoparticle” or “LNP” refers to particles having at least one dimension on the order of nanometers (e.g., 1-1,000 nm) which include one or more of the compounds of the present disclosure (e.g., compounds of Structure (I)) or other specified cationic lipids. In some embodiments, LNPs are included in a 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 (e.g., cell, tissue, organ, tumor, and the like). In some embodiments, the LNPs of the disclosure comprise a nucleic acid. Such LNPs typically comprise a compound of the present disclosure and one or more components selected from neutral lipids, charged lipids, steroids, and polymer conjugated lipids. In some embodiments, the active agent or therapeutic agent, such as a nucleic acid, may be encapsulated in the lipid portion of the lipid nanoparticle or an aqueous space enveloped by some or all the lipid portion of the lipid nanoparticle, thereby protecting it from enzymatic degradation or other undesirable effects induced by the mechanisms of the host organism or cells, e.g., an adverse immune response. In some embodiments, the LNPs have a mean diameter of from about 30 nm to about 150 nm, from about 40 nm to about 150 nm, from about 50 nm to about 150 nm, from about 60 nm to about 130 nm, from about 40 nm to about 100 nm, from about 40 nm to about 90 nm, from about 40 nm to about 80 nm, from about 40 nm to about 70 nm, from about 70 nm to about 110 nm, from about 70 nm to about 100 nm, from about 80 nm to about 100 nm, from about 90 nm to about 100 nm, from about 70 to about 90 nm, from about 80 nm to about 90 nm, from about 70 nm to about 80 nm, or about 30 nm, 35 nm, 40 nm, 45 nm, 50 nm, 55 nm, 60 nm, 65 nm, 70 nm, 75 nm, 80 nm, 85 nm, 90 nm, 95 nm, 100 nm, 105 nm, 110 nm, 115 nm, 120 nm, 125 nm, 130 nm, 135 nm, 140 nm, 145 nm, or 150 nm, and are substantially non-toxic. In certain embodiments, nucleic acids, when present in the LNPs, are resistant in aqueous solution to degradation with a nuclease. Lipid nanoparticles comprising nucleic acids and their method of preparation are disclosed in, e.g., U.S. Patent Publication Nos.2004 / 0142025, 2007 / 0042031 and PCT Pub. Nos. WO 2013 / 016058 and WO 2013 / 086373, the full disclosures of which are herein incorporated by reference in their entirety for all purposes. As used herein, “encapsulated” refers to a lipid nanoparticle that provides an active agent or therapeutic agent, such as a nucleic acid (e.g., mRNA), with full encapsulation, partial encapsulation, or both. In an embodiment, the nucleic acid (e.g., mRNA) is fully encapsulated in the lipid nanoparticle. 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-DMG) and the like. The term “neutral lipid” refers to any of several lipid species that exist either in an uncharged or neutral zwitterionic form at a selected pH. At physiological pH, such lipids include, but are not limited to, phosphotidylcholines such as 1,2-Distearoyl-sn-glycero-3-phosphocholine (DSPC), 1,2-Dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-Dimyristoyl-sn-glycero-3- phosphocholine (DMPC), 1-Palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), 1,2- dioleoyl-sn-glycero-3-phosphocholine (DOPC), phophatidylethanolamines such as 1,2-Dioleoyl- sn-glycero-3-phosphoethanolamine (DOPE), sphingomyelins (SM), ceramides, steroids such as sterols and their derivatives. Neutral lipids may be synthetic or naturally derived. The term “charged lipid” refers to any of a number of lipid species that exist in either a positively charged or negatively charged form independent of the pH within a useful physiological range, e.g., pH ~3 to pH ~9. Charged lipids may be synthetic or naturally derived. Examples of charged lipids include phosphatidylserines, phosphatidic acids, phosphatidylglycerols, phosphatidylinositols, sterol hemisuccinates, dialkyl trimethylammonium-propanes, (e.g., DOTAP, DOTMA), dialkyl dimethylaminopropanes, ethyl phosphocholines, dimethylaminoethane carbamoyl sterols (e.g., DC-Chol). As used herein, the term “aqueous solution” refers to a composition comprising water. “Alkyl” refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, which is saturated, and having, for example, from one to thirty carbon atoms (C1-C30 alkyl), ten to thirty carbon atoms (C10-C30 alkyl), four to twenty carbon atoms (C4- C20 alkyl), six to sixteen carbon atoms (C6-C16 alkyl), six to nine carbon atoms (C6-C9 alkyl), one to fifteen carbon atoms (C1-C15 alkyl),one to twelve carbon atoms (C1-C12 alkyl), one to eight carbon atoms (C1-C8 alkyl) or one to six carbon atoms (C1-C6 alkyl) and which is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1-methylethyl (iso propyl), n- butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl, and the like. Unless stated otherwise specifically in the specification, an alkyl group is substituted or unsubstituted. “Alkenyl” refers to an unsaturated, straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, which contains one or more carbon-carbon double bonds, having, e.g., from two to thirty carbon atoms (C2-C30 alkenyl), ten to thirty carbon atoms (C10-C30 alkenyl), four to twenty carbon atoms (C4-C20 alkenyl), six to sixteen carbon atoms (C6- C16 alkenyl), six to nine carbon atoms (C6-C9 alkenyl), two to fifteen carbon atoms (C2-C15 alkenyl), two to twelve carbon atoms (C2-C12 alkenyl), two to eight carbon atoms (C2-C8 alkenyl) or two to six carbon atoms (C2-C6 alkenyl) and which is attached to the rest of the molecule by a single bond, e.g., ethenyl, prop-1-enyl, but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted. “Alkynyl” refers to an unsaturated, straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, which contains one or more carbon-carbon triple bonds, having, e.g., from two to thirty carbon atoms (C2-C30 alkynyl), ten to thirty carbon atoms (C10-C30 alkynyl), four to twenty carbon atoms (C4-C20 alkynyl), six to sixteen carbon atoms (C6- C16 alkynyl), six to nine carbon atoms (C6-C9 alkynyl), two to fifteen carbon atoms (C2-C15 alkynyl), two to twelve carbon atoms (C2-C12 alkynyl), two to eight carbon atoms (C2-C8 alkynyl) or two to six carbon atoms (C2-C6 alkynyl) and which is attached to the rest of the molecule by a single bond, e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted. “Halo” refers to a halogen substituent (i.e., F, Cl, Br, or I). “Alkylene” or “alkylene chain” refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation, and having from one to twelve carbon atoms, e.g., methylene, ethylene, propylene, n-butylene, ethenylene, propenylene, n-butenylene, propynylene, n-butynylene, and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless stated otherwise specifically in the specification, an alkylene group or linker is optionally substituted. The term “substituted” used herein means any of the above groups (e.g., alkyl, alkenyl and / or alkynyl) wherein at least one hydrogen atom is replaced by a bond to a non-hydrogen atoms such as, but not limited to: a halogen atom, such as F, Cl, Br, and I, cyano, -OH, or -NH2.”Optional” or “optionally” (e.g., optionally substituted) means that the subsequently described event of circumstances may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. For example, “optionally substituted alkyl” means that the alkyl radical may or may not be substituted and that the description includes both substituted alkyl radicals and alkyl radicals having no substitution. In some embodiments, “optionally substituted” means a particular radical is substituted with one or more substituents selected from halo (e.g., F, Cl, Br, and I). This disclosure is also meant to encompass all pharmaceutically acceptable compounds of the present disclosure (e.g., compounds of Structure (I)) being isotopically labelled by having one or more atoms replaced by an atom having a different atomic mass or mass number. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as2H,3H,11C,13C,14C,13N,15N,15O,17O,18O,31P,32P,35S,18F,36Cl,123I, and125I, respectively. These radiolabeled compounds could be useful to help determine or measure the effectiveness of the compounds, by characterizing, for example, the site or mode of action, or binding affinity to pharmacologically important site of action. Certain isotopically labelled compounds of the present disclosure (e.g., compounds of Structure (I)), for example, those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. The radioactive isotopes tritium, i.e.,3H, and carbon-14, i.e.,14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Substitution with heavier isotopes such as deuterium, i.e.,2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances. Substitution with positron emitting isotopes, such as11C,18F,15O and13N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically labeled compounds of the present disclosure (e.g., compounds of Structure (I)) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the Preparations and Examples as set out below using an appropriate isotopically labeled reagent in place of the non-labeled reagent previously employed. This disclosure is also meant to encompass the in vivo metabolic products of the disclosed compounds. Such products may result from, for example, the oxidation, reduction, hydrolysis, amidation, esterification, and the like of the administered compound, primarily due to enzymatic processes. Accordingly, the disclosure includes compounds produced by a process comprising administering a compound of this disclosure to a mammal for a period sufficient to yield a metabolic product thereof. Such products are typically identified by administering a radiolabeled compound of the disclosure in a detectable dose to an animal, such as rat, mouse, guinea pig, monkey, or to human, allowing sufficient time for metabolism to occur, and isolating its conversion products from the urine, blood, or other biological samples. “Stable compound” and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. “Mammal” includes humans and both domestic animals such as laboratory animals and household pets (e.g., cats, dogs, swine, cattle, sheep, goats, horses, rabbits), and non-domestic animals such as wildlife and the like. “Pharmaceutically acceptable carrier, diluent, or excipient” includes without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier which has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals. “Pharmaceutically acceptable salt” includes both acid and base addition salts. “Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2- hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, undecylenic acid, and the like. “Pharmaceutically acceptable base addition salt” refers to those salts which retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Preferred inorganic salts are the ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benethamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine. A “pharmaceutical composition” refers to a formulation of a compound of the disclosure and a medium generally accepted in the art for the delivery of the biologically active compound to mammals, e.g., humans. Such a medium includes all pharmaceutically acceptable carriers, diluents, or excipients therefor. An “effective amount” or “therapeutically effective amount” of an active agent or therapeutic agent such as a therapeutic nucleic acid is an amount sufficient to produce the desired effect, e.g., an increase or inhibition of expression of a target sequence in comparison to the normal expression level detected in the absence of the nucleic acid. An increase in expression of a target sequence is achieved when any measurable level is detected in the case of an expression product that is not present in the absence of the nucleic acid. In the case where the expression product is present at some level prior to contact with the nucleic acid, an in increase in expression is achieved when the fold increase in value obtained with a nucleic acid such as mRNA relative to control is about 1.05, 1.1, 1.2, 1.3, 1.4, 1.5, 1.75, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 40, 50, 75, 100, 250, 500, 750, 1000, 5000, 10000 or greater. Inhibition of expression of a target gene or target sequence is achieved when the value obtained with a nucleic acid such as antisense oligonucleotide relative to the control is about 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 5%, or 0%. Suitable assays for measuring expression of a target gene or target sequence include, e.g., examination of protein or RNA levels using techniques known to those of skill in the art such as dot blots, northern blots, in situ hybridization, ELISA, immunoprecipitation, enzyme function, fluorescence or luminescence of suitable reporter proteins, as well as phenotypic assays known to those of skill in the art. “Treating” or “treatment” as used herein covers the treatment of the disease or condition of interest in a mammal, preferably a human, having the disease or condition of interest, and includes: (i) preventing the disease or condition from occurring in a mammal, in particular, when such mammal is predisposed to the condition but has not yet been diagnosed as having it; (ii) inhibiting the disease or condition, i.e., arresting its development; (iii) relieving the disease or condition, i.e., causing regression of the disease or condition; or (iv) relieving the symptoms resulting from the disease or condition, i.e., relieving pain without addressing the underlying disease or condition. As used herein, the terms “disease” and “condition” may be used interchangeably or may be different in that the particular malady or condition may not have a known causative agent (so that etiology has not yet been worked out) and it is therefore not yet recognized as a disease but only as an undesirable condition or syndrome, wherein a more or less specific set of symptoms have been identified by clinicians. The compounds of the present disclosure (e.g., compounds of Structure (I)), or their pharmaceutically acceptable salts may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)- or, as (D)- or (L)- for amino acids. The present disclosure is meant to include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, for example, chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high-pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included. A “stereoisomer” refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable. The present disclosure contemplates various stereoisomers and mixtures thereof and includes “enantiomers”, which refers to two stereoisomers whose molecules are non-superimposable mirror images of one another. Compounds In an aspect, the disclosure provides novel lipid compounds which can combine with other components such as cationic lipids, neutral lipids, charged lipids, steroids, and / or polymer conjugated lipids to form lipid nanoparticles. Without wishing to be bound by theory, it is thought that these lipid nanoparticles shield oligonucleotides from degradation in the serum and provide for effective delivery of oligonucleotides to cells in vitro and in vivo. One embodiment provides a compound having the following Structure (I):

[0002] wherein: G1and G2are each independently -C(=O)-O- or -O-C(=O)-; R1and R2are each independently C1-C8 alkyl; L1is C1-C4 alkylene; L2and L3are each independently C4-C12 alkylene; R3aand R3care each independently C4-C12 alkyl; R3band R3dare each independently C6-C16 alkyl; and R4a, R4b, R4c, and R4dare each independently hydrogen or halo; and each alkyl and each alkylene is optionally substituted with one or more halo In certain embodiments, the compound has the following Structure (Ia): . In some embodiments, the compound has the following Structure (Ib):

[0003] wherein: R1and R2are each independently C1-C8 alkyl; L1is C1-C4 alkylene; L2and L3are each independently C6-C10 alkylene; R3aand R3care each independently C6-C8 alkyl; R3band R3dare each independently C8-C12 alkyl; and R4a, R4b, R4c, and R4dare each independently hydrogen or halo; and each alkyl and each alkylene is optionally substituted with one or more halo. In some embodiments, R1is C1-C4 alkyl. In certain embodiments, R1is methyl. In certain embodiments, R2is C1-C4 alkyl. In some embodiments, R2is methyl. In some embodiments, L1is C1-C2 alkylene. In some embodiments, L1is ethylene. In some embodiments, L2and L3are each independently C5-C12 alkylene. In some embodiments, L2and L3are each independently C6-C10 alkylene. In certain embodiments, L2is C6-C8 alkylene. In some embodiments, L2is C7 alkylene. In certain embodiments, L3is C7-C9 alkylene. In some embodiments, L3is C8 alkylene. In some embodiments, R3ais C6-C8 alkyl. In certain embodiments, R3ais C6 alkyl. In some embodiments, R3ais C8 alkyl. In some embodiments, R3bis C8-C10 alkyl. In some embodiments, R3bis C10 alkyl. In some embodiments, R3bis C8 alkyl. In some embodiments, R3cis C6-C8 alkyl. In some embodiments, R3cis C8 alkyl. In some embodiments, R3cis C6 alkyl. In certain embodiments, R3dis C8-C10 alkyl. In some embodiments, R3dis C10 alkyl. In some embodiments, R3dis C8 alkyl. In some embodiments, R3aand R3care each independently C6-C8 alkyl. In certain embodiments, R3band R3dare each independently C8-C12 alkyl. In certain embodiments, L2and L3are each independently C6-C10 alkylene, R3aand R3care each independently C6-C8 alkyl, and R3band R3dare each independently C8-C12 alkyl. In certain embodiments, R4a, R4b, R4c, and R4dare all hydrogen. In some embodiments, at least one of R4a, R4b, R4c, and R4dis fluoro. In certain embodiments, one of R4a, R4b, R4c, and R4dis fluoro. In some embodiments, two of R4a, R4b, R4c, and R4dare fluoro. In certain embodiments, three of R4a, R4b, R4c, and R4dare fluoro. In some embodiments, all four of R4a, R4b, R4c, and R4dare fluoro. In some embodiments, at least one alkyl (e.g., R1, R2, R3a, R3b, R3c, or R3d) is substituted with at least one fluoro. In some embodiments, one substituent selected from R1, R2, R3a, R3b, R3c, and R3dis substituted with one or more fluoro substituents. In certain embodiments, two substituents selected from R1, R2, R3a, R3b, R3c, and R3dare substituted with one or more fluoro substituents. In some embodiments, three substituents selected from R1, R2, R3a, R3b, R3c, and R3dare substituted with one or more fluoro substituents. In certain embodiments, four substituents selected from R1, R2, R3a, R3b, R3c, and R3dare substituted with one or more fluoro substituents. In some embodiments, five substituents selected from R1, R2, R3a, R3b, R3c, and R3dare substituted with one or more fluoro substituents. In certain embodiments, all six substituents selected from R1, R2, R3a, R3b, R3c, and R3dare substituted with one or more fluoro substituents. In some embodiments, at least one alkylene (e.g., L1, L2, or L3) is substituted with at least one fluoro. In certain embodiments, one linker selected from L1, L2, and L3is substituted with one or more fluoro substituents. In some embodiments, two linkers selected from L1, L2, and L3are substituted with one or more fluoro substituents. In certain embodiments, all three linkers selected from L1, L2, and L3are substituted with one or more fluoro substituents. In certain embodiments, each alkyl and alkylene is unsubstituted. One embodiment provides a compound having one of the following structures: . or a stereoisomer or pharmaceutically acceptable salt thereof. In some embodiments, the compound has the following structure: , or a stereoisomer or pharmaceutically acceptable salt thereof. In certain embodiments, the compound has the following structure: , or a stereoisomer or pharmaceutically acceptable salt thereof. In some embodiments, the compound has the following structure: , or a stereoisomer or pharmaceutically acceptable salt thereof. In certain embodiments, the compound has the following structure: , or a stereoisomer or pharmaceutically acceptable salt thereof. It is understood that such substitutions are permissible only if the substitution results in stable compounds. In various embodiments, the compound has one of the structures set forth in Table 1 below.

[0004] Table 1. Representative compound of the present disclosure The compounds of the present disclosure (e.g., compounds of Structure (I)) may be used as components of LNPs, which in turn may be used for delivery of therapeutic agents, such as nucleic acids. The compounds of the disclosure (e.g., compounds of Structure (I)) are present in the LNPs in an amount which is effective to form an LNP and deliver a therapeutic agent, e.g., for treating a particular disease or condition of interest. Appropriate concentrations and dosages can be readily determined by one skilled in the art. Accordingly, one embodiment provides a lipid nanoparticle that comprises a compound having one of the following structures: or a stereoisomer or pharmaceutically acceptable salt thereof. In certain embodiments, the LNP comprises a compound having the following structure: or a stereoisomer or pharmaceutically acceptable salt thereof. In some embodiments, the LNP comprises a compound having the following structure: or a stereoisomer or pharmaceutically acceptable salt thereof. In some embodiments, the LNP comprises a compound having the following structure: or a stereoisomer or pharmaceutically acceptable salt thereof. In certain embodiments, the LNP comprises a compound having the following structure: or a stereoisomer or pharmaceutically acceptable salt or tautomer thereof. In some embodiments the lipid nanoparticle further comprises a therapeutic agent and optionally additional lipid excipients. Exemplary therapeutic agents and lipid excipients are described herein and known in the art. Another embodiment provides a composition, for example a pharmaceutical composition, comprising a compound having one of the following structures: or a pharmaceutically acceptable salt or stereoisomer thereof and a therapeutic agent. In some embodiments, the compound is a component of an LNP, which partially or fully encapsulates the therapeutic agent. In some embodiments, of the LNPs and compositions the therapeutic agent comprises a nucleic acid. In certain embodiments, the nucleic acid is selected from antisense and messenger RNA. For example, in some embodiments the messenger RNA encodes an antigen, such as an influenza antigen (e.g., influenza A or influenza B antigen) or respiratory syncytial virus (RSV) antigen. In other embodiments, the therapeutic agent comprises a Cas9 mRNA or a ribonucleoprotein. In some embodiments, the composition or LNP further comprises an additional cationic lipid. In some embodiments, the composition or LNP further comprises a neutral lipid. In some embodiments, the composition or LNP further comprises a steroid. In some embodiments, the composition or LNP further comprises a polymer conjugated lipid (e.g., a pegylated lipid). In some embodiments, the composition or LNP comprising a compound of the disclosure further comprises a neutral lipid, a steroid, a polymer conjugated lipid (e.g., pegylated lipid), or a combination thereof. In some embodiments, the composition or LNP comprising a compound of the disclosure further comprises an additional cationic lipid, a neutral lipid, a steroid, a polymer conjugated lipid (e.g., pegylated lipid), or a combination thereof. In some embodiments, the composition or lipid nanoparticle comprising compounds of the present disclosure (e.g., compounds of Structure (I)) further comprises additional cationic lipids. Exemplary cationic lipids and their synthesis can be found in the following publications: US Patent Nos. US 9,738,593; US 10,221,127; US 10,166,298; US 11,357,856; US 11,712,481; US 11,453,639; US Patent Publication Nos: US 2018 / 0185516; US 2022 / 0106257; PCT Publication Nos. WO 2017 / 117528; WO 2016 / 176330; WO 2018 / 191719; WO 2018 / 200943; WO 2019 / 036000; WO 2019 / 036028; WO 2019 / 036030; WO 2019 / 036008; WO 2019 / 089828; WO 2020 / 061426; WO 2020 / 081938; WO 2021 / 030701; WO 2023 / 114944; WO 2023 / 114939; WO 2023 / 114943, the disclosures of which are hereby incorporated by reference. One embodiment provides a composition or LNP comprising a compound of the disclosure and at least one neutral lipid selected from the group consisting of 1,2-Distearoyl-sn-glycero-3- phosphocholine (DSPC), 1,2-Dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2- Dimyristoyl-sn-glycero-3-phosphocholine (DMPC), 1-Palmitoyl-2-oleoyl-sn-glycero-3- phosphocholine (POPC), l,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2-Dioleoyl-sn- glycero-3-phosphoethanolamine (DOPE), a sphingomyelin (SM), and combinations thereof. In some embodiments, the at least one neutral lipid comprises 1,2-Distearoyl-sn-glycero-3- phosphocholine (DSPC). In some embodiments, the neutral lipid is present at a concentration ranging from about 5 to about 15 mol% of the LNP. In some embodiments, the molar ratio of the compound of the disclosure to the neutral lipid ranges from about 2:1 to about 8:1. As used herein, “mol percent,” “mole percent,” or “mol%” refers to a component’s molar percentage relative to the total number of mols of all components of a LNP excluding a therapeutic agent (e.g., total mols of cationic lipid(s), neutral lipid(s), steroid(s), and polymer conjugated lipid(s)). In certain embodiments, the LNPs comprise a compound of the disclosure and a steroid, such as cholesterol. In some embodiments, the steroid is present at a concentration ranging from about 7 to about 13 mol%, or from about 9 to about 11 mol%. In some embodiments, the molar ratio of the compound of the present disclosure to cholesterol ranges from about 2:1 to about 1:1. In certain embodiments, the molar ratio of the compound to cholesterol ranges from about 5:1 to about 1:1 or from about 2:1 to about 1:1. In certain embodiments, the LNPs comprise a compound of the disclosure and a polymer conjugated lipid, such as a pegylated lipid. For example, some embodiments include a pegylated diacylglycerol (PEG-DAG) such as 1-(monomethoxy-polyethyleneglycol)-2,3-dimyristoylglycerol (PEG-DMG), a pegylated phosphatidylethanoloamine (PEG-PE), a PEG succinate diacylglycerol (PEG-S-DAG) such as 4- O-(2’,3’-di(tetradecanoyloxy)propyl-1-O-(^-methoxy(polyethoxy)ethyl) butanedioate (PEG-S- DMG), a pegylated ceramide (PEG-cer), or a PEG dialkoxypropylcarbamate such as ^- methoxy(polyethoxy)ethyl-N-(2,3-di(tetradecanoxy)propyl)carbamate or 2,3- di(tetradecaneoxy)propyl-N-(^-methoxy(polyethoxy)ethyl) carbamate. In some embodiments, the molar ratio of the compound of the disclosure to the pegylated lipid ranges from about 100:1 to about 10:1 or from about 100:1 to about 25:1. In some embodiments, the molar ratio of the compound of the disclosure to pegylated lipid ranges from about 100:1 to about 20:1 or from about 100:1 to about 10:1. In some embodiments, the pegylated lipid is PEG-DMG. In some embodiments, the pegylated lipid is PEG-DAG, PEG-PE, PEG-S- DAG, PEG-cer or a PEG dialkyoxypropylcarbamate. In some embodiments, the composition or LNP further comprises at least one pegylated lipid having a structure of Formula (II): or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: R5and R6are each independently a straight or branched alkyl, alkenyl, or alkynyl containing from 10 to 30 carbon atoms, wherein each alkyl, alkenyl, or alkynyl is optionally substituted with at least one fluoro; and z is an integer ranging from 30 to 60. In some embodiments, R5and R6are each independently straight, alkyl chains containing from 12 to 16 carbon atoms, wherein each alkyl is optionally substituted with at least one fluoro. In certain embodiments, R5and R6are each independently straight alkyl chains containing from 12 to 16 carbon atoms. In some embodiments, R5and R6are each independently: , . In some embodiments, z is an integer ranging from 35 to 55. In certain embodiments, z is an integer ranging from about 40 to 50. In some embodiments, z is an integer ranging from about 42 to 47. In some embodiments, z is an integer ranging from 45 to 50. In some embodiments, z is an integer ranging from 42 to 48. In some embodiments, the at least one pegylated lipid has the following structure: . In some embodiments, the composition or lipid nanoparticle comprises a plurality of pegylated lipids of Formula (II). In some embodiments, the plurality of pegylated lipids has an average value of z ranging from 40 to 55. In some embodiments, the plurality of pegylated lipids has an average value of z ranging from 40 to 50, or 42 to 48. In some embodiments, the plurality of pegylated lipids has an average value of z ranging from 30 to 55, 30 to 50, 30 to 45, 30 to 40, or 30 to 35. In some embodiments, the plurality of lipids has an average value of z ranging from 35 to 55, 40 to 55, 42 to 55, 45 to 55, or 48 to 55. Synthesis of pegylated lipids (e.g., compounds of Formula (II)) can be found in US Patent No.9,738,593, the disclosure of which is hereby incorporated by reference. In some embodiments, a compound of the present disclosure is present at a concentration ranging from about 35 to about 70 mol% of the LNP. In some embodiments, a compound of the present disclosure is present at a concentration ranging from about 35 to about 70 mol%, from about 40 to about 60 mol%, from about 45 to about 50 mol%, from about 45 to about 49 mol%, from about 40 to about 55 mol%, or from about 46 to about 48 mol% of the LNP. In some embodiments, the concentration of the pegylated lipid (e.g., compounds of Formula (II)) ranges from about 1.0 to about 10.0 mol% of the LNP. In some embodiments, the concentration of the pegylated lipid (e.g., compounds of Formula (II)) ranges from about 1.3 to about 2.0 mol% of the LNP. In some embodiments, the concentration of the pegylated lipid (e.g., compounds of Formula (II)) ranges from about 2.0 to about 2.5 mol% of the LNP. In some embodiments, the concentration of the pegylated lipid (e.g., compounds of Formula (II)) is about 1.5. In certain embodiments, the concentration of the pegylated lipid (e.g., compounds of Formula (II)) is about 1.7 or 1.8 mol%. In certain embodiments, the LNP comprises at least one steroid. In certain embodiments, the at least one steroid comprises cholesterol. In some embodiments, the steroid is present at a concentration ranging from about 39 to about 49 mol% of the LNP. In some embodiments, the steroid is present at a concentration ranging from about 40 to about 50 mol%, from about 41 to about 49 mol%, or from about 46 to about 44 mol%. In some embodiments, the LNP further comprises at least one therapeutic agent. In certain embodiments, the therapeutic agent comprises a nucleic acid. In some embodiments, the therapeutic agent is a nucleic acid. In certain embodiments, the nucleic acid comprises an antisense RNA, a messenger RNA, or a combination thereof. In some embodiments, the at least one therapeutic agent comprises Cas9 mRNA or ribonucleoprotein. In some embodiments, the messenger RNA encodes an antigen. In some embodiments, the antigen is an influenza antigen or a respiratory syncytial virus (RSV) antigen. In certain embodiments, the influenza antigen is an influenza A antigen or an influenza B antigen. In certain embodiments, the LNP has a diameter of about 40 nm to about 70 nm. In some embodiments, the lipid nanoparticle has a size of about 45 nm to about 65 nm, about 50 nm to about 60 nm, about 30 nm to about 70 nm, about 35 nm to about 75 nm, about 45 nm to about 80 nm, about 25 nm to about 100 nm, about 20 nm to about 90 nm, about 15 nm to about 150 nm, or about 10 nm to about 200 nm. One embodiment provides a pharmaceutical composition, comprising a LNP of the present disclosure and a pharmaceutically acceptable diluent or excipient. Administration of the compositions of the disclosure can be carried out via any of the accepted modes of administration of agents for serving similar utilities. The pharmaceutical compositions of the disclosure may be formulated into preparations in solid, semi-solid, liquid, or gaseous forms, such as tablets, capsules, powders, granules, ointments, solutions, suspensions, suppositories, injections, inhalants, gels, microspheres, and aerosols. Typical routes of administering such pharmaceutical compositions include, without limitation, oral, topical, transdermal, inhalation, parenteral, sublingual, buccal, rectal, vaginal, and intranasal. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intradermal, intrasternal injection or infusion techniques. Pharmaceutical compositions of the disclosure are formulated to allow the active ingredients contained therein to be bioavailable upon administration of the composition to a patient. Methods of preparing such pharmaceutical compositions are known, or will be apparent, to those skilled in this art; for example, see Remington: The Science and Practice of Pharmacy, 20th Edition (Philadelphia College of Pharmacy and Science, 2000). The composition to be administered will, in any event, contain an LNP comprising a compound of the disclosure and a therapeutically effective amount of a therapeutic agent for treatment of a disease or condition of interest in accordance with the teachings of this disclosure. A pharmaceutical composition of the disclosure may be in the form of a solid or liquid. In one aspect, the carrier(s) are particulate, so that the compositions are, for example, in tablet or powder form. The carrier(s) may be liquid, with the compositions being, for example, an oral syrup, injectable liquid, or an aerosol, which is useful in, for example, inhalatory administration. When intended for oral administration, the pharmaceutical composition is preferably in either solid or liquid form, where semi-solid, semi-liquid, suspension and gel forms are included within the forms considered herein as either solid or liquid. As a solid composition for oral administration, the pharmaceutical composition may be formulated into a powder, granule, compressed tablet, pill, capsule, chewing gum, wafer, or the like form. Such a solid composition will typically contain one or more inert diluents or edible carriers. In addition, one or more of the following may be present: binders such as carboxymethylcellulose, ethyl cellulose, microcrystalline cellulose, gum tragacanth or gelatin; excipients such as starch, lactose or dextrins, disintegrating agents such as alginic acid, sodium alginate, Primogel, corn starch and the like; lubricants such as magnesium stearate or Sterotex; glidants such as colloidal silicon dioxide; sweetening agents such as sucrose or saccharin; a flavoring agent such as peppermint, methyl salicylate or orange flavoring; and a coloring agent. When the pharmaceutical composition is in the form of a capsule, for example, a gelatin capsule, it may contain, in addition to materials of the above type, a liquid carrier such as polyethylene glycol or oil. The pharmaceutical composition may be in the form of a liquid, for example, an elixir, syrup, solution, emulsion, or suspension. The liquid may be for oral administration or for delivery by injection, as two examples. When intended for oral administration, preferred composition contain, in addition to the present LNPs, one or more of a sweetening agent, preservatives, dye / colorant and flavor enhancer. In a composition intended to be administered by injection, one or more of a surfactant, preservative, wetting agent, dispersing agent, suspending agent, buffer, stabilizer, and isotonic agent may be included. The liquid pharmaceutical compositions of the disclosure, whether they be solutions, suspensions or other like form, may include one or more of the following adjuvants: sterile diluents such as water for injection, saline solution, preferably physiological saline, Ringer's solution, isotonic sodium chloride, fixed oils such as synthetic mono or diglycerides which may serve as the solvent or suspending medium, polyethylene glycols, glycerin, propylene glycol or other solvents; antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose; agents to act as cryoprotectants such as sucrose or trehalose. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. Physiological saline is a preferred adjuvant. An injectable pharmaceutical composition is preferably sterile. A liquid pharmaceutical composition of the disclosure intended for either parenteral or oral administration should contain an amount of a LNP of the disclosure such that a suitable dosage of the therapeutic agent will be obtained. The pharmaceutical composition of the disclosure may be intended for topical administration, in which case the carrier may suitably comprise a solution, emulsion, ointment or gel base. The base, for example, may comprise one or more of the following: petrolatum, lanolin, polyethylene glycols, bee wax, mineral oil, diluents such as water and alcohol, and emulsifiers and stabilizers. Thickening agents may be present in a pharmaceutical composition for topical administration. If intended for transdermal administration, the composition may include a transdermal patch or iontophoresis device. The pharmaceutical composition of the disclosure may be intended for rectal administration, in the form, for example, of a suppository, which will melt in the rectum and release the drug. The composition for rectal administration may contain an oleaginous base as a suitable nonirritating excipient. Such bases include, without limitation, lanolin, cocoa butter, and polyethylene glycol. The pharmaceutical composition of the disclosure may include various materials, which modify the physical form of a solid or liquid dosage unit. For example, the composition may include materials that form a coating shell around the active ingredients. The materials that form the coating shell are typically inert, and may be selected from, for example, sugar, shellac, and other enteric coating agents. Alternatively, the active ingredients may be encased in a gelatin capsule. The pharmaceutical composition of the disclosure in solid or liquid form may include an agent that binds to the LNP of the disclosure and thereby assists in the delivery of the LNP. Suitable agents that may act in this capacity include a monoclonal or polyclonal antibody, or a protein. The pharmaceutical composition of the disclosure may consist of dosage units that can be administered as an aerosol. The term aerosol is used to denote a variety of systems ranging from those of colloidal nature to systems consisting of pressurized packages. Delivery may be by a liquefied or compressed gas or by a suitable pump system that dispenses the active ingredients. Aerosols of LNPs of the present disclosure may be delivered in single phase, bi-phasic, or tri-phasic systems to deliver the active ingredient(s). Delivery of the aerosol includes the necessary container, activators, valves, sub-containers, and the like, which together may form a kit. One skilled in the art, without undue experimentation may determine preferred aerosols. The pharmaceutical compositions of the disclosure may be prepared by methodology well known in the pharmaceutical art. For example, a pharmaceutical composition intended to be administered by injection can be prepared by combining the LNPs of the disclosure with sterile, distilled water or other carrier to form a solution. A surfactant may be added to facilitate the formation of a homogeneous solution or suspension. Surfactants are compounds that non-covalently interact with the compound of the disclosure to facilitate dissolution or homogeneous suspension of the compound in the aqueous delivery system. The compositions of the disclosure, or their pharmaceutically acceptable salts, are administered in a therapeutically effective amount, which will vary depending upon a variety of factors including the activity of the specific therapeutic agent employed; the metabolic stability and length of action of the therapeutic agent; the age, body weight, general health, sex, and diet of the patient; the mode and time of administration; the rate of excretion; the drug combination; the severity of the particular disorder or condition; and the subject undergoing therapy. Compositions of the disclosure may also be administered simultaneously with, prior to, or after administration of one or more other therapeutic agents. Such combination therapy includes administration of a single pharmaceutical dosage formulation of a composition of the disclosure and one or more additional active agents, as well as administration of the composition of the disclosure and each active agent in its own separate pharmaceutical dosage formulation. For example, a composition of the disclosure and the other active agent can be administered to the patient together in a single oral dosage composition such as a tablet or capsule, or each agent administered in separate oral dosage formulations. Where separate dosage formulations are used, the compounds of the present disclosure (e.g., compounds of Structure (I)) and one or more additional active agents can be administered at essentially the same time, i.e., concurrently, or at separately staggered times, i.e., sequentially; combination therapy is understood to include all these regimens. Preparation methods for the above compounds and compositions are described herein below and / or known in the art. It will be appreciated by those skilled in the art that in the process described herein the functional groups of intermediate compounds may need to be protected by suitable protecting groups. Such functional groups include hydroxy, amino, mercapto and carboxylic acid. Suitable protecting groups for hydroxy include trialkylsilyl or diarylalkylsilyl (for example, t- butyldimethylsilyl, t-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl, and the like. Suitable protecting groups for amino, amidino and guanidino include t-butoxycarbonyl, benzyloxycarbonyl, and the like. Suitable protecting groups for mercapto include -C(O)-R″ (where R″ is alkyl, aryl or arylalkyl), p-methoxybenzyl, trityl and the like. Suitable protecting groups for carboxylic acid include alkyl, aryl or arylalkyl esters. Protecting groups may be added or removed in accordance with standard techniques, which are known to one skilled in the art and as described herein. The use of protecting groups is described in detail in Green, T.W. and P.G.M. Wutz, Protective Groups in Organic Synthesis (1999), 3rdEd., Wiley. As one of skill in the art would appreciate, the protecting group may also be a polymer resin such as a Wang resin, Rink resin or a 2-chlorotrityl-chloride resin. Furthermore, all compounds of this disclosure which exist in free base or acid form can be converted to their pharmaceutically acceptable salts by treatment with the appropriate inorganic or organic base or acid by methods known to one skilled in the art. Salts of the compounds of the present disclosure (e.g., compounds of Structure (I)) can be converted to their free base or acid form by standard techniques. SYNTHETIC EXAMPLE 1 SYNTHESIS OF COMPOUND I-1 Synthesis of ethyl 9-hydroxynonanoate:

[0005] To a stirred solution of diethyl azelate (10g, 41 mmol) in anhydrous ethanol (150 mL), sodium borohydride (10.60 g) was added gradually at room temperature. After addition, the mixture was stirred at room temperature for 1 hour. Subsequently, the reaction mixture was heated at 50-55 °C using an oil bath and monitored by thin layer chromatography (TLC). After 2 hours, the reaction mixture was cooled to room temperature, diluted with cold brine, and extracted with hexanes-ethyl acetate (ca 4:1) (3 × 100 mL); the aqueous phase obtained contained solid, which was filtered out. and filtered to remove the solid. The solid was identified as the fully reduced product. The combined hexanes-ethyl acetate extracts were then dried over Na2SO4, filtered, and concentrated to yield a colorless oil (7.29 g). The crude product was purified by flash dry column chromatography on TLC grade silica gel (ethyl acetate in hexanes, 0 to 25%) to yield 9- hydroxynonanoate (3.95 g, 19.5 mmol, 47.6%) as an oil. Synthesis of 9-ethoxy-9-oxononanoic acid: To a solution of diethyl azelate (20 g, 82 mmol) in ethanol (200 mL), a solution of KOH (1eq., 1M, 82 mL, 82 mmol) was added at room temperature. The resulting solution was stirred at room temperature for 16 hours, with TLC indicating approximately 50% conversion of the starting material. An additional 15 mmol of 1M KOH was added and the mixture was stirred overnight. While starting material was still detectable by TLC (hexanes-ethyl acetate 9:1), no diacid (TLC DCM-methanol, 9:1) could be observed. The reaction mixture was adjusted to pH 7 (using approximately 50% N HCl), and most of the ethanol was removed under reduced pressure. The mixture was then extracted with approximately 25% ethyl acetate in hexanes (three extractions; the first extract contained starting material and was not combined with the others). The aqueous phase was further extracted with dichloromethane (DCM) twice, with TLC indicating incomplete extraction. The aqueous phase was adjusted to pH 3-4 (using approximately 50% N HCl, about 10 mL). White precipitates formed, and DCM was added. The mixture was filtered, and the filtrate was washed with water. This process yielded a white solid (TLC, DCM-methanol, 19:1, confirming it to be the diacid; note: for acidification, dilute HCl should be used). The filtrate was separated, and the aqueous phase was extracted with DCM once. All other extracts were combined and concentrated. The residue was taken up in ca 1% methanol in DCM and filtered to remove any solid. The filtrate was concentrated and purified by column chromatography on silica gel (0 to 2% methanol in DCM). The desired monoacid, 9-ethoxy-9- oxononanoic acid, was obtained as oil (5.78 g, 27 mmol, 33%). Synthesis of ethyl 9-bromononanoate: A dry flask was charged with triphenylphosphine (1.5 eq, 35.3 mmol, 9.26 g) and purged with nitrogen. DCM (12.5 mL / mmol, 200 mL) was added, and the solution was cooled to about - 10 °C. Bromine (1.4 eq, 32.9 mmol, 5.26 g, 1.69 mL) was slowly added, and the reaction mixture stirred for 30 min (-5 C to 0 °C). Then pyridine (1.7 eq, 40 mmol, 3.16 g, 3.24 mL) was added and the reaction mixture was stirred for an additional 30 min. A solution of 9-hydroxynonanoate (1 eq., 4.75 g, 23.5 mmol) in DCM (3.75 mL / mmol, 50mL) was then added. The reaction mixture was stirred at 0 °C for 2.5 hours (TLC, hexane / ethyl acetate = 4:1), and quenched with water. The two phases were separated, and the aqueous phase extracted with DCM. The combined organic phases were washed with water, brine, dried over Na2SO4, filtered, and concentrated to yield a white solid (ca 16 g). The resulting white solid was taken up in hexanes (150 mL), stirred well, filtered, and washed with hexanes. The hexanes filtrate was passed through a silica gel pad (1.2 cm height × 6.5 width) and eluted with a mixture of hexanes and ethyl acetate (0 to 5%). The desired product was obtained as a colorless oil (6.22 g, 23.5 mmol, 100%). Synthesis of ethyl 9-((2-(dimethylamino)ethyl)amino)nonanoate: A mixture of N,N-dimethylethylenediamine (5 eq, 18.87 mmol, 1.66 g, 2.06 mL), 9- bromononanoate (1 eq.1.0 g, 3.77 mmol ) and K2CO3 (1 eq., 3.77 mmol, 521 mg) in 40 mL of CH3CN was sealed in a pressure bottle and heated at 70 °C (oil bath) overnight. The reaction mixture was filtered and washed with ethyl acetate. The filtrate was concentrated, and the residue was taken up in ethyl acetate (100 mL) and washed with water. The organic phase was further washed with brine, dried over Na2SO4, and concentrated. This gave the desired product as pinkish- clear oil. After drying under high vacuum overnight, the desired product (745 mg, 2.74 mmol, 73%) was used for the next step without further purification. Synthesis of ethyl 9-((2-(dimethylamino)ethyl)(9-ethoxy-9-oxononyl)amino)-9- oxononanoate:

[0006] To a solution of 9-ethoxy-9-oxononanoic acid (3.01 mmol, 652 mg) in DCM (10 mL) and DMF (one drop), oxalyl chloride (4.6 eq, 13.7 mmol, 1.75 g, 1.20 mL) was added at room temperature (RT). The mixture was stirred at RT for 3 h, concentrated, and the residue was dissolved in DCM (10 mL). The solution was concentrated again to remove any excess oxalyl chloride. The resulting residue was dissolved in 10 mL of DCM and added to a solution of 9-((2- (dimethylamino)ethyl)amino)nonanoate (745 mg, 2.74 mmol), triethylamine (1.9 mL), and DMAP (10 mg) in DCM (20 mL) at 5 °C over 10 minutes. After the addition, the resulting mixture was stirred at RT overnight. Methanol (MeOH, 1 mL) was added to the mixture to remove excess acyl chloride. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (using a gradient mixture of hexane, acetate, and Et3N, from 95:5:1 to 50:50:2). The desired product (1.03 g, 2.19 mmol, 80%) was obtained as a slightly yellow oil. Synthesis of 9-((8-carboxyoctyl)(2-(dimethylamino)ethyl)amino)-9-oxononanoic acid:

[0007] A solution of ethyl 9-((2-(dimethylamino)ethyl)(9-ethoxy-9-oxononyl)amino)-9- oxononanoate (0.890 g, 1.89 mmol) in a mixture of ethanol (26 mL) and aqueous KOH solution (249 mg KOH in 2.49 mL of water) was stirred overnight. The mixture was adjusted to pH 5 with HCl (50% aqueous solution). The resulting mixture was concentrated (0.945 mg). The crude product was used for the next step without further purification. Synthesis of 2-octyldodecyl 9-((2-(dimethylamino)ethyl)(9-((2-octyldodecyl)oxy)-9- oxononyl)amino)-9-oxononanoate (compound I-1) N,N’-dicyclohexylcarbodiimide (DCC, 4.4 equiv. 2.77 mmol, 572 mg) was added to a solution of the diacid, 9-((8-carboxyoctyl)(2-(dimethylamino)ethyl)amino)-9-oxononanoic acid (310 mg), 2-octyl-1-dodecanol (3.15 mmol, 940 mg), and 4-dimethylaminopyridine (DMAP) (1.89 mmol, 230 mg) in dichloromethane (20 mL). The resulting mixture was stirred at room temperature (RT) overnight. After concentration, the residue was taken up in a mixture of hexane- EtOAc-Et3N (80:20:1), filtered through a pad of silica gel, and washed with the same solvent mixture. The filtrate was concentrated, and the residue (300 mg) was purified by gravity column chromatography on silica gel (230-400 mesh silica gel, 40 g, MeOH in DCM, 0 to 5.5%). The desired product was obtained as a colorless oil (144 mg, 0.15 mmol, 24% in two steps). 1H NMR (400 MHz, CDCl3) ^: 3.975, 3.969 (2 sets of doublets with ratio of 0.5:1, J = 5.786 Hz, J = 5.786 Hz, 4H), 3.46-3.21 (m, 4H), 2.47-2.39 (m, 2H), 2.33-2.25 (m, 6H), 2.278 (s, 6H), 1.68-1.47 (m, 8H), 1.38-1.20 (m, 80H), 0.89 (t, J = 6.8 Hz, 12H). SYNTHETIC EXAMPLE 2 SYNTHESIS OF COMPOUND I-2 Synthesis of 2-hexyldecyl 9-bromononanoate 2-Bromononanoic acid (400.00 mg, 1.79 mmol), 2-hexyldecan-1-ol (900.00 mg, 3.71 mmol), DMAP (30.00 mg, 0.24 mmol) and DCC (400.00 mg, 1.94 mmol) in 15 mL DCM were stirred over night at room temperature. After that, the reaction mixture was diluted with hexanes and filtered. The residue was directly applied on SiO2 column and purified with hexane / ethyl acetate gradient (100% hexanes to 50% ethyl acetate in hexanes). The yield of the pure product: 597.1 mg (72%). ESI-MS: C25H49BrO2+, [M+H]+, calculated: 461.30; found: 461.35. Synthesis of 2-hexyldecyl 9-((2-(dimethylamino)ethyl)amino)nonanoate: 2-Hexyldecyl 9-bromononanoate (500.0 mg, 1.08 mmol), N,N’-dimethylethane-1,2- diamine (0.50 mL, 415.0 mg, 4.71 mmol), potassium carbonate (149.3 mg, 1.08 mmol) and diisopropylethylamine (0.70 mL, 0.518 g, 4.0 mmol) were dissolved in 20 mL of acetonitrile. The solution was placed into the pressure bottle and stirred over night at 70 °C. After cooling down, the solvent was removed under vacuum, and the residue was partitioned between the ethyl acetate and water. The organic layer was dried over anhydrous sodium sulfate, concentrated, and purified on SiO2column with DCM / MeOH gradient (100% DCM to 50% MeOH in DCM). The yield of the pure product: 349.3 mg (69%). ESI-MS: C29H61N2O2+, [M+H]+, calculated: 469.47; found: 469.50. Synthesis of 9-((2-hexyldecyl)oxy)-9-oxononanoic acid: Azelaic acid (1.20 g, 6.37 mmol), 2-hexyldecan-1-ol (1. 54 g, 6.35 mmol), DMAP (62.1 mg, 0.5 mmol) and DCC (1.61 mg, 7.76 mmol) in 25 mL DCM were stirred over night at room temperature. After that, the reaction mixture was diluted with hexanes and filtered. The residue was directly applied on SiO2 column DCM / MeOH gradient (100% DCM to 50% MeOH in DCM). The yield of the pure product: 816.7 mg (30%). ESI-MS: C26H53O4+, [M+H]+, calculated: 429.39; found: 429.43. Synthesis of 2-hexyldecyl 9-((2-(dimethylamino)ethyl)(9-((2-hexyldecyl)oxy)-9- oxononyl)amino)-9-oxononanoate (compound I-2): 9-((2-Hexyldecyl)oxy)-9-oxononanoic acid (0.59 g, 1.38 mmol) was dissolved in 10.0 mL of DCM. To this solution, 1 drop of DMF was added, followed by 4.13 equivalents of oxalyl chloride (0.71 g, 5.71 mmol, 0.50 mL). The reaction mixture was stirred at room temperature for 1 hour. After that, the solvent was removed under vacuum, the residue was redissolved in 2 mL of DCM and concentrated again. Finally, acid chloride was dissolved in 5 mL of DCM and added dropwise to the solution of 2-hexyldecyl 9-((2-(dimethylamino)ethyl)amino)nonanoate (590.1 mg, 1.26 mmol), triethyl amine (0.20 g, 1.97 mmol, 0.27 mL) and DMAP (20.1 mg, 0.16 mmol) in 10 mL of DCM. The reaction mixture was stirred at room temperature for 1 hour and quenched by adding 1 mL of methanol. The reaction mixture was then diluted with 20 mL of ethyl acetate, washed with water, and dried over anhydrous sodium sulfate. After the removal of the solvent under vacuum, the crude product was purified on SiO2 column with hexane / ethyl acetate (spiked with 1% triethyl amine) gradient (100% hexanes to 50% ethyl acetate in hexanes). The yield of the pure product: 383.8 mg (35.3%). 1H NMR (400 MHz, CDCl3) δ 3.96 (m, 4H), 3.53 – 3.15 (m, 5H), 2.41 (m, 2H), 2.36 – 2.20 (m, 14H), 1.70 – 1.43 (m, 16H), 1.37 – 1.13 (m, 72H), 0.93 – 0.80 (m, 12H). ESI-MS: C54H107N2O5+, [M+H]+, calculated: 863.82; found: 863.95. SYNTHETIC EXAMPLE 3 SYNTHESIS OF COMPOUND I-3 Synthesis of bis(2-ethylhexyl) 10-(N-(3- (dimethylamino)propyl)nonanamido)nonadecanedioate (compound I-3) The compound was prepared according to the general procedures in U.S. Patent Publication No.2016 / 0376224, to yield 0.08 g of pale-yellow oil. 1H NMR (400 MHz, CDCl3) δ: 3.98 (dt, J = 6.0, 1.7 Hz, 4H), 3.69-3.56 (m, 1H), 3.15-3.06 (m, 2H), 2.28 (m, 8H), 2.22 (m, 6H), 1.76-1.55 (m, 12H), 1.48-1.12 (m, 52H), 0.94-0.80 (m, 15H). ESI-MS: MW for C49H96N2O5 [M+H]+, calculated 793.7; found 793.83. SYNTHETIC EXAMPLE 4 SYNTHESIS OFCOMPOUNDI-4 Synthesis of bis(2-octyldodecyl)amine: 9-(bromomethyl)nonadecane (10.56 g, 29.22 mmol), 2-octyldodecan-1-amine (10.00 mg, 33.61 mmol), and potassium carbonate (4.64 g, 33.57 mmol) were dissolved in 100 mL of acetonitrile (ACN). The solution was placed into the pressure bottle and stirred over night at 70 °C. After cooling down, the solvent was removed under vacuum, and the residue was partitioned between the ethyl acetate and water. The organic layer was dried over anhydrous sodium sulfate, concentrated, and purified on SiO2 column with hexane / ethyl acetate (spiked with 1% triethyl amine) gradient (100% hexanes to 50% ethyl acetate in hexanes). The yield of the pure product: 7.60 g (45%). ESI-MS: C40H84+, [M+H]+, calculated: 578.66; found: 578.68.

[0008] Synthesis of 8-bromo-N,N-bis(2-octyldodecyl)octanamide: 8-Bromooctanoic acid (0.50 g, 2.24 mmol) was dissolved in 15 mL of DCM. To this solution, 1 drop of DMF was added, followed by 4.33 equivalents of oxalyl chloride (1.2 g, 9.71 mmol, 0.85 mL). The reaction mixture was stirred at room temperature for 1 hour. After that, the solvent was removed under vacuum, the residue was redissolved in 2 mL of DCM and concentrated again. Finally, 8-bromooctanoil chloride was dissolved in 5 mL of DCM and added dropwise to the solution of bis(2-octyldodecyl) amine (1.10 g, 1.90 mmol), triethyl amine (1.09 g, 10.76 mmol, 1.50 mL) and DMAP (0.1 g, 0.81 mmol) in 20 mL of DCM. The reaction mixture was stirred at room temperature for 1 hour and quenched by adding 2 mL of MeOH. The reaction mixture was then diluted with 20 mL of ethyl acetate, washed with water, and dried over anhydrous sodium sulfate. After the removal of the solvent under vacuum, the crude product was purified on SiO2 column with hexane / ethyl acetate gradient (100% hexanes to 50% ethyl acetate in hexanes). The yield of the pure product: 1.34 g (90%). ESI-MS: C48H97BrNO+, [M+H]+, calculated: 782.67; found: 782.69. Synthesis of 8-(dimethylamino)-N,N-bis(2-octyldodecyl)octanamide (compound I-4): 8-bromo-N,N-bis(2-octyldodecyl)octanamide (1.30 g, 7.09 mmol) was dissolved in 20.0 mL of 2M dimethyl amine THF solution (40.0 mmol, 5.6 eq). The solution was placed into the pressure bottle and stirred over night at 70 °C. After cooling down, the solvent was removed under vacuum, and the residue was partitioned between the ethyl acetate and water. The organic layer was dried over anhydrous sodium sulfate, concentrated, and purified on SiO2 column with hexane / ethyl acetate (spiked with 1% triethyl amine) gradient (100% hexanes to 50% ethyl acetate in hexanes). The yield of the pure product: 1.34 g (90%). 1H NMR (400 MHz, CDCl3) δ 3.25 (d, J = 7.4 Hz, 2H), 3.11 (d, J = 7.4 Hz, 2H), 2.33 – 2.25 (m, 4H), 2.23 (s, 6H), 1.64 (m, J = 6.8 Hz, 4H), 1.51 – 1.35 (m, 3H), 1.35 (s, 77H), 0.93 – 0.84 (m, 12H). ESI-MS: C50H103N2O+, [M+H]+, calculated: 747.81; found: 747.76. FORMULATION EXAMPLE 1 LIPID NANOPARTICLE FORMATION A compound of the present disclosure, DSPC, cholesterol, and pegylated lipid(s) are solubilized in ethanol at desirable molar percentages (e.g., 50:10:38.5:1.5 or 47.5:10:40.7:1.8). Lipid nanoparticles (LNP) are prepared at a total lipid to mRNA weight ratio of approximately 10:1 to 30:1. The mRNA is diluted to 0.2 mg / mL in 10 to 50 mM citrate buffer, pH 4 or 10 to 25 mM acetate buffer, pH 4. Syringe pumps are used to mix the ethanolic lipid solution with the mRNA aqueous solution at a ratio of about 1:5 to 1:3 (vol / vol) with total flow rates above 15 mL / min. The ethanol is then removed, and the external buffer replaced with PBS by dialysis. Finally, the lipid nanoparticles are filtered through a 0.2 μm pore sterile filter. Lipid nanoparticle particle size is determined using quasi-elastic light scattering via a Nicomp 370 submicron particle sizer (Santa Barbara, CA). Alternatively, particle size can also be as determined by quasi-elastic light scattering using a Malvern Zetasizer Nano ZS (Malvern, UK). BIOLOGICAL EXAMPLE 1 LUCIFERASE MRNAIN VIVOEVALUATIONUSINGLIPID NANOPARTICLE COMPOSITIONS The following protocol was used to determine efficacy of lipid nanoparticle formulations containing cationic lipids according to the present disclosure using an in vivo luciferase mRNA expression model in rodents. Compounds were prepared according to the example described above. Studies were performed in 6–8-week-old female C57BL / 6 mice (Charles River) 8–10-week-old CD-1 (Harlan) mice (Charles River) according to guidelines established by an institutional animal care committee (ACC) and the Canadian Council on Animal Care (CCAC). Varying doses of mRNA-lipid nanoparticle were systemically administered by tail vein injection and animals euthanized at a specific time point (e.g., 4 hours) post-administration. Liver and spleen were collected in pre- weighed tubes, weights determined, immediately snap frozen in liquid nitrogen, and stored at -80 °C until processing for analysis. For liver, approximately 50 mg was dissected for analyses in a 2 mL FastPrep tubes (MP Biomedicals, Solon OH). ¼” ceramic sphere (MP Biomedicals) was added to each tube and 500 µL of Glo Lysis Buffer – GLB (Promega, Madison WI) equilibrated to room temperature was added to liver tissue. Liver tissues were homogenized with the FastPrep24 instrument (MP Biomedicals) at 2 × 6.0 m / s for 15 seconds. Homogenate was incubated at room temperature for 5 minutes prior to a 1:4 dilution in GLB and assessed using SteadyGlo Luciferase assay system (Promega). Specifically, 50 µL of diluted tissue homogenate was reacted with 50 µL of SteadyGlo substrate, shaken for 10 seconds followed by 5-minute incubation and then quantitated using a CentroXS³ LB 960 luminometer (Berthold Technologies, Germany). The amount of protein assayed was determined by using the BCA protein assay kit (Pierce, Rockford, IL). Relative luminescence units (RLU) were then normalized to total µg protein assayed. To convert RLU to ng luciferase a standard curve was generated with QuantiLum Recombinant Luciferase (Promega). The FLuc mRNA (L-6107) from Trilink Biotechnologies expresses a luciferase protein, originally isolated from the firefly, photinus pyralis. FLuc is commonly used in mammalian cell culture to measure both gene expression and cell viability. It emits bioluminescence in the presence of the substrate, luciferin. This capped and polyadenylated mRNA is fully substituted with 5- methylcytidine and pseudouridine. Activity was determined by measuring luciferase expression in the liver 4 hours following administration via tail vein injection. The activity was compared at a dose of 1.0, 0.3, or 0.1 mg mRNA / kg and expressed as ng luciferase / g liver measured 4 hours after administration. Table 2: Novel Cationic Lipids and Associated Activity The various embodiments described above can be combined to provide further embodiments. All of the U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications and non-patent publications referred to in this specification, including U.S. Provisional Patent Application No. 63 / 554,013, filed February 15, 2024, are incorporated herein by reference, in their entirety. Aspects of the embodiments can be modified, if necessary to employ concepts of the various patents, applications, and publications to provide yet further embodiments. These and other changes can be made to the embodiments considering the above-detailed description. In general, in the following claims, the terms used should not be construed to limit the claims to the specific embodiments disclosed in the specification and the claims but should be construed to include all possible embodiments along with the full scope of equivalents to which such claims are entitled. Accordingly, the claims are not limited by the disclosure.

Claims

CLAIMS 1. A compound having the following Structure (I):wherein: G1and G2are each independently -C(=O)-O- or -O-C(=O)-; R1and R2are each independently C1-C8 alkyl; L1is C1-C4 alkylene; L2and L3are each independently C4-C12 alkylene; R3aand R3care each independently C4-C12 alkyl; R3band R3dare each independently C6-C16 alkyl; and R4a, R4b, R4c, and R4dare each independently hydrogen or halo; and each alkyl and each alkylene is optionally substituted with one or more halo2. The compound of claim 1 wherein the compound has the following Structure (Ia): .

3. The compound of claim 1, wherein the compound has the following Structure (Ib): .

4. The compound of any one of claims 1-3, wherein R1is C1-C4 alkyl.

5. The compound of any one of claims 1-4, wherein R1is methyl.

6. The compound of any one of claims 1-5, wherein R2is C1-C4 alkyl.

7. The compound of any one of claims 1-6, wherein R2is methyl.

8. The compound of any one of claims 1-7, wherein L1is C1-C2 alkylene.

9. The compound of any one of claims 1-8, wherein L1is ethylene.

10. The compound of any one of claims 1-9, wherein L2and L3are each independently C5-C12 alkylene 11. The compound of any one of claims 1-10, wherein L2and L3are each independently C6-C10 alkylene.

12. The compound of any one of claims 1-11, wherein L2is C6-C8 alkylene.

13. The compound of any one of claims 1-12, wherein L2is C7 alkylene.

14. The compound of any one of claims 1-13, wherein L3is C7-C9 alkylene.

15. The compound of any one of claims 1-14, wherein L3is C8 alkylene.

16. The compound of any one of claims 1-15, wherein R3ais C6-C8 alkyl.

17. The compound of any one of claims 1-16, wherein R3ais C6 alkyl.

18. The compound of any one of claims 1-16, wherein R3ais C8 alkyl.

19. The compound of any one of claims 1-18, wherein R3bis C8-C10 alkyl.

20. The compound of any one of claims 1-19, wherein R3bis C8 alkyl.

21. The compound of any one of claims 1-19, wherein R3bis C10 alkyl.

22. The compound of any one of claims 1-21, wherein R3cis C6-C8 alkyl.

23. The compound of any one of claims 1-22, wherein R3cis C6 alkyl.

24. The compound of any one of claims 1-22, wherein R3cis C8 alkyl.

25. The compound of any one of claims 1-24, wherein R3dis C8-C10 alkyl.

26. The compound of any one of claims 1-25, wherein R3dis C8 alkyl.

27. The compound of any one of claims 1-25, wherein R3dis C10 alkyl.

28. The compound of any one of claims 1-16, wherein R3aand R3care each independently C6-C8 alkyl.

29. The compound of any one of claims 1-19, wherein R3band R3dare each independently C8-C12 alkyl.

30. The compound of any one of claims 1-10, wherein L2and L3are each independently C6-C10 alkylene, R3aand R3care each independently C6-C8 alkyl, and R3band R3dare each independently C8-C12 alkyl.

31. The compound of any one of claims 1-30, wherein R4a, R4b, R4c, and R4dare all hydrogen.

32. The compound of any one of claims 1-31, wherein at least one alkyl is substituted with at least one fluoro.

33. The compound of any one of claims 1-31, wherein each alkyl and alkylene is unsubstituted.

34. A compound having one of the following structures:or a pharmaceutically acceptable salt or stereoisomer thereof.

35. The compound of claim 34, wherein the compound has the following structure:or a pharmaceutically acceptable salt or stereoisomer thereof.

36. The compound of claim 34, wherein the compound has the following structure:or a pharmaceutically acceptable salt or stereoisomer thereof.

37. The compound of claim 34, wherein the compound has the following structure:or a pharmaceutically acceptable salt or stereoisomer thereof.

38. The compound of claim 34, wherein the compound has the following structure:or a pharmaceutically acceptable salt or stereoisomer thereof.

39. A lipid nanoparticle comprising the compound of any one of claims 1-38 and a therapeutic agent.

40. A composition comprising the compound of any one of claims 1-38, or the nanoparticle of claim 39, and a therapeutic agent and optionally a pharmaceutically acceptable excipient.

41. The lipid nanoparticle or composition of any one of claims 39-40, further comprising one or more component selected from neutral lipids, steroids, and polymer conjugated lipids.

42. The lipid nanoparticle or composition of any one of claims 39-40, comprising one or more neutral lipids selected from DSPC, DPPC, DMPC, DOPC, POPC, DOPE and SM.

43. The lipid nanoparticle or composition of claim 41-42, wherein the neutral lipid is DSPC.

44. The lipid nanoparticle or composition of any one of claims 41-43, wherein the molar ratio of the compound to the neutral lipid ranges from about 2:1 to about 8:

1.

45. The lipid nanoparticle or composition of any one of claims 41-44, wherein the steroid is cholesterol.

46. The lipid nanoparticle or composition of claim 45, wherein the molar ratio of the compound to cholesterol ranges from about 5:1 to about 1:1 or from about 2:1 to about 1:

1.

47. The lipid nanoparticle or composition of any one of claims 41-46, wherein the polymer conjugated lipid is a pegylated lipid.

48. The lipid nanoparticle or composition of any one of claims 41-47, wherein the molar ratio of the compound to the polymer conjugated lipid ranges from about 100:1 to about 20:1 or from about 100:1 to about 10:

1.

49. The lipid nanoparticle or composition of any one of claims 41-48, wherein the pegylated lipid is PEG-DAG, PEG-PE, PEG-S-DAG, PEG-cer or a PEG dialkyoxypropylcarbamate.

50. The lipid nanoparticle or composition of any one of claims 41-48, wherein the pegylated lipid has the following Formula (II):or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: R5and R6are each independently a straight or branched alkyl, alkenyl, or alkynyl containing from 10 to 30 carbon atoms, wherein each alkyl, alkenyl, or alkynyl is optionally substituted with at least one fluoro; and z is an integer ranging from 30 to 60.

51. The lipid nanoparticle or composition of claim 50, wherein R5and R6are each independently a straight alkyl chain containing from 12 to 16 carbon atoms.

52. The lipid nanoparticle or composition of claim 50, wherein z ranges from 40 to 50.

53. The lipid nanoparticle or composition of any one of claims 39-52, wherein the therapeutic agent comprises a nucleic acid.

54. The lipid nanoparticle or composition of claim 53, wherein the nucleic acid comprises an antisense RNA, a messenger RNA, or a combination thereof.

55. The lipid nanoparticle or composition of any one of claims 39-52, wherein the therapeutic agent comprises a Cas9 mRNA or a ribonucleoprotein.

56. The lipid nanoparticle or composition of claim 54, wherein the messenger RNA encodes an antigen.

57. The lipid nanoparticle or composition of claim 56, wherein the antigen is an influenza antigen or a respiratory syncytial virus (RSV) antigen.

58. The lipid nanoparticle or composition of claim 57, wherein the influenza antigen is an influenza A antigen or an influenza B antigen.

59. The lipid nanoparticle or composition of any one of claims 39-58, wherein the lipid nanoparticle has a diameter of 40 nm to 100 nm.

60. A method for administering a therapeutic agent to a patient in need thereof, the method comprising preparing or providing the lipid nanoparticle or composition of any one of claims 39-59 and administering the composition to the patient.