Lipid nanoparticles comprising coding RNA molecules for use in gene editing and as vaccines and therapeutic agents

Abstract

The present disclosure describes improved LNP-based RNA vaccines, nucleobase editing systems, and therapeutics for use in treating and / or immunization against disease. In particular, the disclosure describes improved LNPs, including novel and improved ionizable lipids for making LNPs, that enhance the targeted delivery of LNP-based RNA vaccines and therapeutics based on linear and / or circular mRNAs. The improved LNPs protect linear and / or circular mRNA payloads from degradation and clearance while achieving targeted systemic or local delivery for use as enhanced vaccines and / or therapeutic agents.

Description

LIPID NANOPARTICLES COMPRISING CODING RNA MOLECULES FOR USE IN GENE EDITING AND AS VACCINES AND THERAPEUTIC AGENTS TECHNICAL FIELD

[0001] The present disclosure generally relates to the field of nucleic acid lipid nanoparticle (LNP) compositions and delivery thereof for use as vaccines and / or therapeutics for the treatment of disease. The disclosure further relates to compositions comprising LNPs formulated with coding RNAs, including linear and / or circular mRNAs, for the delivery of encoded vaccine antigens and / or therapeutic proteins for the vaccination against infectious agents and / or treatment of disease, including infectious disease and cancer. SEQUENCE LISTING

[0002] The instant application contains a Sequence Listing which has been submitted electronically in xml format and is hereby incorporated by reference in its entirety. The xml copy, created on February 15, 2024, is named RNG025-WO1.xml and is 44,129 bytes in size. BACKGROUND

[0003] There are many challenges associated with the delivery of nucleic acids to affect a desired response in a biological system, such as an immune response or the production of a therapeutically beneficial protein to treat a disease. Nucleic acid-based therapeutics and vaccines have enormous potential but there remains a need for more effective delivery of nucleic acids to appropriate sites within a cell or organism in order to realize this potential.

[0004] Nucleic acid-based therapeutics and vaccines are generally composed of DNA or RNA. DNA is known to be relatively stable and easy to handle, however, the use of DNA bears the risk of undesired insertion into a cell’s genome which potentially may produce mutagenic events. As a further concern, the delivery of DNA is associated with unwanted immunogenicity and the production of anti-DNA antibodies. Yet another concern in the use of DNA is the limited expression level of the encoded peptide or protein that is achievable due to the requirement that the administered DNA must first enter the nucleus to undergo transcription prior to translation into a desired protein product (e.g., antigen or therapeutic protein).

[0005] In contrast to DNA, the use of RNA is substantially safer because RNA does not involve the risk of being integrated into the genome of a transfected cell, thus eliminating the concern that the introduced genetic material will disrupt the normal functioning of an essential gene or cause a mutation. In addition, RNA-based agents do not require extraneous promoter sequences for effective expression of an encoded protein and are also less immunogenic than DNA-based agents, in part because RNA has a relatively short half-life unlike DNA. In addition, while DNA must enter the nuclease to perform its function, RNA performs its function outside of the nucleus and is therefore more efficient.

[0006] Despite the advantages of using RNA-based therapeutics and vaccines, the stability of RNA (e.g., mRNA) is far lower than DNA, especially when it reaches the cytoplasm of a cell and is exposed to RNA-degrading enzymes. In addition, the presence of a hydroxyl group on the second carbon of the sugar moiety in RNA causes steric hindrance that prevents the RNA from forming a more stable double helix structure like in the case of DNA, thus making RNA more prone to hydrolytic degradation than DNA.

[0007] To circumvent these challenges, delivery of RNA vaccines (e.g., mRNA vaccines) and therapeutics has recently focused on the use of lipid nanoparticles (LNPs). Indeed, LNPs have emerged as the most promising nonviral delivery vehicle for exogenous mRNA (see e.g., Guan et al., “Nanotechnologies in delivery of mRNA therapeutics using nonviral vector-based delivery systems,” Gene Ther, 24 (2017), pp.133-143). The LNP is a complex nanostructured body that provides protection to payload RNA molecules encapsulated within from the harshly degrading nuclease environment in vivo while facilitating intracellular delivery. LNPs are formed through self-assembly by combining the RNA payload with several lipid components, including an ionizable lipid that plays a central role in delivery efficacy (e.g., Miao et al., “Delivery of mRNA vaccines with heterocyclic lipids increases anti-tumor efficacy by STING-mediated immune cell activation,” Nat. Biotechnol., 27 (2019), pp.1174-1185). Entrapment of RNA is achieved by mixing RNA with lipids at an acidic pH at which the ionizable lipid is positively charged, thus ensuring a charge-driven interaction with the negatively charged RNA molecules (e.g., Mindy et al., “Mechanism of macromolecular structure evolution in self-assembled lipid nanoparticles for siRNA delivery," Langmuir, 20 (2014), pp.4613-4622). The pH is then adjusted to above the pKa of the ionizable lipid, which results in a near-neutral surface charge desirable for clinical administration (see Id.). In addition, the incorporation of a pegylated lipid into the mixture achieves a sterically stabilized core shell nanoparticle useful for clinical applications as vaccines and / or therapeutics.

[0008] In spite of the development of LNPs, the delivery of RNA payloads to cells in vivo in a targeted manner that also allows for sufficient levels of protein production (e.g., production of vaccine antigens or therapeutic proteins) remains an important and significant challenge.

[0009] Genome editing tools encompass a diverse set of technologies that can make many types of genomic alterations in various contexts. These technologies have evolved over the last couple of decades to provide a range of user-programmable editing tools that include ZFN (zinc finger) nuclease editing systems, meganuclease editing systems, and TALENS (transcription activator-like effector nucleases). The past decade has seen an explosive growth in a new generation of genome editing systems based on components from bacterial immune pathways, including CRISPR (clustered regularly interspaced short palindromic repeats) and the associated CRISPR-associated proteins (e.g., CRISPR-Cas9) (Jinek et al., “A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity,” Science, Vol.337 (6096), pp.816-821), meganuclease editors (Boissel et al.,“megaTALs: a rare-cleaving nuclease architecture for therapeutic genome engineering,” Nucleic Acids Research 42: pp.2591-2601) and bacterial retron systems (Schubert et al., “High-throughput functional variant screens via in vivo production of single-stranded DNA,” PNAS, April 27, 2021, Vol.118(18), pp.1-10). In particular, CRISPR-Cas9 has been derivatized in numerous ways to expand upon its guide RNA-based programmable double-strand cutting activity to form systems ranging from finding alternative CRISPR Cas nuclease enzymes having different PAM requirements and cutting properties (e.g., engineered Cas9 proteins and other naturally-occurring Cas9 homologs, including, but not limited to, Cas12a, Cas12f, Cas13a, and Cas13b, and their engineered variants) to base editing (Komor et al., “Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage,” Nature, May 19, 2016, 533 (7603); pp.420- 424 [cytosine base editors or CBEs] and Gaudelli et al., “Programmable base editing of A-T to G-C in genomic DNA without DNA cleavage,” Nature, Vol.551, pp.464-471 [adenine base editors or ABEs]) to prime editing (Anzalone et al., “Search-and-replace genome editing without double-strand breaks or donor DNA,” Nature, Dec 2019, 576 (7789): pp.149-157) to twin prime editing (Anzalone et al., “Programmable deletion, replacement, integration and inversion of large DNA sequences with twin prime editing,” Nature Biotechnology, Dec 9, 2021, vol.40, pp.731-740) to epigenetic editing (Kungulovski and Jeltsch, “Epigenome Editing: State of the Art, Concepts, and Perspective,” Trends in Genetics, Vol.32, 206, pp.101-113) to CRISPR-directed integrase editing (Yarnell et al., “Drag- and-drop genome insertion of large sequences without double-stranded DNA cleavage using CRISPR- directed integrases,” Nature Biotechnology, Nov 24, 2022, (“PASTE”)).

[0010] While the expansion of genome editing tools has exploded, the development of safe and effective gene editing tool delivery systems has lagged behind. There remain numerous challenges associated with the delivery of gene editing tools—including, but not limited to, CRISPR- Cas9 and alternative Cas nuclease editors, retron editors, base editors, prime editors, twin prime editors, epigenetic editors, and integrase editors—to achieve safe and effective therapeutic application of such tools in cells and patients for treating disease and / or otherwise modifying the nucleotide sequence of a target nucleic acid molecule (e.g., a gene or genome) particularly as it relates to delivery in vivo. That said, the use of lipid nanoparticles (LNPs) has emerged as a leading delivery option for the safe, effective, and targeted delivery of gene editing tools to target tissues and cells. However, there remains a need for improved LNPs, including better performing ionizable lipids, that will enhance the targeted delivery of LNP-based gene editing tools. Preferably, such improved LNPs would protect payloads from degradation and clearance while achieving targeted delivery, be suitable for systemic or local delivery, and provide delivery of RNA cargo, including those relating to a wide variety of gene editing tools, such as those mentioned above. In addition, such improved LNP-based therapeutics should exhibit low toxicity and provide an adequate therapeutic index, such that patient treatment at an effective dose of the LNP minimizes risk to the patient while maximizing therapeutic benefit.

[0011] Thus, improved LNPs that enhance the delivery of LNP-based RNA vaccines and therapeutics to cells, tissues, and bodily sites and which are more protective of RNA payloads would advance the art. Preferably, such improved LNPs would protect RNA payloads from degradation and clearance while achieving delivery, be suitable for ex vivo or in vivo delivery , and provide delivery of any target, including RNA in linear and / or circular and / or modified form.. In addition, such improved LNP-based RNA vaccines and therapeutics should exhibit low toxicity and provide an adequate therapeutic index, such that patient treatment at an effective dose of the LNP minimizes risk to the patient while maximizes therapeutic benefit. The present disclosure provides these and related advantages.SUMMARY

[0012] Described herein are compositions, methods, processes, kits and devices for the selection, design, preparation, manufacture, formulation, and / or use of LNP-based RNA medicines (e.g., vaccines and gene-editing therapeutics). In particular, described herein are compositions, methods, processes, kits and devices for the selection, design, preparation, manufacture, formulation, and / or use of LNP-based RNA medicines (e.g., vaccines and gene editing therapeutics) for the delivery of one or more coding and / or non-coding RNA molecules. In various embodiments, the non- coding RNAs may comprise one or more guide RNAs relating to a gene editing system, such as one based on CRISPR-Cas9 or CRISPR-Casl2a, each of which require complexing with a guide RNA that facilitates the localizing the protein-RNA complex to a target sequence having an enzyme- specific PAM site (protospaccr adjacent motif - recognized by the CRISPR enzyme) and a target nucleotide sequence (i.e., the protospacer) that is complementary to a portion of the guide RNA (i.e., to the spacer region). In other embodiments, the coding RNA may encode any protein component of LNP-based RNA medicine, such as, but limited to a virus antigen (e.g., a viral envelope spike protein), a therapeutic protein (e.g., a functional version of a defective protein), or one or more gene editing components (e.g., a programmable nuclease or other effector protein, such as a deaminase or reverse transcriptase). Further described herein are compositions, methods, processes, kits and devices for the selection, design, preparation, manufacture, formulation, and / or use of LNP-based RNA medicines (e.g., vaccines and / or gene editing therapeutics) for the delivery of one or more RNA molecules, e.g., a coding RNA that codes for one or more therapeutic proteins for the prophylactic and / or therapeutic treatment of one or more diseases or a symptom thereof, or a non-coding RNA, such as, but not limited to a guide RNA for a gene editing system. In various embodiments, the RNA molecule delivered by the herein disclosed LNPs can be a linear mRNA. In other embodiments, the RNA molecule delivered by the herein disclosed LNPs can be a circular mRNA. In still other embodiments, the RNA molecule delivered by the herein disclosed LNPs can include both linear and circular forms of mRNA. In further embodiments, the RNA may comprise one or more modifications, including chemical modifications (e.g., ribonucleotide analogs, alternative phosphate chain linkers), sequence modification (e.g., relative to a wild type sequence), and / or structuralmodification (e.g., secondary-folded structures, such as, but not limited to, stem-loops, hairpins, and G-quadruplexes, and tertiary structural elements, such as, but not limited to, helical duplexes and triple-stranded structures). In various other embodiments, the disclosure provides novel lipid components of the herein disclosed LNPs, including, but not limited to, novel ionizable lipids.

[0013] The present disclosure describes improved LNP-based RNA medicines (e.g., vaccines and therapeutics) for use in treating and / or immunization against disease. In particular, the disclosure describes improved LNPs, including better performing ionizable lipids, that enhance the targeted delivery of LNP-based RNA vaccines and therapeutics based on linear and / or circular mRNAs. The improved LNPs protect linear and / or circular mRNA cargos (i.e., the circular and / or linear mRNA molecules encapsulated by the LNPs) from degradation and clearance while achieving targeted systemic or local delivery for use as enhanced vaccines and / or therapeutic agents.

[0014] In an aspect of the disclosure, provided herein is a compound having a structure of any of Formulae (S-A’), (S-A), (S-B), (S-C), (S-D), (S-E), (S-F), (S-G), (S-H), (S-I), (S-Ia), (S-Ib), (S-J), (S-K), (S-L), (AT), (AT-A), (AT-A1), (AT-A2), (AT-B), (AT-B’), (AT-C), (AT-D), (AT-D’), (AT-D’a), (AT-D’b), (AT-E), (AT-E’’), (AT-F), (AT-F’), (AT-F’’), (AT-F’’’), (AT-F’’’’), (AT- F’’’’’), (AT-G), (AT-G’), (AT-H), (AT-H’), (AT-H’’), (AT-H’’’), (AT-I), (AT-J), (AT-J’), (AT-K), (AT-K’), (AT-L), (AT-L’), (AT-L’’), (AT-L’’’), (AT-M), (AT-N), (AT-N’), (AT-O), (AT-O’), (AT- P), (AT-P’), (AT-P’’), (AT-P’’’), (AT-Q), (AT-Q1), (AT-Q2), (AT-R), (AT-R’), (AT-S), (AT-S’), (AT-S’’), (AT-T), (AT-T’), (AT-T’’), (AT-T’’’), (AT-T’’’’), (AT-T’’’’’), (AC’), (AC), (AC-A), (AC- B), (AC-C), (AC-D), (AC-D1), (AC-D2), (AC-E), (AC-F), (AC-G), (AC-H), (AC-I), (CO’), (CO), (CO-A), (CO-B), (CO-C), (CO-D), (CO-E), (CO-F), (CO-G), (CO-G’), (CO-H), (CO-H’), (CO-I), (CO-I’), (CO-J), (CO-K), (CO-L), (CO-L’), (CO-M), (CO-M’), (CO-N), (CO-N’), (CO-O), (CO-O’), (CC’), (CC), (CC-A), (CC-B), (CC-C), (CC-D), (CC-E), (CC-F), (CC-F’), (CC-G), (CC-H), (CC-I), (CC-J), (CC-K), (CC-L), (CC-M), or a pharmaceutically acceptable salt thereof, or any lipid in Tables (I-A), (I-B), (I-C), (I-D) or (I-E), or a pharmaceutically salt, solvate, stereoisomer, or enantiomer thereof, see below, collectively referred to as "Lipids of the Disclosure" and each individually referred to as a "Lipid of the Disclosure."

[0015] In an aspect of the disclosure, provided herein is a pharmaceutical composition comprising a compound as disclosed herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0016] In an aspect, provided herein is a pharmaceutical composition comprising: a) at least one lipid nanoparticle comprising at least one compound having a structure of any of Formulae (S- A’), (S-A), (S-B), (S-C), (S-D), (S-E), (S-F), (S-G), (S-H), (S-I), (S-Ia), (S-Ib), (S-J), (S-K), (S-L), (AT), (AT-A), (AT-A1), (AT-A2), (AT-B), (AT-B’), (AT-C), (AT-D), (AT-D’), (AT-D’a), (AT-D’b), (AT-E), (AT-E’’), (AT-F), (AT-F’), (AT-F’’), (AT-F’’’), (AT-F’’’’), (AT-F’’’’’), (AT-G), (AT-G’), (AT-H), (AT-H’), (AT-H’’), (AT-H’’’), (AT-I), (AT-J), (AT-J’), (AT-K), (AT-K’), (AT-L), (AT-L’),(AT-L’’), (AT-L’’’), (AT-M), (AT-N), (AT-N’), (AT-O), (AT-O’), (AT-P), (AT-P’), (AT-P’’), (AT- P’’’), (AT-Q), (AT-Q1), (AT-Q2), (AT-R), (AT-R’), (AT-S), (AT-S’), (AT-S’’), (AT-T), (AT-T’), (AT-T’’), (AT-T’’’), (AT-T’’’’), (AT-T’’’’’), (AC’), (AC), (AC-A), (AC-B), (AC-C), (AC-D), (AC- D1), (AC-D2), (AC-E), (AC-F), (AC-G), (AC-H), (AC-I), (CO’), (CO), (CO-A), (CO-B), (CO-C), (CO-D), (CO-E), (CO-F), (CO-G), (CO-G’), (CO-H), (CO-H’), (CO-I), (CO-I’), (CO-J), (CO-K), (CO-L), (CO-L’), (CO-M), (CO-M’), (CO-N), (CO-N’), (CO-O), (CO-O’), (CC’), (CC), (CC-A), (CC-B), (CC-C), (CC-D), (CC-E), (CC-F), (CC-F’), (CC-G), (CC-H), (CC-I), (CC-J), (CC-K), (CC- L), (CC-M), or a pharmaceutically acceptable salt thereof, or any lipid in Tables (I-A), (I-B), (I-C), (I- D) or (I-E), or a pharmaceutically salt or solvate, or a pharmaceutically acceptable salt, solvate, stereoisomer, or enantiomer thereof, or any lipid in Tables (I-A), (I-B), (I-C), (I-D) or (I-E), or a salt, solvate, stereoisomer, or enantiomer thereof; and b) at least one nucleobase editing system.

[0017] In an aspect, provided herein is a method of delivering a nucleobase editing system to a subject in need thereof, the method comprising administering to the subject the pharmaceutical composition disclosed herein.

[0018] In an aspect of the disclosure, provided herein is a lipid nanoparticle (LNP) comprising a compound having a structure of any of Formulae (S-A’), (S-A), (S-B), (S-C), (S-D), (S- E), (S-F), (S-G), (S-H), (S-I), (S-Ia), (S-Ib), (S-J), (S-K), (S-L), (AT), (AT-A), (AT-A1), (AT-A2), (AT-B), (AT-B’), (AT-C), (AT-D), (AT-D’), (AT-D’a), (AT-D’b), (AT-E), (AT-E’’), (AT-F), (AT- F’), (AT-F’’), (AT-F’’’), (AT-F’’’’), (AT-F’’’’’), (AT-G), (AT-G’), (AT-H), (AT-H’), (AT-H’’), (AT-H’’’), (AT-I), (AT-J), (AT-J’), (AT-K), (AT-K’), (AT-L), (AT-L’), (AT-L’’), (AT-L’’’), (AT- M), (AT-N), (AT-N’), (AT-O), (AT-O’), (AT-P), (AT-P’), (AT-P’’), (AT-P’’’), (AT-Q), (AT-Q1), (AT-Q2), (AT-R), (AT-R’), (AT-S), (AT-S’), (AT-S’’), (AT-T), (AT-T’), (AT-T’’), (AT-T’’’), (AT- T’’’’), (AT-T’’’’’), (AC’), (AC), (AC-A), (AC-B), (AC-C), (AC-D), (AC-D1), (AC-D2), (AC-E), (AC-F), (AC-G), (AC-H), (AC-I), (CO’), (CO), (CO-A), (CO-B), (CO-C), (CO-D), (CO-E), (CO-F), (CO-G), (CO-G’), (CO-H), (CO-H’), (CO-I), (CO-I’), (CO-J), (CO-K), (CO-L), (CO-L’), (CO-M), (CO-M’), (CO-N), (CO-N’), (CO-O), (CO-O’), (CC’), (CC), (CC-A), (CC-B), (CC-C), (CC-D), (CC- E), (CC-F), (CC-F’), (CC-G), (CC-H), (CC-I), (CC-J), (CC-K), (CC-L), (CC-M), or a pharmaceutically acceptable salt thereof, or any lipid in Tables (I-A), (I-B), (I-C), (I-D) or (I-E), or a pharmaceutically acceptable salt, solvate, stereoisomer, or enantiomer thereof, or any lipid in Table (I), or a salt, solvate, stereoisomer, or enantiomer thereof.

[0019] In another aspect of the disclosure, provided herein is a method for delivering a nucleic acid to a cell comprising contacting the cell with a LNP disclosed herein or a pharmaceutical composition disclosed herein.

[0020] In another aspect of the disclosure, provided herein is a method for treating a disease characterized by a deficiency of a functional protein, the method comprising administering to a subject having the disease, a LNP formulation comprising a LNP disclosed herein, wherein themRNA encodes the functional protein or a protein having the same biological activity as the functional protein.

[0021] In another aspect of the disclosure, provided herein is a method for treating a disease characterized by overexpression of a polypeptide, comprising administering to a subject having the disease a LNP formulation comprising a LNP disclosed herein and a siRNA, wherein the siRNA targets expression of the overexpressed polypeptide. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] FIG.1 is a diagram illustrating the LNP-based RNA vaccines and therapeutics disclosed herein which are encapsulated with RNA payloads (e.g., linear and / or circular mRNAs).

[0023] FIG.2 is a diagram illustrating an originator polynucleotide construct of the present disclosure which may be linear or circular. DETAILED DESCRIPTION I. Introduction

[0024] The instant specification describes compositions, methods, processes, kits and devices for the selection, design, preparation, manufacture, formulation, and / or use of LNP-based RNA medicines (e.g., vaccines, gene therapies, or gene-editing therapeutics). In various embodiments, the LNP-based RNA medicines comprise an LNP delivery system (as described in detail herein) and an encapsulated cargo / payload (e.g., RNA in the case of RNA medicines).

[0025] In various embodiments and as described further herein, the LNP delivery vehicle is a complex nanostructured body that provides protection to an encapsulated RNA payload (i.e., one or more RNA molecules) environmental damage (e.g., an intracellular environment). LNPs are formed through self-assembly of multiple lipid components, including (i) an ionizable lipid (e.g., ALC-0315 as in COMIRNATY® (Pfizer-BioNTech), SM-102 as in SPIKEVAX® (Moderna), or MC3 as in ONPATTRO® (Alnylam), or those ionizable lipids described herein), (ii) a helper lipid (such as, but not limited to, 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC)), (iii) a sterol (e.g., cholesterol), and (iv) a PEG-lipid (e.g., PEG-DSPE).

[0026] In various embodiments and as described further herein, the RNA payload in the herein described LNP-based medicines may comprise coding and / or non-coding RNA, and / or mixtures thereof. The particular RNA payload constituents will generally reflect the medicine. For example, an LNP-based vaccine or therapeutic may comprise only coding RNA for expressing a vaccine antigen or a therapeutic protein, respectively. However, an LNP-based gene editing medicine may comprise a combination of coding RNA (e.g., encoding a CRISPR nuclease) and non-coding RNAs (e.g., guide RNAs). In various embodiments, the RNA molecule delivered by the herein disclosed LNPs can be a linear mRNA. In other embodiments, the RNA molecule delivered by theherein disclosed LNPs can be a circular mRNA. In still other embodiments, the RNA molecule delivered by the herein disclosed LNPs can include both linear and circular forms of mRNA. In further embodiments, the RNA may comprise one or more modifications, including chemical modifications (e.g., ribonucleotide analogs, alternative phosphate chain linkers), sequence modification (e.g., relative to a wild type sequence), and / or structural modification (e.g., secondary- folded structures, such as, but not limited to, stem-loops, hairpins, and G-quadruplexes, and tertiary structural elements, such as, but not limited to, helical duplexes and triple-stranded structures).A. LNP-Based RNA Vaccines

[0027] Described herein in certain aspects are improved LNP-based RNA vaccines for use in immunization against disease. In various aspects, the disclosure describes improved LNPs, including better performing ionizable lipids, that enhance the targeted delivery of LNP-based RNA vaccines and therapeutics based on linear and / or circular mRNAs. The improved LNPs protect linear and / or circular mRNA cargos (i.e., the circular and / or linear mRNA molecules encapsulated by the LNPs) from degradation and clearance while achieving targeted systemic or local delivery for use as enhanced vaccines.

[0028] The instant specification describes compositions, methods, processes, kits and devices for the selection, design, preparation, manufacture, formulation, and / or use of LNP-based RNA vaccines. In particular, as described herein are compositions, methods, processes, kits and devices for the selection, design, preparation, manufacture, formulation, and / or use of LNP-based RNA vaccines for the delivery of an RNA molecule that codes for one or more immunogenic viral antigens for use as vaccine and / or immunogenic compositions. In various embodiments, the RNA molecules delivered by the herein disclosed LNPs can be linear mRNA. In other embodiments, the RNA molecules delivered by the herein disclosed LNPs can be circular mRNA. In still other embodiments, the RNA molecule delivered by the herein disclosed LNPs can include both linear and circular forms of mRNA. In further embodiments, the RNA may comprise one or more modifications, including chemical modifications (e.g., ribonucleotide analogs, alternative phosphate chain linkers), sequence modification (e.g., relative to a wild type sequence), and / or structural modification (e.g., secondary-folded structures, such as, but not limited to, stem-loops, hairpins, and G-quadruplexes, and tertiary structural elements, such as, but not limited to, helical duplexes and triple-stranded structures). In various other embodiments, the disclosure provides novel lipid components of the herein disclosed LNPs, including, but not limited to, novel ionizable lipids.B. LNP-Based RNA Therapeutics

[0029] Described herein in certain aspects are improved LNP-based RNA therapeutics for use in treating disease or a symptom thereof. In various aspects, the disclosure describes improved LNPs, including better performing ionizable lipids, that enhance the targeted delivery of LNP-based RNA therapeutics based on linear and / or circular mRNAs. The improved LNPs protect linear and / orcircular mRNA cargos (i.c., the circular and / or linear mRNA molecules encapsulated by the LNPs) from degradation and clearance while achieving targeted systemic or local delivery for use as enhanced therapeutic agents.

[0030] The instant specification describes compositions, methods, processes, kits and devices for the selection, design, preparation, manufacture, formulation, and / or use of LNP-based RNA therapeutics. In particular, described herein are compositions, methods, processes, kits and devices for the selection, design, preparation, manufacture, formulation, and / or use of LNP-based RNA therapeutics for the delivery of an RNA molecule that codes for one or more therapeutic proteins for use treating a disease or a symptom thereof. Further described herein are compositions, methods, processes, kits and devices for the selection, design, preparation, manufacture, formulation, and / or use of LNP-based RNA therapeutics for the administration of an RNA molecule that codes for one or more therapeutic proteins for the prophylactic and / or therapeutic treatment of one or more diseases or a symptom thereof. In various embodiments, the RNA molecules delivered by the herein disclosed LNPs can be linear mRNA. In other embodiments, the RNA molecules delivered by the herein disclosed LNPs can be circular mRNA. In still other embodiments, the RNA molecules delivered by the herein disclosed LNPs can include both linear and circular forms of mRNA. In further embodiments, the RNA may comprise one or more modifications, including chemical modifications (e.g., ribonucleotide analogs, alternative phosphate chain linkers), sequence modification (e.g., relative to a wild type sequence), and / or structural modification (e.g., secondary- folded structures, such as, but not limited to, stem-loops, hairpins, and G-quadruplexes, and tertiary structural elements, such as, but not limited to, helical duplexes and triple-stranded structures). In various other embodiments, the disclosure provides novel lipid components of the herein disclosed LNPs, including, but not limited to, novel ionizable lipids.C. LNP-Based Gene Editing Therapeutics

[0031] Also described herein are LNP compositions comprising gene editing systems for use in treating disease and / or otherwise modifying the sequence and / or expression of target nucleotide sequences. The disclosure provides LNPs capable of delivering a gene editing system to a target organ, tissue, and / or cell. The gene editing systems may be delivered to cells under in vitro or ex vivo conditions and to organs, tissues, or cells under in vivo conditions (e.g., administered to a subject in an effective amount).

[0032] The disclosure also provides in various aspects therapeutic or pharmaceutical compositions comprising LNPs comprising gene editing systems or one or more components thereof. The gene editing systems may comprise DNA components, RNA components, protein components, nucleoprotein components, polysaccharide components, or combinations thereof. In other aspects, the disclosure provides nucleic acid molecules (e.g., RNA or DNA) that encode and / or constitute various componentry of the deliverable gene editing systems contemplated herein. In addition, other aspectsof the disclosure provide nucleic acid molecules as components of the herein contemplated gene editing systems, such as, but not limited to plasmids or vectors encoding one or more components of a gene editing system, RNAs encoding one or more components of a gene editing system (e.g., mRNAs coding for a nuclease domain of a gene editing system), and non-coding RNAs (e.g., guide RNAs capable of complexing with and targeting a nucleic acid-programmable DNA binding domain to a specific target nucleotide sequence or a retron ncRNAs).

[0033] In further embodiments, the nucleic acid components (e.g., RNA) may comprise one or more modifications, including chemical modifications (e.g., ribonucleotide analogs, alternative phosphate chain linkers), sequence modification (e.g., relative to a wild type sequence), and / or structural modification (e.g., secondary-folded structures, such as, but not limited to, stem-loops, hairpins, and G-quadruplexes, and tertiary structural elements, such as, but not limited to, helical duplexes and triple- stranded structures).

[0034] The disclosure, in other aspects, describes various protein components (which may be encoded by the nucleic acid components described herein) of the various gene editing systems contemplated herein, including, but not limited to, user-programmable DNA binding proteins and various effector proteins, such as nucleases, polymerases, reverse transcriptases, recombinases, integrases, endonucleases, exonucleases, transposases, and deaminases.

[0035] The disclosure also describes nucleoprotein components of the gene editing systems contemplated herein, such as, but not limited to nuclease-guide RNA complexes. The disclosure also provides methods of modifying the sequence and / or expression level of a target nucleic acid molecule through the delivery and / or administration of an LNP described herein that comprises a gene editing system or components thereof. Still further, the disclosure provides methods of treating a disease by administering a therapeutically effective amount of an LNP-based gene editing system that results in the modification in the sequence and / or expression level of a target nucleic acid molecule (e.g., a disease-associated gene or regulatory sequence, such as a promoter, transcription factor binding site, or gene enhancer site).

[0036] The gene editing systems deliverable by the herein disclosed LNPs can be any type of gene editing system. Without limitation, the gene editing systems contemplated herein can include (A) nucleobase gene editing systems which result in one or more the changes to the sequence of a target nucleic acid molecule (e.g., a gene or gene regulatory sequence) (sequence modifications may include, but are not limited to, an insertion of one or more base pairs, a deletion of one of more base pairs, a substitution or one or more base pairs, a conversion of a base pair to another base pair (e.g., a G:C pair converted to an A:T pair), an inversion, or a translocation), (B) an epigenetic editing system which results in one or more modifications to the epigenome to bring about an effect on gene expression without altering the sequence of a nucleic acid molecule, and (C) gene editing systems that combine the features of nucleobase editing systems and epigenetic editing systems (e.g., combiningcomponents from both types of systems to change the sequence and an epigenomic component with one system).

[0037] Nucleobase editing systems include a wide array of configurations with various combinations of protein functionalities and / or nucleic acid molecule components, all of which are contemplated herein. In general, nucleobase editing systems comprise at least a (i) DNA binding domain that is user-programmable to target a specific sequence in a nucleic acid molecule and optionally (ii) one or more effector domains that facilitate the modification of the sequence of the nucleic acid molecule. User-programmability may comprise amino acid sequence-programmable DNA binding domains (e.g., TALENS, zinc finger-binding domains, meganucleases (or homing endonucleases)) or nucleic acid sequence-programmable DNA binding domains or proteins (“naspDBP”) (e.g., CRISPR-Cas9, CRISPR-Cas12a, CRISPR-Cas12f, CRISPR-Cas13a, CRISPR- Cas13b, or TnpB).

[0038] Similarly, epigenetic editing systems comprise at least a (i) DNA binding domain that targets a specific sequence in a nucleic acid molecule and (ii) one or more effector domains that facilitates the modification of one or more epigenomic features of the nucleic acid molecule.

[0039] Gene editing systems may comprise one or more effector domains that provide various functionalities that facilitate changes in nucleotide sequence and / or gene expression, such as, but not limited to, single-strand DNA binding proteins, nucleases, endonucleases, exonucleases, deaminases (e.g., cytidine deaminases or adenosine deaminases), polymerases (e.g., reverse transcriptases), integrases, recombinases, etc., and fusion proteins comprising one or more functional domains linked together.

[0040] In addition, gene editing systems that utilize a nucleic acid sequence-programmable DNA binding domain or protein (naspDBP) may also comprise one or more non-coding nucleic acids, such as, one or more guide RNAs which complex with the nucleic acid programmable DNA binding protein (naspDBP) and target the complex to a specific nucleotide sequence. In the case of prime editing, the guide RNA may be a prime editing guide RNA (“pegRNA”) which comprises a specialized RNA template molecule that provides a template or coding sequence for a reverse transcriptase of the prime editing system. In some embodiments, the RNA template molecule may be coupled to a guide RNA as an extension arm at the 5’ or 3’ end of the guide RNA. In other embodiments, the RNA template molecule may be provided in trans as a separate molecule in a manner such that the RNA template molecule may itself become localized and associated with the target sequence and / or the gene editing system at the site of editing. In some embodiments, co- localization of an in trans RNA template molecule may be achieved with an aptamer or other RNA structure which binds to a binding partner that is coupled to, integrated with, or otherwise associated with the editing complex.

[0041] In the case of editing systems comprising a nucleic acid sequence-programmableDNA binding protein (naspDBP), such as a CRISPR-Cas9 or CRISPR-Casl2a nuclease, appropriate guides may be designed and synthesized using methods, software, and commercial sources which are well known to those having ordinary skill in the art such that guide RNAs for any given naspDBP may be obtained without undue experimentation.

[0042] Reference may be made to the following references providing information and tools for the design, synthesis, modification, and structural configuration of guide RNAs: (1) Mohr SE, Hu Y, Ewen-Campen B, Housden BE, Viswanatha R, Perrimon N. CR1SPR guide RNA design for research applications. FEBS J. 2016 Sep;283(17):3232-8. doi: 10.1111 / febs.13777. Epub 2016 Jun 22. PMID: 27276584: PMCID: PMC5014588; (2) Hoberecht L, Perampalam P, Lun A, Fortin JP. A comprehensive Bioconductor ecosystem for the design of CRISPR guide RNAs across nucleases and technologies. Nat Commun. 2022 Nov 2; 13( 1 ):6568. doi: 10.1038 / s41467-022-34320-7. PMID: 36323688: PMCID: PMC9630310; (3) Cram D, Kulkami M, Buchwaldt M, Rajagonalan N, Bhowmik P. Rozwadowski K, Parkin IAP, Sharpe AG, Kagale S. WheatCRISPR: a web-based guide RNA design tool for CRlSPR / Cas9-mediated genome editing in wheat. BMC Plant Biol. 2019 Nov 6;19(1):474. doi: 10.1186 / sl2870-019-2097-z. PMID: 31694550; PMCID: PMC6836449; (4) Pliatsika V, Rjgoutsos I. "Off-Spotter": very fast and exhaustive enumeration of genomic lookalikes for designing CRISPR / Cas guide RNAs. Biol Direct. 2015 Jan 29; 10:4. doi: 10.1186 / sl3062-015- 0035-z. PMID: 25630343; PMCID: PMC4326336; (5) Hoof JB, Nfodvig CS, Mortensen UH. Genome Editing: CRISPR-Cas9. Methods Mol Biol. 2018;1775:119-132. doi: 10.1007 / 978-l-4939-7804-5_l 1. PMID: 29876814; (6) Laban K, Krause M, Torres Cleuren Y, Valen E. CRISPR Genome Editing Made Easy Through the CHOPCHOP Website. Cunt Protoc. 2021 Apr;l (4):e46. doi: 10.1002 / cpzl.46. PMID: 33905612; (7) Lee CM, Davis TH, Bao G. Examination of CRISPR / Cas9 design tools and the effect of target site accessibility on Cas9 activity. Exp Physiol. 2018 Apr l;103(4):456-460. doi: 10.U13 / EP086043. Epub 2017 Apr 12. PMID: 28303677; PMCID: PMC7266697; (8) Ma S, Lv J, Feng Z, Rong Z, Lin Y. Get ready for the CRISPR / Cas system: A beginner's guide to the engineering and design of guide RNAs. J Gene Med. 2021 Nov;23(l l):e3377. doi: 10.1002Zjgm.3377. Epub 2021 Jul 28. PMID: 34270141; (9) Hiranniramol K, Chen Y, Wang X. CRISPR / Cas9 Guide RNA Design Rules for Predicting Activity. Methods Mol Biol. 2020;2115:35 I- 364. doi: 10.1007 / 978- 1-0716-0290-4J 9. PMID: 32006410; (10) Wiles MV, Qin W, Cheng AW, Wang II. CRISPR-Cas9-mediated genome editing and guide RNA design. Mamm Genome. 2015 0ct;26(9-10):501- l0. doi: 10.1007 / s00335-015-9565-z. Epub 2015 May 20. PMID: 25991564;PMCID: PMC4602062; (11) Creutzburg SCA, Wu WY, Mohanraju P, Swartjes T, Alkan F, Gorodkin J, Staals RHJ, van der Oost J. Good guide, bad guide: spacer sequence-dependent cleavage efficiency of Casl2a. Nucleic Acids Res. 2020 Apr 6;48(6):3228-3243. doi: 10.1093 / nar / gkzl240. PMID: 31989168; PMCID: PMC7102956; (12) Heigwer F, Boutros M. Cloud-Based Design of Short Guide RNA (sgRNA) Libraries for CRISPR Experiments. Methods Mol Biol. 2021;2162:3-22. doi:10.1007 / 978-1-0716-0687-2 1. PMID: 32926374; (13) Dronina J, Samukaitc-Bubnicne U, Ramanavicius A. Towards application of CRISPR-Casl2a in the design of modern viral DNA detection tools (Review). J Nanobiotechnology. 2022 Jan 21;20(l ):41. doi: 10.1186 / s 12951-022- 01246-7. PMID: 35062978: PMCID: PMC8777428; (14) Krysler AR, Cromwell CR, Tu T, Jovel J, Hubbard BP. Guide RNAs containing universal bases enable Cas9 / Casl2a recognition of polymorphic sequences. Nat Common. 2022 Mar 25; 13(1): 1617. doi: 10.1038 / s41467-022-29202-x. PMID: 35338140; PMCID: PMC8956631; ( 15) Shin HR, Kweon J, Kim Y. Gene Manipulation Using Fusion Guide RNAs for Cas9 and Casl2a. Methods Mol Biol. 2021 ;2162:185-193. doi: 10.1007 / 978- 1-0716-0687-2..10. PMID: 32926383; (16) Schubert MS, Thommandru B, Woodley J, TurkR, Yan S, Kurgan G, McNeill MS, Rettig GR. Optimized design parameters for CRISPR Cas9 and Casl2a homology-directed repair. Sci Rep. 2021 Sep 30; 11(1):19482. doi: 10.1038 / s41598-021-98965-y. PMID: 34593942; PMCID: PMC8484621; (17) Crone MA, MacDonald JT, Freemont PS, Siciliano V. gDesigner: computational design of synthetic gRNAs for Casl2a-based transcriptional repression in mammalian cells. NPJ Syst Biol Appl. 2022 Sep 16;8(1):34. doi: 10.1038 / s41540-022-00241-w. PMID: 361 14193; PMCID: PMC9481559; ( 18) Konstantakos V, Nentidis A, Krithara A, Paliouras G. CRISPR-Cas9 gRN A efficiency prediction: an overview of predictive tools and the role of deep learning. Nucleic Acids Res. 2022 Apr 22:50(7):3616-3637. doi: 10.1093 / nar / gkacl92. PMID: 35349718; PMCID: PMC9023298; (19) Wang J, Zhang X, Cheng 1.., Luo Y. An overview and metanalysis of machine and deep learning-based CRISPR gRNA design tools. RNA Biol. 2020 Jan;17(l):13-22. doi: 10.1080 / 15476286.2019.1669406. Epub 2019 Sep 27. PMID: 31533522; PMCID: PMC6948960; and (20) Cram D, Kulkami M, Buchwaldt M, Rajagopalan N, Bhowmik P, Rozwadowski K, Parkin IAP, Sharpe AG, Kagale S. WheatCRISPR: a web-based guide RNA design tool for CRISPR / Cas9-mediated genome editing in wheat. BMC Plant Biol. 2019 Nov 6; 19(1):474. doi: 10.1186 / sl2870-019-2097-z. PMID: 31694550; PMCID: PMC6836449: each of which are incorporated herein by reference in their entireties.

[0043] In the case of prime editing, in particular, further reference may be made to the following references providing information and tools for the design, synthesis, modification, and structural configuration of pegRNAs: (1) Hsu JY, Griinewald J, Szalay R, Shih J, Anzalone AV, Lam KC, Shen MW, Petri K, Liu DR, Joung JK, Pinello L. PrimeDesign software for rapid and simplified design of prime editing guide RNAs. Nat Common. 2021 Feb 15; 12(1): 1034. doi: 10.1038 / s41467- 021-21337-7. PMID: 33589617; PMCID: PMC7884779; (2) Li Y, Chen J, Tsai SQ. Cheng Y. Easy- Prime: a machine learning-based prime editor design tool. Genome Biol. 2021 Aug 19;22(1):235. doi: 10.1186 / S13059-021-02458-0. PMID: 34412673; PMCID: PMC8377858; (3) Zhang W, Petri K, Ma J, Lee H, Tsai CL, Joung JK, Yeh JI. Enhancing CRISPR prime editing by reducing misfolded pegRNA interactions. bioRxiv [Preprint], 2023 Aug 15:2023.08.14.553324. doi:10.1101 / 2023.08.14.553324. PMID: 37645936; PMCID: PMC10462064; (4) Jin S, Lin Q, Gao Q, Gao C. Optimized prime editing in monocot plants using PlantPegDesigner and engineered plantprime editors (cPPEs). Nat Protoc. 2023 Mar;18(3):831-853. doi: 10.1038 / s41596-022-00773-9. Epub 2022 Nov 25. PMID: 36434096; (5) Lin Q, Jin S, Zong Y, Yu II, Zhu Z, Liu G, Kou L, Wang Y, Qin JL, Li J, Gao C. High-efficiency prime editing with optimized, paired pegRNAs in plants. Nat Biotechnol. 2021 Aug;39(8):923-927. doi: 10.1038 / s41587-021-00868-w. Epub 2021 Mar 25. PMID: 33767395; (6) Standage-Beier K, Tekel SJ, Brafman DA, Wang X. Prime Editing Guide RNA Design Automation Using PINE-CONE. ACS Synth Biol. 2021 Feb 19; 10('2):422-427. doi: 10.1021 / acssynbio.0c00445. Epub 2021 Jan 19. PMID: 33464043; PMCID: PMC7901017; (7) Zhang W, Petri K, Ma J, Lee H. Tsai CL, Joung JK, Yeh J.l. Enhancing CRISPR prime editing by reducing misfolded pegRNA interactions. bioRxiv [Preprint]. 2023 Aug 15:2023.08.14.553324. doi: 10.1101 / 2.023.08.14.553324. PMID: 37645936; PMCID: PMC 10462064; (8) Chow RD, Chen JS, Shen J, Chen S. A web tool for the design of prime-editing guide RNAs. Nat Biomed Eng. 2021 Feb;5(2):190-194. doi: 10.1038 / s41551-020-00622-8. Epub 202.0 Sep 28. PMID: 32989284; PMCID: PMC7882013; each of which are incorporated herein by reference in their entireties.

[0044] Reference may also be made to the following commercial vendors which sell guide RNAs for CRISPR editing applications (including base editing and prime editing) and provide various tools and instruction for the ordering, design, synthesis, modification, and structural configuration of guide RNAs: GENSCRIPT, SYNTHEGO, TAKARA BIO, INTEGRATED DNA TECHNOLOGIES, LC SCIENCES, HORIZON DISCOVERY; SIGMA-ALDRICH; ORIGENE, and TWIST BIOSCIENCES, among others.

[0045] In addition, guide RNA may be modified with chemical modifications and / or structural modifications for enhancing various properties thereof, including specificity, stability, and limiting off-target activity. One of ordinary skill in the art will be able to modify a guide RNA with any known modification without undue experimentation. Guide modifications are discussed in the following references: (1) Ke Y, Ghalandari B, Huang S, Li S, Huang C, Zhi X, Cui D, Ding X. 2'- O- Methyl modified guide RNA promotes the single nucleotide polymorphism (SNP) discrimination ability of CR1SPR-Casl2a systems. Chem Sei. 2022 Feb 1; 13(7):2050-2061. doi: 10.1039 / dlsc06832f. PMID: 35308857: PMCID: PMC8848812; (2) Allen D, Rosenberg M, Hendel A. Using Synthetically Engineered Guide RNAs to Enhance CRISPR Genome Editing Systems in Mammalian Cells. Front Genome Ed. 2.021 Jan 28;2:617910. doi: 10.3389 / fgeed.202.0.617910. PMID: 34713240; PMCID: PMC8525374; (3) Basila M, Kelley ML, Smith AVB. Minimal 2'-O-methyl phosphorothioate linkage modification pattern of synthetic guide RNAs for increased stability and efficient CRISPR-Cas9 gene editing avoiding cellular toxicity. PLoS One. 2017 Nov27;12( 1 l):e0188593. doi: 10.1371 / joumal,pone.0188593. PMID: 29176845; PMCID: PMC5703482; (4) Sakovina L, Vokhfantsev I, Vorobyeva M, Vorobyev P, Novopashina D. Improving Stability and Specificity of CR1SPR / Cas9 System by Selective Modification of Guide RNAs with 2'-fluoro and Locked Nucleic Acid Nucleotides. Int J Mol Sei 2022 Nov 3 :23(21 ): 13460 doi:10.3390 / ijms232113460. PMID: 36362256; PMCID: PMC9655745; (5) Shapiro J, Tovin A, laocu O,Allen D, Hendcl A. Chemical Modification of Guide RNAs for Improved CRISPR Activity in CD34+ Human Hematopoietic Stem and Progenitor Cells. Methods Mol Biol. 2021;2162:37-48. doi: 10.1007 / 978-l-0716-0687-2_3. PM1D: 32926376; (6) Filippova J, Matveeva A, Zhuravlev E, Stepanov G. Guide RNA modification as a way to improve CRISPR / Cas9-based genome-editing systems. Biochimie. 2019 Dec; 167:49-60. doi: 10.1016 / j.biochi.2019.09.003. Epub 2019 Sep 4. PMID: 31493470: (7 ) Hendel A, Bak RO, Clark JT, Kennedy AB, Ryan DE, Roy S, Steinfeld I, Lunstad BD, Kaiser RJ, Wilkens AB, Bacchetta R, Tsalenko A, Dellinger D, Bruhn L, Porteus MH. Chemically modified guide RNAs enhance CRISPR-Cas genome editing in human primary cells. Nat Biotechnol. 2015 Sep;33C9'):985-989. doi: 10.1038 / nbt.3290. Epub 2015 Jun 29. PMID: 26121415: PMCID: PMC4729442; (8)_ Ryan DE, Taussig D, Steinfeld I, Phadnis SM, Lunstad BD, Singh M, Vuong X, Okochi KD, McCaffrey R, Olesiak M, Roy S, Yung CW, Curry B, Sampson JR, Bruhn L, Dellinger DJ. Improving CRISPR-Cas specificity with chemical modifications in single-guide RNAs. Nucleic Acids Res. 2018 Jan 25;46(2):792-803. doi: 10.1093 / nar / gkxll99. Erratum in: Nucleic Acids Res. 2022 Mar 21 ;50(5):2986. PMID: 29216382; PMCID: PMC5778453; (9) Palumbo CM, Gutierrez-Bujari JM, O'Geen H, Segal DJ, Beal PA. Versatile 3’ Functionalization of CRISPR Single Guide RNA. Chembiochem. 2020 Jun 2;21 (11): 1633-1640. doi: 10.1002 / cbic.201900736. Epub 2020 Mar 5. PMID: 31943634; PMCID: PMC7323579; (10) MuUally G, van Aelst K, Naqvi MM, Diffin FM, Karvelis T, Gasiunas G, Siksnys V, Szczelkun MD. 5’ modifications to CRISPR-Cas9 gRNA can change the dynamics and size of R-loops and inhibit DNA cleavage. Nucleic Acids Res. 2020 Jul 9;48(12):6811 -6823. doi: 10.1093 / nar / gkaa477. PMID: 32496535; PMCID: PMC7337959; (12) Lu S, Zhang Y, Yin H. Chimeric DNA-RNA Guide RNA Designs. Methods Mol Bioi. 2021;2162:79-85. doi: 10.1007 / 978- 1 -0716-0687-2_6. PMID: 32926379; each of which are incorporated by reference herein in their entireties.

[0046] In the specific case of prime editing, pegRNAs may be modified with chemical modifications and / or structural modifications for enhancing various properties thereof, including specificity, stability, and limiting off-target activity. One of ordinary skill in the art will be able to modify a pegRNA for prime editing with any known modification without undue experimentation. pegRNA modifications are discussed in the following references: (1) Nelson JW, Randolph PB, Siren SP, Everette KA, Chen PJ, Anzalone AV, An M, Newby GA, Chen JC, Hsu A, Liu DR. Engineered pegRNAs improve prime editing efficiency. Nat Biotechnol. 2022 Mar;40(3):402-410. doi: 10.1038 / S41587-021-01039-7. Epub 2021 Oct 4. Erratum in: Nat Biotechnol. 2021 Dec 8;: PMID: 34608327; PMCID: PMC8930418; (2) Liu B, Dong X, Cheng H, Zheng C, Chen Z. Rodrfguez TC, Liang SQ, Xue W, Sontheimer EJ. A split prime editor with untethered reverse transcriptase and circular RNA template. Nat Biotechnol. 2022 Sep;40(9):1388-1393. doi: 10.1038 / s41587-022-01255- 9. Epub 2022 Apr 4. PMID: 35379962; each of which are incorporated by reference herein in their entireties.

[0047] Other specialized guide RNAs may be included depending upon the requirements and / or nature of the gene editing system and the cognate nucleic acid programmable proteins. For example, TnpB enzymes require a specialized guide RNA referred to as reRNA. Also, guide RNAs have different characteristics (e.g., PAM preferences, the spacer length, and the scaffold portion that binds to the nuclease protein) depending upon the programmable nuclease requirements.

[0048] The gene editing systems contemplated here may introduce a wide variety of changes, including (A) a change in the sequence of the target nucleic acid molecule, such as, but not limited to, (i) a nucleobase substitution (e.g., a purine to a pyrimidine), (ii) a deletion of one or more nucleobases, (iii) an insertion of one or more nucleobases, (iv) a combination of a deletion and insertion of one or more nucleobases, (v) an inversion of a nucleobase sequence, a (vi) translocation of a nucleobase sequence, and (vii) a combination or two or more such modifications, and (B) one or more modifications to the epigenome to bring about an effect on gene expression without altering the sequence of a nucleic acid molecule wherein said epigenetic change results in altered gene expression through altered chromatin structure or accessibility.

[0049] The LNP compositions and / or gene editing systems described herein may include a variety of coding RNA molecules that code for the various components of gene editors. In various aspects, the coding RNA may be linear mRNA. In other embodiments, the coding RNA may be circular mRNA. In various aspects, the improved LNPs protect linear and / or circular mRNA cargos from degradation and clearance while achieving targeted systemic or local delivery for use as enhanced gene editing platforms and / or therapeutic agents.

[0050] In various other aspects, the LNP compositions and / or gene editing systems described herein may also include a repair template, e.g., an homology -directed repair (HDR) -dependent repair template (or HDR template). Such HDR templates are well-known in the art and can include single- strand or double-stranded DNA (e.g., oligos) or RNA. Further information regarding HDR and HDR templates for use in editing systems for various applications, such as gene knock-in, may be found in Fu YW. Dai XY, Wang WT, Yang ZX, Zhao JJ, Zhang JP, Wen W, Zhang F, Oberg KC, Zhang I... Cheng T, Zhang XB. Dynamics and competition of CR1SPR-Cas9 ribonucleoproteins and AAV donor-mediated NHEJ, MMEJ and HDR editing. Nucleic Acids Res. 2021 Jan 25;49(2 ):969-985. doi: 10. 1093 / nar / gkaa 1251. PMID: 33398341 ; PMCIDt PMC7826255; Iyer S, Mir A, Vega-Badillo J, Roscoe BP, Ibraheim R, Zhu LJ, Lee J, Liu P, Luk K, Mintzer E, Guo D, Soares de Brito J, Emerson CP Jr, Zarnore PD, Sontheimer El, Wolfe SA. Efficient Homology-Directed Repair wiih Circular Single-Stranded DNA Donors. CR1SPR J. 2022 Oct;5(5):685-701 . doi: 10.1089 / crispr.2022.0058. Epub 2022 Sep 7. PMID: 36070530; PMCID: PMC9595650; and Richardson CD. Ray GJ, DeWitt MA, Curie GL, Corn JE. Enhancing homology-directed genome editing by catalytically active and inactive CR1SPR-Cas9 using asymmetric donor DNA. Nat Biotechnol. 2016 Mar;34(3):339-44. doi:10.1038 / nbt.3481. Epub 2016 Jan 20. PMID: 26789497, each of which arc incorporated herein by reference in their entireties.

[0051] Accordingly, the instant specification describes compositions, methods, processes, kits and devices for the selection, design, preparation, manufacture, formulation, and / or use of LNP- based gene editing systems as therapeutic compositions. Further described herein are compositions, methods, processes, kits and devices for the selection, design, preparation, manufacture, formulation, and / or use of LNP-based gene editing therapeutics for the prophylactic and / or therapeutic treatment of one or more diseases or a symptom thereof. The components capable of being encapsulated by or otherwise incorporated by the LNPs described herein may be referred to as LNP “payloads” and may include all of the biological materials described above, including DNA molecules, RNA molecules (coding and / or non-coding), proteins, and nucleoproteins (e.g., Cas / guide RNA complexes).II. LNP delivery systems

[0052] The RNA payloads (e.g., linear and circular mRNAs) described herein may be encapsulated and delivered by lipid nanoparticles (LNPs) and compositions and / or formulations comprising RNA-encapsulated LNPs.

[0053] Below describes LNPs that may be used as the RNA payload delivery vehicles contemplated herein, as well as the various ionizable lipids, structural lipids, PEGylated lipids, and phospholipids that may be used to make the herein LNPs for delivery RNA payloads to cells. In addition, below describes additional LNP components that are contemplated, such as targeting moieties and other lipid components.A. Lipid Nanoparticle Compositions

[0054] In one aspect, the present disclosure further provides delivery systems for delivery of a therapeutic payload (e.g., the RNA payloads described herein which may encode a polypeptide of interest, e.g., an antigen or a therapeutic protein) disclosed herein. In some embodiments, a delivery system suitable for delivery of the therapeutic payload disclosed herein comprises a lipid nanoparticle (LNP) formulation.

[0055] In some embodiments, an LNP of the present disclosure comprises an ionizable lipid, a structural lipid, a PEGylated lipid (aka PEG lipid), and a phospholipid. In alternative embodiments, an LNP comprises an ionizable lipid, a structural lipid, a PEGylated lipid (aka PEG lipid), and a zwitterionic amino acid lipid. In some embodiments, an LNP further comprises a 5th lipid, besides any of the aforementioned lipid components. In some embodiments, the LNP encapsulates one or more elements of the active agent of the present disclosure. In some embodiments, an LNP further comprises a targeting moiety covalently or non-covalently bound to the outer surface of the LNP. In some embodiments, the targeting moiety is a targeting moiety that binds to, or otherwise facilitates uptake by, cells of a particular organ system.

[0056] In some embodiments, an LNP has a diameter of at least about 20nm, 30 nm, 40nm, 50nm, 60nm, 70nm, 80nm, or 90nm. In some embodiments, an LNP has a diameter of less than about lOOnm, HOnm, 120nm, 130nm, 140nm, 150nm, or 160nm. In some embodiments, an LNP has a diameter of less than about 120 nm. In some embodiments, an LNP has a diameter of less than about lOOnm. In some embodiments, an LNP has a diameter of less than about 90nm. In some embodiments, an LNP has a diameter of less than about 80nm. In some embodiments, an LNP has a diameter of about 60-100nm. In some embodiments, an LNP has a diameter of about 50-120nm. In some embodiments, an LNP has a diameter of about 75-80nm.

[0057] In some embodiments, the lipid nanoparticle compositions of the present disclosure are described according to the respective molar ratios of the component lipids in the formulation. As a non-limiting example, the mol-% of the ionizable lipid may be from about 10 mol-% to about 80 mol- %. As a non-limiting example, the mol-% of the ionizable lipid may be from about 20 mol-% to about 70 mol-%. As a non-limiting example, the mol-% of the ionizable lipid may be from about 30 mol-% to about 60 mol-%. As a non-limiting example, the mol-% of the ionizable lipid may be from about 35 mol-% to about 55 mol-%. As a non-limiting example, the mol-% of the ionizable lipid may be from about 40 mol-% to about 50 mol-%. As a non-limiting example, the mol-% of the ionizable lipid may be from about 30 mol-% to about 40 mol-%. As a non-limiting example, the mol-% of the ionizable lipid may be from about 25 mol-% to about 35 mol-%. In some embodiments, the mol-% of the ionizable lipid is about 10 mol-%. In some embodiments, the mol-% of the ionizable lipid is about 15 mol-%. In some embodiments, the mol-% of the ionizable lipid is about 20 mol-%. In some embodiments, the mol-% of the ionizable lipid is about 25 mol-%. In some embodiments, the mol-% of the ionizable lipid is about 30 mol-%. In some embodiments, the mol-% of the ionizable lipid is about 33 mol-%. In some embodiments, the mol-% of the ionizable lipid is about 35 mol-%. In some embodiments, the mol-% of the ionizable lipid is about 40 mol-%. In some embodiments, the mol-% of the ionizable lipid is about 45 mol-%. In some embodiments, the mol-% of the ionizable lipid is about 55 mol-%. In some embodiments, the mol-% of the ionizable lipid is about 60 mol-%.

[0058] In some embodiments, the mol-% of the phospholipid may be from about 1 mol-% to about 50 mol-%. In some embodiments, the mol-% of the phospholipid may be from about 2 mol-% to about 45 mol-%. In some embodiments, the mol-% of the phospholipid may be from about 3 mol- % to about 40 mol-%. In some embodiments, the mol-% of the phospholipid may be from about 4 mol-% to about 35 mol-%. In some embodiments, the mol-% of the phospholipid may be from about 5 mol-% to about 30 mol-%. In some embodiments, the mol-% of the phospholipid may be from about 10 mol-% to about 20 mol-%. In some embodiments, the mol-% of the phospholipid may be from about 5 mol-% to about 20 mol-%. In some embodiments, the mol-% of the phospholipid is from about 30 mol-% to about 60 mol-%. In some embodiments, the mol-% of the phospholipid is from about 35 mol-% to about 55 mol-%. In some embodiments, the mol-% of the phospholipid is fromabout 35 mol-% to about 45 mol-%. In some embodiments, the mol-% of the phospholipid is about 10 mol-%. In some embodiments, the mol-% of the phospholipid is about 15 mol-%. In some embodiments, the mol-% of the phospholipid is about 20 mol-%. In some embodiments, the mol-% of the phospholipid is about 25 mol-%. In some embodiments, the mol-% of the phospholipid is about 30 mol-%. In some embodiments, the mol-% of the phospholipid is about 35 mol-%. In some embodiments, the mol-% of the phospholipid is about 40 mol-%. In some embodiments, the mol-% of the phospholipid is about 45 mol-%. In some embodiments, the mol-% of the phospholipid is about 55 mol-%. In some embodiments, the mol-% of the phospholipid is about 60 mol-%.

[0059] In some embodiments, the mol-% of the phospholipid as described above comprises two or more phospholipids at an individual mol-% that totals to an aforementioned amount. In certain embodiments, the mol-% of the phospholipid is about 20 mol-% each of two phospholipids. In certain embodiments, the mol-% of the phospholipid is about 15 mol-% each of two phospholipids. In certain embodiments, the mol-% of the phospholipid is about 25 mol-% each of two phospholipids. In certain embodiments, the mol-% of the phospholipid is about 30 mol-% each of two phospholipids. In certain embodiments, the mol-% of the phospholipid is about 15 mol-% of a first phospholipid and about 20 mol-% of a second phospholipid. In certain embodiments, the mol-% of the phospholipid is about 30 mol-% of a first phospholipid and about 10 mol-% of a second phospholipid. In certain embodiments, the mol-% of the phospholipid is about 25 mol-% of a first phospholipid and about 10 mol-% of a second phospholipid. In certain embodiments, the mol-% of the phospholipid is about 25 mol-% of a first phospholipid and about 20 mol-% of a second phospholipid. In certain embodiments, the mol-% of the phospholipid is about 15 mol-% of a first phospholipid and about 20 mol-% of a second phospholipid.

[0060] In some embodiments, the mol-% of the structural lipid may be from about 10 mol-% to about 80 mol-%. In some embodiments, the mol-% of the structural lipid may be from about 20 mol-% to about 70 mol-%. In some embodiments, the mol-% of the structural lipid may be from about 30 mol-% to about 60 mol-%. In some embodiments, the mol-% of the structural lipid may be from about 35 mol-% to about 55 mol-%. In some embodiments, the mol-% of the structural lipid may be from about 40 mol-% to about 50 mol-%.

[0061] In some embodiments, the mol-% of the PEG lipid may be from about 0.1 mol-% to about 10 mol-%. In some embodiments, the mol-% of the PEG lipid may be from about 0.2 mol-% to about 5 mol-%. In some embodiments, the mol-% of the PEG lipid may be from about 0.5 mol-% to about 3 mol-%. In some embodiments, the mol-% of the PEG lipid may be from about 1 mol-% to about 2 mol-%. In some embodiments, the mol-% of the PEG lipid may be about 1 .5 mol-%. Tn some embodiments, the mol-% of the PEG lipid may be about 2.5 mol-%. In some embodiments, the mol-% of the PEG lipid may be about 3 mol-%. In some embodiments, the mol-% of the PEG lipid may be about 3.5 mol-%.

[0062] Where reference is made above to “mol-%” or “mol %”, the amount of the noted LNP component is intended to be the mol% of the specific component as compared to the total lipid component content of the lipid nanoparticle. i. Ionizable lipids

[0063] In some embodiments, an LNP disclosed herein comprises an ionizable lipid. In some embodiments, an LNP comprises two or more ionizable lipids. Series “S”

[0064] Described below are a number of exemplary ionizable lipids of the present disclosure. Formula (S-A’)

[0065] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-A): (S-A’), or a pharmaceutically acceptable salt thereof, wherein: A is -N(-X1R1)-, -C(R')(-L1-N(R")R6)-, -C(R')(-OR7a)-, -C(R')(-N(R")R8a)- , -C(R')(-C(=O)OR9a)-, -C(R')(-OC(=O)R9a)-, -C(R')(-C(=O)N(R")R10a)-, or -C(=N-R11a)-; T is -X2a-Y1a-Q1aor -X3-C(=O)OR4; X1is optionally substituted C2-C6alkylenyl; R1is selected from the group consisting of -OH, -N(R3)2, , , , , , , , , , , , , , , , , , , , , , , and ; each R is independently -H or C1-C6 aliphatic;RZis NR2or OH; Z1is optionally substituted C1-C6alkyl; Z1ais hydrogen or optionally substituted C1-C6 alkyl; XZis optionally substituted C2-C14 alkylenyl or optionally substituted C2-C14 alkenylenyl; X2and X2aare independently optionally substituted C2-C14alkylenyl or optionally substituted C2-C14alkenylenyl; X3is optionally substituted C2-C14alkylenyl or optionally substituted C2-C14alkenylenyl; (i) Y1is , , , , , , or ; wherein the bond marked with an "*" is attached to X2; Y1ais , , , , , , or ; wherein the bond marked with an "*" is attached to X2a; each Z2is independently H or optionally substituted C1-C8 alkyl; each Z3is independently optionally substituted C1-C6 alkylenyl; Q1is -CH(SR2)(SR3); Q1ais -CH(SR2')(SR3'); R2and R3are independently hydrogen, optionally substituted C1-C14alkyl, optionally substituted C2-C14 alkenylenyl, or -(CH2)m-G-(CH2)nH; R2'and R3'are independently hydrogen, optionally substituted C1-C14 alkyl, optionally substituted C2-C14 alkenylenyl, or -(CH2)m-G-(CH2)nH; G is a C3-C8cycloalkylenyl; each m is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; each n is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; X3is optionally substituted C2-C14alkylenyl; R4is optionally substituted C4-C14 alkyl; L1is C1-C8 alkylenyl; R6is C1-C6 alkyl, (hydroxy)C1-C6 alkyl, or (amino)C1-C6 alkyl R7ais -C(=O)N(R'")R7b, -C(=S)N(R'")R7b, -N=C(R7b)(R7c), or; R7bis C1-C6 alkyl, (hydroxy)C1-C6 alkyl, or (amino)C1-C6 alkyl; R7cis hydrogen or C1-C6 alkyl; R8ais -C(=O)N(R'")R8b, -C(=S)N(R'")R8b, -N=C(R8b)(R8c), or , R8bis C1-C6 alkyl, (hydroxy)C1-C6 alkyl, or (amino)C1-C6 alkyl; R8cis hydrogen or C1-C6 alkyl; R9ais -N=C(R9b)(R9c); R9bis C1-C6alkyl, (hydroxy)C1-C6alkyl, or (amino)C1-C6alkyl; R9cis hydrogen or C1-C6alkyl; R10ais -N=C(R10b)(R10c); R10bis C1-C6alkyl, (hydroxy)C1-C6alkyl, or (amino)C1-C6alkyl; R10cis hydrogen or C1-C6 alkyl; R11ais -OR11b, -N(R")R11b, -OC(=O)R11b, or -N(R")C(=O)R11b; R11bis C1-C6 alkyl, (hydroxy)C1-C6 alkyl, or (amino)C1-C6 alkyl; R' is hydrogen or C1-C6alkyl; R" is hydrogen or C1-C6alkyl; and R'" is hydrogen or C1-C6alkyl. Formula (S-A)

[0066] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-A): (S-A), or a pharmaceutically acceptable salt thereof, wherein: A is -N(-X1R1)-, -C(R')(-L1-N(R")R6)-, -C(R')(-OR7a)-, -C(R')(-N(R")R8a)- , -C(R')(-C(=O)OR9a)-, -C(R')(-OC(=O)R9a)-, -C(R')(-C(=O)N(R")R10a)-, or -C(=N-R11a)-; T is -X2a-Y1a-Q1aor -X3-C(=O)OR4; X1is optionally substituted C2-C6 alkylenyl; R1is -OH, -R1a, , or ,Z1is optionally substituted C1-C6alkyl; Z1ais hydrogen or optionally substituted C1-C6alkyl; X2and X2aare independently optionally substituted C2-C14 alkylenyl or optionally substituted C2-C14 alkenylenyl; X3is optionally substituted C2-C14 alkylenyl or optionally substituted C2-C14 alkenylenyl; (i) Y1is , , , , , , or ; wherein the bond marked with an "*" is attached to X2; Y1ais , , , , , , or ; wherein the bond marked with an "*" is attached to X2a; each Z2is independently H or optionally substituted C1-C8alkyl; each Z3is independently optionally substituted C1-C6 alkylenyl; Q1is -CH(SR2)(SR3); Q1ais -CH(SR2')(SR3'); R2and R3are independently hydrogen, optionally substituted C1-C14 alkyl, optionally substituted C2-C14alkenylenyl, or -(CH2)m-G-(CH2)nH; R2'and R3'are independently hydrogen, optionally substituted C1-C14alkyl, optionally substituted C2-C14alkenylenyl, or -(CH2)m-G-(CH2)nH; G is a C3-C8 cycloalkylenyl; each m is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; each n is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; X3is optionally substituted C2-C14alkylenyl; R4is optionally substituted C4-C14alkyl; L1is C1-C8alkylenyl; R6is C1-C6alkyl, (hydroxy)C1-C6alkyl, or (amino)C1-C6alkyl R7ais -C(=O)N(R'")R7b, -C(=S)N(R'")R7b, -N=C(R7b)(R7c), or ; R7bis C1-C6alkyl, (hydroxy)C1-C6alkyl, or (amino)C1-C6alkyl; R7cis hydrogen or C1-C6alkyl;R8ais -C(=O)N(R'")R8b, -C(=S)N(R'")R8b, -N=C(R8b)(R8c), or , R8bis C1-C6 alkyl, (hydroxy)C1-C6 alkyl, or (amino)C1-C6 alkyl; R8cis hydrogen or C1-C6alkyl; R9ais -N=C(R9b)(R9c); R9bis C1-C6alkyl, (hydroxy)C1-C6alkyl, or (amino)C1-C6alkyl; R9cis hydrogen or C1-C6alkyl; R10ais -N=C(R10b)(R10c); R10bis C1-C6 alkyl, (hydroxy)C1-C6 alkyl, or (amino)C1-C6 alkyl; R10cis hydrogen or C1-C6 alkyl; R11ais -OR11b, -N(R")R11b, -OC(=O)R11b, or -N(R")C(=O)R11b; R11bis C1-C6alkyl, (hydroxy)C1-C6alkyl, or (amino)C1-C6alkyl; R' is hydrogen or C1-C6alkyl; R" is hydrogen or C1-C6 alkyl; and R'" is hydrogen or C1-C6 alkyl. Formula (S-B)

[0067] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-A), or (S-A’), wherein the Lipids of the Disclosure have a structure of Formula (S-B): (S-B), or a pharmaceutically acceptable salt thereof. Formula (S-C)

[0068] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-A), or (S-A’), wherein the Lipids of the Disclosure have a structure of Formula (S-C): (S-C), or a pharmaceutically acceptable salt thereof.

[0069] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-A), or (S-A'), wherein A is -N(-X1R1)-.

[0070] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-A), or (S-A'), wherein T is -X2a-Y1a-Q1a.

[0071] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-A), or (S-A'), wherein T is -X3-C(=O)OR4.

[0072] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-A), (S-A’), (S-B), or (S-C), wherein X2and / or X2aare / is optionally substituted C2-C14alkylenyl (e.g., C4- C10 alkylenyl, C5-C7 alkylenyl, C5, C6, or C7 alkylenyl). In some embodiments, Lipids of the Disclosure have a structure of Formula (S-A), (S-A’), (S-B), or (S-C), wherein X2is C4-C10 alkylenyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-A), (S-A’), (S-B), or (S-C), wherein X2ais C4-C10 alkylenyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-A), (S-A’), (S-B), or (S-C), wherein X2is C5alkylenyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-A), (S-A’), (S-B), or (S-C), wherein X2is C6alkylenyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-A), (S-A’), (S-B), or (S-C), wherein X2ais C5 alkylenyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-A), (S-A’), (S-B), or (S-C), wherein X2ais C6 alkylenyl.

[0073] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-A), (S-A’), (S-B), or (S-C), wherein Y1and / or Y1aare / is . In some embodiments, Lipids of the Disclosure have a structure of Formula (S-A), (S-A’), (S-B), or (S-C), wherein Y1is . In some embodiments, Lipids of the Disclosure have a structure of Formula (S-A), (S-A’), (S-B), or (S-C), wherein Y1ais . In some embodiments, Lipids of the Disclosure have a structure of Formula (S-A), (S-A’), (S-B), or (S-C), wherein Y1and / or Y1aare / is . In some embodiments, Lipids of the Disclosure have a structure of Formula (S-A), (S-A’), (S-B), or (S-C), wherein Y1is . In some embodiments, Lipids of the Disclosure have a structure of Formula (S-A), (S-A’), (S-B), or (S-C), wherein Y1ais . In some embodiments, Lipids of the Disclosure have a structure of Formula (S-A), (S-A’), (S-B), or (S-C), wherein Y1and / or Y1aare / is , wherein Z2is hydrogen. In some embodiments, Lipids of the Disclosure have astructure of Formula (S-A), (S-A’), (S-B), or (S-C), wherein Y1is , wherein Z2is hydrogen. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-A), (S-A’), (S-B), or (S-C), wherein Y1ais , wherein Z2is hydrogen. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-A), (S-A’), (S-B), or (S-C), wherein Y1and / or Y1aare / is , wherein Z2is hydrogen. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-A), (S-A’), (S-B), or (S-C), wherein Y1is , wherein Z2is hydrogen. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-A), (S-A’), (S-B), or (S-C), wherein Y1ais , wherein Z2is hydrogen. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-A), (S-A’), (S-B), or (S-C), wherein Y1and Y1aare independently or . In some embodiments, Lipids of the Disclosure have a structure of Formula (S-A), (S-A’), (S-B), or (S-C), wherein Y1is independently or . In some embodiments, Lipids of the Disclosure have a structure of Formula (S-A), (S- A’), (S-B), or (S-C), wherein Y1ais independently or . In some embodiments, Lipids of the Disclosure have a structure of Formula (S-A), (S-A’), (S-B), or (S-C), wherein X3is optionally substituted C2-C14 alkylenyl (e.g., C4-C10 alkylenyl, C5-C7 alkylenyl, C5, C6, or C7 alkylenyl). In some embodiments, Lipids of the Disclosure have a structure of Formula (S-A), (S-A’), (S-B), or (S-C), wherein X3is C5-C7alkylenyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-A), (S-A’), (S-B), or (S-C), wherein X3is C5alkylenyl.

[0074] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-A), (S-A’), (S-B), or (S-C), wherein R2, R3, R2', and / or R3'are hydrogen. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-A), (S-A’), (S-B), or (S-C), wherein R2is hydrogen. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-A), (S-A’), (S-B), or (S- C), wherein R3, is hydrogen. In some embodiments, Lipids of the Disclosure have a structure ofFormula (S-A), (S-A’), (S-B), or (S-C), wherein R2'is hydrogen. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-A), (S-A’), (S-B), or (S-C), wherein R3'is hydrogen.

[0075] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-A), (S-A’), (S-B), or (S-C), wherein R2, R3, R2', and / or R3'are optionally substituted C1-C14 alkyl (e.g., C5- C14, C5-C10, C6-C9, C5, C6, C7, C8, C9, C10alkyl). In some embodiments, Lipids of the Disclosure have a structure of Formula (S-A), (S-A’), (S-B), or (S-C), wherein R2is C5-C10alkyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-A), (S-A’), (S-B), or (S-C), wherein R3is C5-C10alkyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-A), (S-A’), (S-B), or (S-C), wherein R2’is C5-C10 alkyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-A), (S-A’), (S-B), or (S-C), wherein R3’is C5-C10 alkyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-A), (S-A’), (S-B), or (S-C), wherein R2is C8alkyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-A), (S-A’), (S-B), or (S-C), wherein R3is C8alkyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-A), (S-A’), (S-B), or (S-C), wherein R2’is C8alkyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-A), (S-A’), (S-B), or (S-C), wherein R3’is C8 alkyl.

[0076] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-A) or (S-C), wherein R4is optionally substituted C4-C14alkyl (e.g., C6-C12, C8-C12, C6, C7, C8, C9, C10, C11, C12alkyl). In some embodiments, Lipids of the Disclosure have a structure of Formula (S-A) or (S-C), wherein R4is C6-C12alkyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-A), (S-A’), (S-B), or (S-C), wherein R4is C11 alkyl.

[0077] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-A), (S-A’), (S-B), or (S-C), wherein R1is OH.

[0078] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-A), (S-A’), (S-B), or (S-C), wherein X1is C2-4alkylenyl (e.g., C2,C3, or C4alkylenyl). In some embodiments, Lipids of the Disclosure have a structure of Formula (S-A), (S-A’), (S-B), or (S-C), wherein X1is C2 alkylenyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-A), (S-A’), (S-B), or (S-C), wherein X1is C4 alkylenyl. Formula (S-D)

[0079] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-D): (S-D), or a pharmaceutically acceptable salt thereof, wherein: A is -C(R')(-L1-N(R")R6)-, -C(R')(-OR7a)-, -C(R')(-N(R")R8a)-, -C(R')(-C(=O)OR9a)- , -C(R')(-C(=O)N(R")R10a)-, or -C(=N-R11a)-; T is -X2a-Y1a-Q1aor -X3-C(=O)OR4;X2and X2aare independently optionally substituted C2-C14alkylenyl or optionally subsituted C2-C14alkenylenyl; X3is optionally substituted C1-C14 alkylenyl or optionally substituted C2-C14 alkenylenyl; Y1is , , , or , wherein the bond marked with an "*" is attached to X2; Y1ais , , , or , wherein the bond marked with an "*" is attached to X2a; each Z3is independently optionally substituted C1-C6 alkylenyl or optionally substituted C2-C14 alkenylenyl; Q1is -CH(SR2)(SR3); Q1ais -CH(SR2’)(SR3’); R2, and R3are independently hydrogen, optionally substituted C1-C14alkyl, optionally substituted C2-C14alkenylenyl, or -(CH2)m-G-(CH2)nH; R2'and R3'are independently hydrogen, optionally substituted C1-C14alkyl, optionally substituted C2-C14 alkenylenyl, or -(CH2)m-G-(CH2)nH; G is a C3-C8 cycloalkylenyl; each m is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; each n is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; X3is optionally substituted C2-C14alkylenyl; R4is optionally substituted C4-C14alkyl; L1is C1-C8alkylenyl; R6is (hydroxy)C1-C6 alkyl, or (amino)C1-C6 alkyl. R7ais -C(=O)N(R'")R7b, -C(=S)N(R'")R7b, -N=C(R7b)(R7c), , , or ; Z1is optionally substituted C1-C6 alkyl; R10is C1-C6 alkylenyl; R7bis C1-C6 alkyl, (hydroxy)C1-C6 alkyl, or (amino)C1-C6 alkyl; R7cis hydrogen or C1-C6alkyl;R8ais -C(=O)N(R'")R8b, -C(=S)N(R'")R8b, -N=C(R8b)(R8c), , or ; R8bis C1-C6 alkyl, (hydroxy)C1-C6 alkyl, or (amino)C1-C6 alkyl; R8cis hydrogen or C1-C6 alkyl; R9ais -N=C(R9b)(R9c); R9bis C1-C6 alkyl, (hydroxy)C1-C6 alkyl, or (amino)C1-C6 alkyl; R9cis hydrogen or C1-C6alkyl; R10ais -N=C(R10b)(R10c); R10bis C1-C6alkyl, (hydroxy)C1-C6alkyl, or (amino)C1-C6alkyl; R10cis hydrogen or C1-C6 alkyl; R11ais -OR11b, -N(R")R11b, -OC(=O)R11b, or -N(R")C(=O)R11b; R11bis C1-C6 alkyl, (hydroxy)C1-C6 alkyl, or (amino)C1-C6 alkyl; R' is hydrogen or C1-C6alkyl; R" is hydrogen or C1-C6alkyl; and R'" is hydrogen or C1-C6alkyl.

[0080] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-D), wherein A is -C(R')(-L1N(R")R6)-.

[0081] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-D), wherein A is -C(R')(-OR7a)-.

[0082] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-D), wherein A is -C(R')(-N(R")R8a).

[0083] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-D), wherein A is C(R')(C(=O)OR9a).

[0084] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-D), wherein A is C(R')(-C(=O)N(R")R10a)-.

[0085] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-D), wherein A is C(=N-R11a)-.

[0086] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-D), wherein T is -X2a-Y1a-Q1a.

[0087] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-D), wherein T is -X3-C(=O)OR4.

[0088] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-D), wherein X2and / or X2aare / is optionally substituted C2-C14alkylenyl (e.g., C2-C10alkylenyl, C2-C8alkylenyl, C2, C3, C4, C5, C6, C7, or C8alkylenyl). In some embodiments, Lipids of the Disclosurehave a structure of Formula (S-D), wherein X2is C2-C14alkylenyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-D), wherein X2ais C2-C14alkylenyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-D), wherein Y1and / or Y1aare / is . In some embodiments, Lipids of the Disclosure have a structure of Formula (S- D), wherein Y1is . In some embodiments, Lipids of the Disclosure have a structure of Formula (S-D), wherein Y1ais . In some embodiments, Lipids of the Disclosure have a structure of Formula (S-D), wherein Y1and / or Y1aare / is . In some embodiments, Lipids of the Disclosure have a structure of Formula (S-D), wherein Y1is . In some embodiments, Lipids of the Disclosure have a structure of Formula (S-D), wherein Y1ais . In some embodiments, Lipids of the Disclosure have a structure of Formula (S-D), wherein Y1and / or Y1aare / is . In some embodiments, Lipids of the Disclosure have a structure of Formula (S-D), wherein Y1is . In some embodiments, Lipids of the Disclosure have a structure of Formula (S-D), wherein Y1ais . In some embodiments, Lipids of the Disclosure have a structure of Formula (S-D), wherein Y1and / or Y1aare / is . In some embodiments, Lipids of the Disclosure have a structure of Formula (S-D), wherein Y1is . In some embodiments, Lipids of the Disclosure have a structure of Formula (S-D), wherein Y1ais .

[0089] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-D), wherein X3is optionally substituted C1-C14alkylenyl (e.g., C1-C6, C1-C4alkylenyl). In someembodiments, Lipids of the Disclosure have a structure of Formula (S-D), wherein X3is C1-C14alkylenyl.

[0090] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-D), wherein R2, R3, R2', and / or R3'are hydrogen. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-D), wherein R2is hydrogen. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-D), wherein R3is hydrogen. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-D), wherein R2’is hydrogen. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-D), wherein R3’is hydrogen.

[0091] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-D), wherein R2, R3, R2', and / or R3'are optionally substituted C1-C14 alkyl (e.g., C4-C10 alkyl, C5, C6. C7. C8, C9alkyl). In some embodiments, Lipids of the Disclosure have a structure of Formula (S-D), wherein R2is C4-C10alkyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-D), wherein R3is C4-C10alkyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-D), wherein R2’is C4-C10alkyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-D), wherein R3’is C4-C10 alkyl.

[0092] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-D), wherein R4is optionally substituted C4-C14alkyl (e.g., C8-C14alkyl, linear C8-C14alkyl, C8, C9, C10, C11, C12, C13, or C14alkyl). In some embodiments, Lipids of the Disclosure have a structure of Formula (S-D), wherein R4is linear C8-C14alkyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-D), wherein R4is linear C11alkyl.

[0093] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-D), wherein L1is C1-C3 alkylenyl.

[0094] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-D), wherein R6is (hydroxy)C1-C6alkyl.

[0095] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-D), wherein R7ais or . In some embodiments, Lipids of the Disclosure have a structure of Formula (S-D), wherein R7ais . In some embodiments, Lipids of the Disclosure have a structure of Formula (S-D), wherein R7ais .

[0096] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-D), wherein R7ais selected from the group consisting of -C(=O)N(R'")R7b, -C(=S)N(R'")R7b, and - N=C(R7b)(R7c). In some embodiments, Lipids of the Disclosure have a structure of Formula (S-D), wherein R7ais -C(=O)N(R'")R7b. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-D), wherein R7ais -C(=S)N(R'")R7b. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-D), wherein R7ais -N=C(R7b)(R7c).

[0097] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-D), wherein R8ais selected from the group consisting of -C(=O)N(R'")R8b, -C(=S)N(R'")R8b, and - N=C(R8b)(R8c). In some embodiments, Lipids of the Disclosure have a structure of Formula (S-D), wherein R8ais -C(=O)N(R'")R8b. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-D), wherein R8ais -C(=S)N(R'")R8b. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-D), wherein R8ais -N=C(R8b)(R8c).

[0098] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-D), wherein R8ais .

[0099] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-D), wherein R9bis (hydroxy)C1-C6alkyl.

[0100] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-D), wherein R10bis (amino)C1-C6 alkyl.

[0101] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-D), wherein R11ais -OR11bor -OC(=O)R11b. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-D), wherein R11ais -OR11b. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-D), wherein R11ais -OC(=O)R11b.

[0102] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-D), wherein R11ais -N(R")R11bor -N(R")C(=O)R11b. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-D), wherein R11ais -N(R")R11b. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-D), wherein R11ais -N(R")C(=O)R11b.

[0103] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-D), wherein R11bis (amino)C1-C6alkyl. Formula (S-E)

[0104] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-E): (S-E),or a pharmaceutically acceptable salt thereof, wherein: A is -N(-X1R1)-; T is -X2a-Y1a-Q1aor -X3-C(=O)OR4; (i) X1is optionally substituted C2-C3 alkylenyl; R1is , -NR"C(O)OR20, or -NR"R21; or (ii) X1is C4-C6alkylenyl , and R1is , , -NR"C(O)OR20, or -NR"R21; Z1is optionally substituted C1-C6alkyl; Z1ais hydrogen or optionally substituted C1-C6alkyl; R20is optionally substituted C1-C6alkyl; R21is -(C2 alkylenyl)-OH; X2and X2aare independently optionally substituted C2-C14 alkylenyl or optionally substituted C2-C14 alkenylenyl; X3is optionally substituted C2-C14alkylenyl or optionally substituted C2-C14alkenylenyl; Y1is a bond, , , , or , wherein the bond marked with an "*" is attached to X2; Y1ais , , , or ; wherein the bond marked with an "*" is attached to X2a; wherein Y1and Y1aare or , when R1is or ; each Z2is independently H or optionally substituted C1-C8 alkyl;each Z3is independently optionally substituted C1-C6alkylenyl or optionally substituted C2-C14alkenylenyl; Q1is -CH(SR2)(SR3); Q1ais -CH(SR2’)(SR3’); R2and R3are independently hydrogen, optionally substituted linear C1-C14 alkyl, optionally substituted C2-C14alkenylenyl, or -(CH2)m-G-(CH2)nH; R2'and R3'are independently hydrogen, optionally substituted linear C1-C14alkyl, or optionally substituted C2-C14alkenylenyl; X3is optionally substituted C2-C14 alkylenyl; R4is optionally substituted C4-C14 alkyl; and R" is hydrogen or C1-C6 alkyl.

[0105] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-E), wherein R1is , wherein Z1is methyl and Z1ais hydrogen or methyl.

[0106] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-E), wherein R1is , wherein Z1is methyl.

[0107] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-E), wherein R1is -NR"C(O)OR20.

[0108] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-E), wherein R1is -NR"R21.

[0109] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-E), wherein R20is t-butyl or benzyl.

[0110] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-E), wherein X2and / or X2aare / is optionally substituted C2-C14alkylenyl (e.g., C4-C8alkylenyl, C4, C5, C6, C7, C8alkylenyl). In some embodiments, Lipids of the Disclosure have a structure of Formula (S-E), wherein X2is C4-C8alkylenyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-E), wherein X2ais C4-C8alkylenyl.

[0111] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-E), wherein Y1and / or Y1aare / is . In some embodiments, Lipids of the Disclosure have astructure of Formula (S-E), wherein Y1is . In some embodiments, Lipids of the Disclosure have a structure of Formula (S-E), wherein Y1ais . In some embodiments, Lipids of the Disclosure have a structure of Formula (S-E), wherein Y1and / or Y1aare / is . In some embodiments, Lipids of the Disclosure have a structure of Formula (S-E), wherein Y1is . In some embodiments, Lipids of the Disclosure have a structure of Formula (S-E), wherein Y1ais . In some embodiments, Lipids of the Disclosure have a structure of Formula (S-E), wherein Y1and / or Y1aare / is , wherein Z3is C2alkylenyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-E), wherein Y1is , wherein Z3is C2alkylenyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-E), wherein Y1ais , wherein Z3is C2alkylenyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-E), wherein Y1and / or Y1aare / is , wherein Z3is C2alkylenyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-E), wherein Y1is , wherein Z3is C2 alkylenyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-E), wherein Y1ais , wherein Z3is C2alkylenyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-E), wherein R2, R3, R2', and R3'are independently hydrogen, optionally substituted linear C1-C14alkyl (e.g., C4-C10alkyl, C6-C8alkyl, C5, C6, C7, C8, C9alkyl). In some embodiments, Lipids of the Disclosure have a structure of Formula (S-E), wherein R2is hydrogen. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-E), wherein R3is hydrogen. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-E), wherein R2’is hydrogen. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-E), wherein R3’is hydrogen. In some embodiments, Lipids of the Disclosure have a structure of Formula(S-E), wherein R2is linear C4-C10alkyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-E), wherein R3is linear C4-C10alkyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-E), wherein R2’is linear C4-C10alkyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-E), wherein R3’is linear C4- C10alkyl. Formula (S-F)

[0112] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-F): (S-F), or a pharmaceutically acceptable salt thereof, wherein R1is , or ; Z1is optionally substituted C1-C6 alkyl; X1is optionally substituted C2-C6 alkylenyl; X2and X2aare independently optionally substituted C2-C14alkylenyl; Y1and Y1aare independently or , Z3is independently optionally substituted C2-C6alkylenyl; R2and R3are independently optionally substituted C4-C14alkyl; R2'and R3'are independently optionally substituted C4-C14alkyl.

[0113] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-F), wherein R1is , wherein Z1is methyl.

[0114] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-F), wherein X1is C2-C4 alkylenyl (e.g., C3 alkylenyl). n some embodiments, Lipids of the Disclosure have a structure of Formula (S-F), wherein X1is C3 alkylenyl.

[0115] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-F), wherein X2is C4-C10 alkylenyl (e.g., C6 alkyl). In some embodiments, Lipids of the Disclosure have a structure of Formula (S-F), wherein X2is C6 alkyl.

[0116] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-F), wherein R2and R3are independently optionally substituted C4-C10alkyl (e.g., C8alkyl). In some embodiments, Lipids of the Disclosure have a structure of Formula (S-F), wherein R2and R3are independently C8alkyl. Formula (S-G)

[0117] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-G): (S-G), or a pharmaceutically acceptable salt thereof, wherein R20is C1-C6alkylenyl-NR20'C(O)OR20''; R20'is hydrogen or optionally substituted C1-C6alkyl; R20''is optionally substituted C1-C6 alkyl, phenyl, or benzyl; Z1is optionally substituted C1-C6 alkyl; X2and X2aare independently optionally substituted C2-C14 alkylenyl; Y1and Y1aare independently or ; wherein the bond marked with an "*" is attached to X2or X2a; Z3is independently optionally substituted C2-C6 alkylenyl; R2and R3are independently optionally substituted C4-C14alkyl; and R2'and R3'are independently optionally substituted C4-C14alkyl.

[0118] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-G), wherein R20is -CH2CH2CH2NHC(O)O-t-butyl or -CH2CH2CH2NHC(O)O-benzyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-G), wherein R20is - CH2CH2CH2NHC(O)O-t-butyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-G), wherein R20is -CH2CH2CH2NHC(O)O-benzyl.

[0119] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-G), wherein X2and X2aare independently C4-C8 alkylenyl (e.g., C5, C6, C7 alkylenyl). In some embodiments, Lipids of the Disclosure have a structure of Formula (S-G), wherein X2is C6 alkyl. Insome embodiments, Lipids of the Disclosure have a structure of Formula (S-G), wherein X2ais C6alkyl

[0120] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-G), wherein Y1and Y1aare , wherein Z3is C2-C4alkylenyl (e.g., C2 alkylenyl). In some embodiments, Lipids of the Disclosure have a structure of Formula (S-G), wherein Y1is , wherein Z3is C2- C4alkylenyl (e.g., C2 alkylenyl). In some embodiments, Lipids of the Disclosure have a structure of Formula (S-G), wherein Y1ais , wherein Z3is C2-C4alkylenyl (e.g., C2alkylenyl).

[0121] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-G), wherein R2, R3, R2'and R3'are independently optionally substituted C4-C10 alkyl (e.g., C6-C9alkyl, C6, C7, C8, C9 alkyl). In some embodiments, Lipids of the Disclosure have a structure of Formula (S-G), wherein R2is C6-C9alkyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-G), wherein R3is C6-C9alkyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-G), wherein R2’is C6-C9alkyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-G), wherein R3’is C6-C9alkyl. Formula (S-H)

[0122] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-H): (S-H), or a pharmaceutically acceptable salt thereof, wherein R1is -OH or ; X1is optionally substituted C4alkylenyl; X2and X2aare independently optionally substituted C2-C14alkylenyl; Y1and Y1aare independently or ; Z3is independently optionally substituted C2-C6alkylenyl;R2and R3are independently optionally substituted C4-C14alkyl or C1-C2alkyl substituted with optionally substituted cyclopropyl; or R2'and R3'are independently optionally substituted C4-C14 alkyl or C1-C2 alkyl substituted with optionally substituted cyclopropyl.

[0123] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-H), wherein X1is C4alkylenyl.

[0124] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-H), wherein X2and X2aare independently optionally substituted C4-C10 alkylenyl (e.g., C5, C6, C7, C8, C9, or C10 alkylenyl). In some embodiments, Lipids of the Disclosure have a structure of Formula (S-H), wherein X2is C4-C10 alkylenyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-H), wherein X2ais C4-C10alkylenyl.

[0125] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-H), wherein Y1and Y1aare independently , wherein Z3is independently C2-C4alkylenyl (e.g., C2, C4alkylenyl).

[0126] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-H), wherein R2, R3, R2'and R3'are independently C6-C14 alkyl (e.g., C6, C7, C8, C9, C10, C11, C12, C13, or C14 alkyl) or C1-C2 alkyl substituted with optionally substituted cyclopropyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-H), wherein R2, R3, R2'and R3'are independently C6-C14alkyl (e.g., C6, C7, C8, C9, C10, C11, C12, C13, or C14alkyl). In some embodiments, Lipids of the Disclosure have a structure of Formula (S-H), wherein R2is C6-C14alkyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-H), wherein R3is C6-C14alkyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-H), wherein R2’is C6- C14 alkyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-H), wherein R3’is C6-C14 alkyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-H), wherein R2is C1-C2 alkyl substituted with substituted cyclopropyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-H), wherein R3is C1-C2alkyl substituted with substituted cyclopropyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-H), wherein R2'is C1-C2alkyl substituted with substituted cyclopropyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-H), wherein R3'is C1-C2 alkyl substituted with substituted cyclopropyl

[0127] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-H), wherein R2, R3, R2'and R3'are independently C1-C2alkyl substituted with cyclopropylene-(C1- C6alkylenyl optionally substituted with cyclopropylene substituted with C1-C6alkyl). In some embodiments, Lipids of the Disclosure have a structure of Formula (S-H), wherein R2is C1-C2alkyl substituted with cyclopropylene-(C1-C6alkylenyl optionally substituted with cyclopropylenesubstituted with C1-C6alkyl). In some embodiments, Lipids of the Disclosure have a structure of Formula (S-H), wherein R3is C1-C2alkyl substituted with cyclopropylene-(C1-C6alkylenyl optionally substituted with cyclopropylene substituted with C1-C6alkyl). In some embodiments, Lipids of the Disclosure have a structure of Formula (S-H), wherein R2'is C1-C2 alkyl substituted with cyclopropylene-(C1-C6alkylenyl optionally substituted with cyclopropylene substituted with C1- C6alkyl). In some embodiments, Lipids of the Disclosure have a structure of Formula (S-H), wherein R3'is C1-C2alkyl substituted with cyclopropylene-(C1-C6alkylenyl optionally substituted with cyclopropylene substituted with C1-C6alkyl). Formula (S-J)

[0128] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-J): (S-J), or a pharmaceutically acceptable salt thereof, wherein R1is -OH or ; X1is branched C2-C8alkylenyl X2and X2aare independently optionally substituted C2-C14alkylenyl; Y1and Y1aare independently or ; Z3is independently optionally substituted C2-C6alkylenyl; R2and R3are independently optionally substituted C4-C14alkyl; R2'and R3'are independently optionally substituted C4-C14alkyl.

[0129] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-J), wherein X1is branched C6 alkylenyl.

[0130] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-J), wherein X2and X2aare independently C4-C10alkylenyl (e.g., C6, C7, C8alkylenyl). In some embodiments, Lipids of the Disclosure have a structure of Formula (S-J), wherein X2is C4-C10alkylenyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-J), wherein X2ais C4-C10 alkylenyl

[0131] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-J), wherein Y1and Y1aare , wherein Z3is independently optionally substituted C2alkylenyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-J), wherein Y1is , wherein Z3is independently optionally substituted C2alkylenyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-J), wherein Y1ais , wherein Z3is independently optionally substituted C2 alkylenyl.

[0132] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-J), wherein R2, R3, R2'and R3'are independently C6-C12alkyl (e.g., C9alkyl) or C4-C10alkyl (e.g., C4,C6alkyl) optionally substituted with C2-C8alkenylene (e.g., C4, C6 alkenylene). In some embodiments, Lipids of the Disclosure have a structure of Formula (S-J), wherein R2is C6-C12 alkyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-J), wherein R3is C6-C12 alkyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-J), wherein R2’is C6- C12alkyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-J), wherein R3’is C6-C12alkyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-J), wherein R2is C4-C10alkyl optionally substituted with C2-C8alkenylene. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-J), wherein R3is C4-C10 alkyl optionally substituted with C2-C8alkenylene. In some embodiments, Lipids of the Disclosure have a structure of Formula (S- J), wherein R2’is C4-C10 alkyl optionally substituted with C2-C8alkenylene. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-J), wherein R3’is C4-C10alkyl optionally substituted with C2-C8alkenylene. Formula (S-K)

[0133] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-K): (S-K), or a pharmaceutically acceptable salt thereof, wherein R1is -OH; X1is optionally substituted C2-C6 alkylenyl; X2and X2aare independently optionally substituted C2-C14 alkylenyl; each of Y1and Y1ais a bond; R2and R3are independently optionally substituted C4-C14alkyl; andR2'and R3'are independently optionally substituted C4-C14alkyl.

[0134] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-K), wherein X1is C4 alkylenyl.

[0135] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-K), wherein X2and X2aare independently C4-C10alkylenyl (e.g., C6-C8alkylenyl, C6, C7, C8alkylenyl). In some embodiments, Lipids of the Disclosure have a structure of Formula (S-K), wherein X2is C4-C10alkylenyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-K), wherein X2ais C4-C10 alkylenyl.

[0136] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-K), wherein R2, R3, R2'and R3'are independently C6-C10 alkyl (e.g., C7. C8 alkyl). In some embodiments, Lipids of the Disclosure have a structure of Formula (S-K), wherein R2is C6-C10alkyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-K), wherein R3is C6-C10alkyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-K), wherein R2’is C6- C10 alkyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-K), wherein R3’is C6-C10 alkyl. Formula (S-L)

[0137] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-L): (S-L), or a pharmaceutically acceptable salt thereof, wherein R1is -OH, -R1a, X1is optionally substituted C2-C6 alkylenyl; (i) Y1is ; Z3is optionally substituted C2-C6 alkylenyl; and R2and R3are independently optionally substituted C4-C14 alkyl; X2and X3are C5 alkylenyl; or (ii) Y1is a bond R2and R3are independently C4-C7alkyl; X2is optionally substituted C2-C14alkylenyl; X3is optionally substituted C5 alkylenyl; R4is optionally substituted C4-C14 alkyl; R1ais:, , , or ; R2a, R2b, and R2care independently hydrogen and C1-C6 alkyl; R3a, R3b, and R3care independently hydrogen and C1-C6alkyl; R4a, R4b, and R4care independently hydrogen and C1-C6alkyl; and R5a, R5b, and R5care independently hydrogen and C1-C6alkyl.

[0138] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-L), wherein R1is OH.

[0139] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-L), wherein X1is C2alkylenyl.

[0140] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-L), wherein Y1is , wherein Z3is C2alkylenyl.

[0141] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-L), wherein R2and R3are independently C6-C12 alkyl (C7, C8, C9, C10, C11 alkyl). In some embodiments, Lipids of the Disclosure have a structure of Formula (S-L), wherein R2is C6-C12 alkyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-L), wherein R3is C6-C12alkyl.

[0142] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-L), wherein Y1is a bond.

[0143] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-L), wherein R2and R3are C4-C7alkyl (e.g., C7alkyl). In some embodiments, Lipids of the Disclosure have a structure of Formula (S-L), wherein R2is C4-C7alkyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-L), wherein R3is C4-C7alkyl.

[0144] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-L), wherein X2is C6-C12 alkylenyl (e.g., C7, C8, C9, C10 alkylenyl). Formula (S-I’)

[0145] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-I’):(S-I’), or a pharmaceutically acceptable salt thereof, wherein: X is N or CH; Y is a bond, , , or , wherein bond marked with an “**” is attached to X; each Z is independently selected from the group consisting of: , , , , , , and wherein the bond marked with an "*" is attached to L; each L is independently C2-C10alkylenyl; R1is OH, -N(R3)2,, , , , , , , , , , , , , , , , , , , , , , and ; each R is independently -H or C1-C6aliphatic; RZis NR2 or OH;XZis optionally substituted C2-C14alkylenyl or optionally substituted C2-C14alkenylenyl; each R2is independently selected from optionally substituted C2-14alkyl and C2-14alkenyl, wherein any –(CH2)2- of the C2-C14 alkyl can be optionally replaced with C3-C6 cycloalkylenyl; each R3independently selected from is H and C1-6alkyl; n is selected from 0 to 6; and each p is independently selected from 1 to 6. Formula (S-I)

[0146] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-I): (S-I), or a pharmaceutically acceptable salt thereof, wherein: X is N or CH; Y is a bond, , , or , wherein bond marked with an “**” is attached to X; each Z is independently selected from the group consisting of: , , , , , , and wherein the bond marked with an "*" is attached to L; each L is independently C2-C10 alkylenyl; R1is OH, N(R3)2, , , , , , , , , , , and ; each R is independently -H or C1-C6 aliphatic; each R2is independently selected from optionally substituted C2-14alkyl and C2-14alkenyl, wherein any –(CH2)2- of the C2-C14alkyl can be optionally replaced with C3-C6cycloalkylenyl;each R3independently selected from is H and C1-6alkyl; n is selected from 1 to 6; and each p is independently selected from 1 to 6. X

[0147] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-I), or (S-I’), or (S-I), wherein X is N. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-I), or (S-I’), or (S-I), wherein X is CH. Y

[0148] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-I), or (S-I’), or (S-I), wherein Y is a bond. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-I), or (S-I’), or (S-I), wherein Y is , wherein bond marked with an “**” is attached to X. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-I), or (S-I’), wherein Y is , wherein bond marked with an “**” is attached to X. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-I), or (S-I’), wherein Y is , wherein bond marked with an “**” is attached to X. Z

[0149] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-I), or (S-I’), wherein Z is , wherein bond marked with an “*” is attached to X. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-I), or (S-I’), wherein Z is , wherein bond marked with an “*” is attached to X. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-I), or (S-I’), wherein Z is , wherein bond marked with an “*” is attached to X. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-I), or (S-I’), wherein Z is , wherein bond marked with an “*” is attached to X. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-I), or (S-I’), wherein Z is , wherein bond marked with an “*” is attached to X. In some embodiments, Lipids of theDisclosure have a structure of Formula (S-I), or (S-I’), wherein Z is , wherein bond marked with an “*” is attached to X. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-I), or (S-I’), wherein Z is , wherein bond marked with an “*” is attached to X. L

[0150] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-I), or (S-I’), wherein L is C2-C10alkylenyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-I), or (S-I’), wherein L is C5-C8alkylenyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-I), or (S-I’), wherein L is C5alkylenyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-I), or (S-I’), wherein L is C6 alkylenyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-I), or (S-I’), wherein L is C7 alkylenyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-I), or (S-I’), wherein L is C8alkylenyl. R1

[0151] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-I), or (S-I’), wherein R1is OH. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-I), or (S-I’), wherein R1is N(R3)2. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-I), or (S-I’), wherein R1is . In some embodiments, Lipids of the Disclosure have a structure of Formula (S-I), or (S-I’), wherein R1is selected from the group consisting of , , , , , , , and , wherein each R is independently -H or C1-C6aliphatic. In certain embodiments, R1is .

[0152] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-I), or

[0153] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-I), or(S-F), wherein R1is selected from the group consisting of OH, N(R!)2. and embodiments, Lipids of the Disclosure have a structure of Formula (S-I), or (S-I'), wherein R1is

[0154] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-Ia): or a pharmaceutically acceptable salt thereof, wherein:each R2is independently selected from optionally substituted C2-14alkyl and C2-14alkenyl, wherein any –(CH2)2- of the C2-C14alkyl can be optionally replaced with C3-C6cycloalkylenyl; n is selected from 1 to 4; each m is independently selected from 2 to 10; and each p is independently selected from 2 to 6.

[0155] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-Ib): (S-Ib), or a pharmaceutically acceptable salt thereof, wherein: each R2is independently selected from optionally substituted C2-14alkyl and C2-14alkenyl, wherein any –(CH2)2- of the C2-C14 alkyl can be optionally replaced with C3-C6 cycloalkylenyl; each R3independently selected from is H and C1-6alkylene; n is selected from 0 to 4; each m is independently selected from 2 to 10; and each p is independently selected from 2 to 6.

[0156] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-Ic): (S-Ic), or a pharmaceutically acceptable salt thereof, wherein: each R2is independently selected from optionally substituted C2-14alkyl and C2-14alkenyl, wherein any –(CH2)2- of the C2-C14 alkyl can be optionally replaced with C3-C6 cycloalkylenyl; n is selected from 1 to 4; each m is independently selected from 2 to 10; and each p is independently selected from 2 to 6. R2

[0157] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-I), Formula (S-I’), Formula (S-Ia), or Formula (S-Ib), wherein R2is optionally substituted C2-14alkyl. Insome embodiments, Lipids of the Disclosure have a structure of Formula (S-I), Formula (S-I’), Formula (S-Ia), or Formula (S-Ib), wherein R2is optionally substituted C7-12alkyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-I), Formula (S-I’), Formula (S- Ia), or Formula (S-Ib), wherein R2is independently selected from the group consisting of: , , , , and .

[0158] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-I), Formula (S-I’), Formula (S-Ia), or Formula (S-Ib), wherein R2is . In some embodiments, Lipids of the Disclosure have a structure of Formula (S-I), Formula (S-I’), Formula (S- Ia), or Formula (S-Ib), wherein R2is . In some embodiments, Lipids of the Disclosure have a structure of Formula (S-I), Formula (S-I’), Formula (S-Ia), or Formula (S-Ib), wherein R2is . In some embodiments, Lipids of the Disclosure have a structure of Formula (S-I), Formula (S-I’), Formula (S-Ia), or Formula (S-Ib), wherein R2is . In some embodiments, Lipids of the Disclosure have a structure of Formula (S-I), Formula (S-I’), Formula (S-Ia), or Formula (S-Ib), wherein R2is optionally substituted C2-14alkenyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-I), Formula (S-I’), Formula (S- Ia), or Formula (S-Ib), wherein R2is independently selected from: and . In some embodiments, Lipids of the Disclosure have a structure of Formula (S-I), Formula (S-I’), Formula (S-Ia), or Formula (S-Ib), wherein R2is .

[0159] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-I), Formula (S-I’), Formula (S-Ia), or Formula (S-Ib), wherein R2is optionally substituted C8-9alkenyl. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-I), Formula (S-I’), Formula (S-Ia), or Formula (S-Ib), wherein R2is . In some embodiments, Lipidsof the Disclosure have a structure of Formula (S-I), Formula (S-I’), Formula (S-Ia), or Formula (S-Ib), wherein R2is . In some embodiments, Lipids of the Disclosure have a structure of Formula (S-I), Formula (S-I’), Formula (S-Ia), or Formula (S-Ib), wherein R2is . R3

[0160] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-I) or Formula (S-Ib), wherein R3is hydrogen.

[0161] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-I), Formula (S-I’), Formula (S-Ia), or Formula (S-Ib), wherein R3is C1-6alkylene. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-I), or (S-I’), wherein each R3is C1alkyl, C2alkyl, C3alkyl, C4alkyl, C5alkyl, or C6alkyl. n

[0162] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-I), Formula (S-I’), Formula (S-Ia), or Formula (S-Ib), wherein n is 3. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-I), Formula (S-I’), Formula (S-Ia), or Formula (S-Ib), wherein n is 4. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-I), Formula (S-I’), Formula (S-Ia), or Formula (S-Ib), wherein n is 1, 2, 5, or 6. m

[0163] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-Ia), or Formula (S-Ib), wherein m is selected from 5 to 8. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-Ia), or Formula (S-Ib), wherein m is 5. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-Ia) or Formula (S-Ib), wherein m is 6. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-Ia) or Formula (S-Ib), wherein m is 7. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-Ia) or Formula (S-Ib), wherein m is 8. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-Ia), or Formula (S-Ib), wherein m is 2, 3, 4, 9, or 10. p

[0164] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-I), Formula (S-I’), Formula (S-Ia), or Formula (S-Ib), wherein p is independently selected from 2 to 4. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-I), Formula (S-I’), Formula (S-Ia), or Formula (S-Ib), wherein p is 2. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-I), Formula (S-I’), Formula (S-Ia), or Formula (S-Ib), wherein p is 3. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-I), Formula (S-I’), Formula (S-Ia), or Formula (S-Ib), wherein p is 4. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-I), Formula (S-I’), Formula (S-Ia), or Formula (S-Ib), wherein p is 5 or6. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-I), or (S-I'), wherein p is 1.Formula (S-M’)

[0165] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-M’): or a pharmaceutically acceptable salt thereof, wherein:X is N or CH;Y is a bond, O wherein bond marked with an“**” is attached to X; each Z is independently selected from the group consisting of: wherein the bond marked with an is attached to L; each L is independently C2-C10 alkylenyl;, , , , , , , , , , and ; each R is independently -H or C1-C6 aliphatic; RZis NR2 or OH; XZis optionally substituted C2-C14 alkylenyl or optionally substituted C2-C14 alkenylenyl;each R3independently selected from is H and C1-6alkyl; R4is -CH(SR6)(SR7); R5is -CH(OR8)(OR9); -CH(SR8)(SR9); -CH(R8)(R9) or optionally substituted C1-C14 aliphatic, wherein one or more methylene linkages are each optionally and independently replaced with an optionally substituted C3-C8cycloalkylenyl, an optionally substituted bridged bicyclic or multicyclic C5-C12cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-; R6and R7are each independently optionally substituted C1-C14 aliphatic, wherein one or more methylene linkages are each optionally and independently replaced with an optionally substituted C3-C8cycloalkylenyl, an optionally substituted bridged bicyclic or multicyclic C5- C12cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or - C(O)O-; and R8and R9are each independently optionally substituted C1-C14aliphatic, wherein one or more methylene linkages are each optionally and independently replaced with an optionally substituted C3-C8 cycloalkylenyl, an optionally substituted bridged bicyclic or multicyclic C5- C12 cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or - C(O)O-; n is selected from 0 to 6; and each p is independently selected from 1 to 6. Formula (S-M)

[0166] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-M):(S-M), or a pharmaceutically acceptable salt thereof, wherein: X is N or CH; Y is a bond, , , or , wherein bond marked with an “**” is attached to X; each Z is independently selected from the group consisting of: , , , , , , and wherein the bond marked with an "*" is attached to L; each L is independently C2-C10 alkylenyl; R1is OH, N(R3)2, , , , , , , , , , , and ; each R is independently -H or C1-C6 aliphatic; each R3independently selected from is H and C1-6alkyl; R4is -CH(SR6)(SR7); R5is -CH(OR8)(OR9); -CH(SR8)(SR9); -CH(R8)(R9) or optionally substituted C1-C14aliphatic, wherein one or more methylene linkages are each optionally and independently replaced with an optionally substituted C3-C8 cycloalkylenyl, an optionally substituted bridged bicyclic or multicyclic C5-C12 cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-; R6and R7are each independently optionally substituted C1-C14aliphatic, wherein one or more methylene linkages are each optionally and independently replaced with an optionally substituted C3-C8cycloalkylenyl, an optionally substituted bridged bicyclic or multicyclic C5-C12cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or - C(O)O-; and R8and R9are each independently optionally substituted C1-C14 aliphatic, wherein one or more methylene linkages are each optionally and independently replaced with an optionally substituted C3-C8 cycloalkylenyl, an optionally substituted bridged bicyclic or multicyclic C5- C12cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or - C(O)O-; n is selected from 1 to 6; and each p is independently selected from 1 to 6.

[0167] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-Ma) (S-Ma) or a pharmaceutically acceptable salt thereof, wherein: n is selected from 1 to 4; each R4and R5is as described in Formula S-M or S-M’; each m is independently selected from 2 to 10; and each p is independently selected from 2 to 6.

[0168] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-Mb) (S-Mb), or a pharmaceutically acceptable salt thereof, wherein: each R3independently selected from is H and C1-6alkyl; n is selected from 1 to 4; each R4and R5is as described in Formula S-M or S-M’; each m is independently selected from 2 to 10; and each p is independently selected from 2 to 6. R1

[0169] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-M), or (S-M’), wherein R1is OH. In some embodiments, Lipids of the Disclosure have a structure ofFormula (S-M), or (S-M’), wherein R1is N(R3)2. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-M), or (S-M’), wherein R1is . In some embodiments, Lipids of the Disclosure have a structure of Formula (S-M), or (S-M’),wherein R1is , , , , , , , and , wherein each R is independently -H or C1-C6aliphatic. In certain embodiments, R1is .

[0170] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-M), or (S-M’), wherein R1is selected from the group consisting of OH, -N(R3)2, , , , , , , , , , , , , , , ,, , , , , , , and .

[0171] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-M’), wherein R1is selected from the group consisting of OH, N(R3)2, and . In some embodiments, Lipids of the Disclosure have a structure of Formula (S-M’), wherein R1is . n

[0172] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-M), Formula (S-M’), Formula (S-Ma), or Formula (S-Mb), wherein n is 3. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-M), Formula (S-M’), Formula (S-Ma), or Formula (S-Mb), wherein n is 4. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-M), Formula (S-M’), Formula (S-Ma), or Formula (S-Mb), wherein n is 1, 2, 5, or 6. p

[0173] In some embodiments, Lipids of the Disclosure have a structure of Formula (S-M), Formula (S-M’), Formula (S-Ma), or Formula (S-Mb), wherein p is independently selected from 2 to 4. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-M), Formula (S- M’), Formula (S-Ma), or Formula (S-Mb), wherein p is 2. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-M), Formula (S-M’), Formula (S-Ma), or Formula (S-Mb), wherein p is 3. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-M), Formula (S-M’), Formula (S-Ma), or Formula (S-Mb), wherein p is 4. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-M), Formula (S-M’), Formula (S-Ma), or Formula (S-Mb), wherein p is 5 or 6. In some embodiments, Lipids of the Disclosure have a structure of Formula (S-M), or (S-M’), wherein p is 1. R4

[0174] As disclosed in Formula (S-M), in certain embodiments, R4is -CH(SR6)(SR7). In certain embodiments, R4is selected from, , , , and . R5

[0175] As disclosed in Formula (S-M), in certain embodiments, R5is -CH(OR8)(OR9); - CH(SR8)(SR9); -CH(R8)(R9) or optionally substituted C1-C14 aliphatic, wherein one or more methylene linkages are each optionally and independently replaced with an optionally substituted C3- C8cycloalkylenyl, an optionally substituted bridged bicyclic or multicyclic C5-C12cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-. In certain embodiments, R5is optionally substituted C1-C14aliphatic, wherein one or more methylene linkages are each optionally and independently replaced with an optionally substituted C3-C8cycloalkylenyl, an optionally substituted bridged bicyclic or multicyclic C5-C12 cycloalkylenyl, phenyl, -O-, -NH-, -S- , -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-. In certain embodiments, R5is optionally substituted C1-C14 aliphatic. In certain embodiments, R5is -CH(OR8)(OR9) . In certain embodiments, R5is -CH(R8)(R9). In certain embodiments, R5is -CH(SR8)(SR9).

[0176] In certain embodiments, R4and R5are the same. In certain embodiments, R4and R5are different.

[0177] In certain embodiments, R5is selected from , , , , , ,, , , , , , , and . R6and R7

[0178] As disclosed in Formula (S-M), in certain embodiments, R6and R7are each independently optionally substituted C1-C14 aliphatic, wherein one or more methylene linkages are each optionally and independently replaced with an optionally substituted C3-C8 cycloalkylenyl, an optionally substituted bridged bicyclic or multicyclic C5-C12 cycloalkylenyl, phenyl, -O-, -NH-, -S-, - SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-.

[0179] In certain embodiments, R6and R7are the same. In certain embodiments, R6and R7are different.

[0180] In certain embodiments, R6is optionally substituted C1-C14 aliphatic. In certain embodiments, R6is optionally substituted C1-C14alkylene. In certain embodiments, R6is optionally substituted C1-C14branched alkylene. In certain embodiments, R6is optionally substituted C1-C14straight chain alkylene. In certain embodiments, R6is optionally substituted C1-C14alkenylene. In certain embodiments, R6is optionally substituted C1-C14branched alkenylene. In certain embodiments, R6is optionally substituted C1-C14 straight chain alkenylene. In certain embodiments, R6is optionally substituted C6-C10 alkylene. In certain embodiments, R6is optionally substituted – (CH2)5CH3. In certain embodiments, R6is optionally substituted –(CH2)6CH3. In certain embodiments, R6is optionally substituted –(CH2)7CH3. In certain embodiments, R6is optionally substituted – (CH2)8CH3. In certain embodiments, R6is optionally substituted –(CH2)9CH3.

[0181] In certain embodiments, one of the methylene linkages of R6is replaced with an optionally substituted C3-C8 cycloalkylenyl, an optionally substituted bridged bicyclic or multicyclic C5-C12 cycloalkylenyl. In certain embodiments, the optionally substituted bridged bicyclic or multicyclic C5-C12 cycloalkylenyl is selected from:, , , , , , , , and .

[0182] In certain embodiments, R7is optionally substituted C1-C14aliphatic. In certain embodiments, R7is optionally substituted C1-C14alkylene. In certain embodiments, R7is optionally substituted C1-C14branched alkylene. In certain embodiments, R7is optionally substituted C1-C14straight chain alkylene. In certain embodiments, R7is optionally substituted C1-C14 alkenylene. In certain embodiments, R7is optionally substituted C1-C14 branched alkenylene. In certain embodiments, R7is optionally substituted C1-C14 straight chain alkenylene. In certain embodiments, R7is optionally substituted C6-C10 alkylene. In certain embodiments, R7is optionally substituted – (CH2)5CH3. In certain embodiments, R7is optionally substituted –(CH2)6CH3. In certain embodiments, R7is optionally substituted –(CH2)7CH3. In certain embodiments, R7is optionally substituted – (CH2)8CH3. In certain embodiments, R6is optionally substituted –(CH2)9CH3.

[0183] In certain embodiments, one of the methylene linkages of R7is replaced with an optionally substituted C3-C8 cycloalkylenyl, an optionally substituted bridged bicyclic or multicyclic C5-C12 cycloalkylenyl. In certain embodiments, the optionally substituted bridged bicyclic or multicyclic C5-C12cycloalkylenyl is selected from: , , , , , , , , and .

[0184] In certain embodiments, R6and R7are selected from , , , , , and .

[0185] . In certain embodiments, each R6and R7are each independently selected from an optionally substituted bridged bicyclic C5-C12 cycloalkylenyl. In certain embodiments, R6is an optionally substituted bridged multicyclic C5-C12 cycloalkylenyl. In certain embodiments, R7is an optionally substituted bridged bicyclic C5-C12 cycloalkylenyl. In certain embodiments, the optionally substituted bridged bicyclic or multicyclic C5-C12cycloalkylenyl is selected from adamantyl, bicyclo[2.2.2]octyl, cubanyl, bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, and bicyclo[3.2.1]octyl. In certain embodiments, the optionally substituted bridged bicyclic or multicyclic C5-C12 cycloalkylenyl is selected from: , , , , , , , , and . In certain embodiments, the substituted bridged bicyclic or multicyclic C5-C12 cycloalkylenyl is a structure selected from , , , , , , , , and , wherein one or more C-H bonds are substituted.

[0186] In certain embodiments, R6and R7taken together form an optionally substituted bridged bicyclic or multicyclic C5-C12 cycloalkylenyl. In certain embodiments, the optionally substituted bridged bicyclic or multicyclic C5-C12cycloalkylenyl is selected from: , , , and . R8and R9

[0187] As disclosed in Formula (S-M), in certain embodiments, R8and R9are each independently optionally substituted C1-C14 aliphatic, wherein one or more methylene linkages are each optionally and independently replaced with an optionally substituted C3-C8 cycloalkylenyl, an optionally substituted bridged bicyclic or multicyclic C5-C12 cycloalkylenyl, phenyl, -O-, -NH-, -S-, - SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-.

[0188] In certain embodiments, R8and R9are the same. In certain embodiments, R8and R9are different.

[0189] In certain embodiments, R8is optionally substituted C1-C14aliphatic. In certain embodiments, R8is optionally substituted C1-C14 alkylene. In certain embodiments, R8is optionally substituted C1-C14 branched alkylene. In certain embodiments, R8is optionally substituted C1-C14 straight chain alkylene. In certain embodiments, R8is optionally substituted C1-C14 alkenylene. In certain embodiments, R8is optionally substituted C1-C14branched alkenylene. In certain embodiments, R8is optionally substituted C1-C14straight chain alkenylene. In certain embodiments, R8is optionally substituted C6-C10alkylene. In certain embodiments, R8is optionally substituted – (CH2)5CH3. In certain embodiments, R8is optionally substituted –(CH2)6CH3. In certain embodiments, R8is optionally substituted –(CH2)7CH3. In certain embodiments, R8is optionally substituted – (CH2)8CH3. In certain embodiments, R8is optionally substituted –(CH2)9CH3.

[0190] In certain embodiments, one of the methylene linkages of R8is replaced with an optionally substituted C3-C8cycloalkylenyl, an optionally substituted bridged bicyclic or multicyclic C5-C12cycloalkylenyl. In certain embodiments, the optionally substituted bridged bicyclic or multicyclic C5-C12cycloalkylenyl is selected from: , , , , , , , , and .

[0191] In certain embodiments, R9is optionally substituted C1-C14aliphatic. In certain embodiments, R9is optionally substituted C1-C14 alkylene. In certain embodiments, R9is optionally substituted C1-C14 branched alkylene. In certain embodiments, R9is optionally substituted C1-C14 straight chain alkylene. In certain embodiments, R9is optionally substituted C1-C14 alkenylene. In certain embodiments, R9is optionally substituted C1-C14branched alkenylene. In certain embodiments, R9is optionally substituted C1-C14straight chain alkenylene. In certain embodiments, R9is optionally substituted C6-C10alkylene. In certain embodiments, R9is optionally substituted – (CH2)5CH3. In certain embodiments, R9is optionally substituted –(CH2)6CH3. In certain embodiments, R9is optionally substituted –(CH2)7CH3. In certain embodiments, R9is optionally substituted – (CH2)8CH3. In certain embodiments, R9is optionally substituted –(CH2)9CH3.

[0192] In certain embodiments, one of the methylene linkages of R9is replaced with an optionally substituted C3-C8cycloalkylenyl, an optionally substituted bridged bicyclic or multicyclic C5-C12cycloalkylenyl. In certain embodiments, the optionally substituted bridged bicyclic or multicyclic C5-C12 cycloalkylenyl is selected from:, , , , , , , , and .

[0193] In certain embodiments, R8and R9are selected from , , , , , and .

[0194] In some embodiments, R8and R9taken together form an optionally substituted bridged bicyclic or multicyclic C4-C14 cycloalkyl or optionally substituted bridged bicyclic or multicyclic 4-14 membered heterocyclyl.

[0195] In certain embodiments, each R8and R9are each independently selected from an optionally substituted bridged bicyclic C5-C12cycloalkylenyl. In certain embodiments, R8is an optionally substituted bridged multicyclic C5-C12cycloalkylenyl. In certain embodiments, R9is an optionally substituted bridged bicyclic C5-C12 cycloalkylenyl. In certain embodiments, the optionally substituted bridged bicyclic or multicyclic C5-C12 cycloalkylenyl is selected from adamantyl, bicyclo[2.2.2]octyl, cubanyl, bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, and bicyclo[3.2.1]octyl. In certain embodiments, the optionally substituted bridged bicyclic or multicyclic C5-C12cycloalkylenyl is selected from: , , , , , , , , and . In certain embodiments, the substituted bridged bicyclic or multicyclic C5-C12cycloalkylenyl is a structure selected from ,, , , , , , , and , wherein one or more C-H bonds are substituted.

[00196] In certain embodiments, R8and R9taken together form an optionally substituted bridged bicyclic or multicyclic C5-C12cycloalkylenyl. In certain embodiments, the optionally substituted bridged bicyclic or multicyclic C5-C12 cycloalkylenyl is selected from: , , , and .

[0197] In some embodiments, Lipids of the Disclosure comprise an acyclic core. In some embodiments, Lipids of the Disclosure are selected from any lipid in Table (I-A) below or a pharmaceutically acceptable salt thereof: Table (I-A). Non-Limiting Examples of Ionizable Lipids Cmpd StructureN S[ ] escr e eow are a num er o exempary onza e p s o e presen scosure. Formula (AT)

[0199] In some embodiments, Lipids of the Disclosure have a structure of Formula (AT) (AT), or a pharmaceutically acceptable salt thereof, wherein: i) A is N; Z is a bond; X1is optionally substituted C1-C6 aliphatic, wherein the optional substituent is not oxo when X1is C1 aliphatic; and R1is selected from the group consisting of: , , and ; or ii) A is CH; Z is , , , , , , , , , , or ; wherein the bond marked with an "*" is attached to X1; X1is a bond or optionally substituted C1-C6aliphatic; R1is selected from the group consisting of:, , , , , , , , and ; X4is a bond or optionally substituted C1-C6aliphatic; RZis NR2or OH; each R is independently -H or C1-C6 aliphatic; X2and X3are each independently optionally substituted C1-C12 aliphatic; Y1and Y2are independently selected from the group consisting of , , , , , , , and ; wherein the bond marked with an "*" is attached to X2for Y1or X3for Y2; R2is optionally substituted C1-C6aliphatic; R3is optionally substituted C1-C6aliphatic; R4is -CH(OR6)(OR7), -CH(SR6)(SR7), -CH(R6)(R7), or optionally substituted C1-C14aliphatic, wherein one or more methylene linkages are each optionally and independently replaced with an optionally substituted C3-C8 cycloalkylenyl, an optionally substituted bridged bicyclic or multicyclic C5-C12 cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-; R5is -CH(OR8)(OR9), -CH(SR8)(SR9), -CH(R8)(R9), or optionally substituted C1-C14aliphatic, wherein one or more methylene linkages are each optionally and independently replaced with an optionally substituted C3-C8cycloalkylenyl, an optionally substituted bridged bicyclic or multicyclic C5-C12 cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-; R6and R7are each independently optionally substituted C1-C14 aliphatic, wherein one or more methylene linkages are each optionally and independently replaced with an optionally substituted C3-C8cycloalkylenyl, an optionally substituted bridged bicyclic or multicyclic C5- C12cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or - C(O)O-; andR8and R9are each independently optionally substituted C1-C14aliphatic, wherein one or more methylene linkages are each optionally and independently replaced with an optionally substituted C3-C8 cycloalkylenyl, an optionally substituted bridged bicyclic or multicyclic C5- C12 cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or - C(O)O-. Formula (AT-A)

[0200] In certain embodiments, Lipids of the Disclosure have a structure of Formula (AT), wherein the Lipids of the Disclosure have a structure of Formula (AT-A): (AT-A), or a pharmaceutically acceptable salt thereof, wherein R1, R, X1, Z, X2, X3, X4, RZ, Y1, Y2, R2, R3, R4, R5, R6, R7, R8, and R9are as described in Formula (AT) or as otherwise described in any embodiments below. Formula (AT-A1)

[0201] In certain embodiments, Lipids of the Disclosure have a structure of Formula (AT), wherein the Lipids of the Disclosure have a structure of Formula (AT-A1): (AT-A1), or a pharmaceutically acceptable salt thereof, wherein Z is or , wherein the bond marked with an "*" is attached to X1; Y1and Y2are independently selected from the group consisting of , , , , , and ; wherein the bond marked with an "*" is attached to R2for Y1or R3for Y2; and R1, R, X1, X2, X3, X4, RZ, R2, R3, R4, R5, R6, R7, R8, and R9are as described in Formula (AT) or as otherwise described in any embodiments below. Formula (AT-A2)

[0202] In certain embodiments, Lipids of the Disclosure have a structure of Formula (AT), wherein the Lipids of the Disclosure have a structure of Formula (AT-A2):(AT-A2), or a pharmaceutically acceptable salt thereof, wherein Z is or , wherein the bond marked with an "*" is attached to X1; Y1and Y2are each ,wherein the bond marked with an "*" is attached to R2for Y1or R3for Y2; and R1, R, X1, X2, X3, X4, RZ, R2, R3, R4, R5, R6, R7, R8, and R9are as described in Formula (AT) or as otherwise described in any embodiments below. Formula (AT-B)

[0203] In certain embodiments, Lipids of the Disclosure have a structure of Formula (AT), wherein the Lipids of the Disclosure have a structure of Formula (AT-B): (AT-B), or a pharmaceutically acceptable salt thereof, wherein R1, R, X1, Z, X2, X3, X4, RZ, R2, R3, R4, R5, R6, R7, R8, and R9are as described in Formula (AT) or as otherwise described in any embodiments below. Formula (AT-B’)

[0204] In certain embodiments, Lipids of the Disclosure have a structure of Formula (AT), wherein the Lipids of the Disclosure have a structure of Formula (AT-B’):(AT-B’), or a pharmaceutically acceptable salt thereof, wherein R1, R, X1, Z, X2, X3, X4, RZ, R2, R3, R4, R5, R6, R7, R8, and R9are as described in Formula (AT) or as otherwise described in any embodiments below. Formula (AT-C)

[0205] In certain embodiments, Lipids of the Disclosure have a structure of Formula (AT), wherein the Lipids of the Disclosure have a structure of Formula (AT-C): (AT-C), or a pharmaceutically acceptable salt thereof, wherein R1, R, X1, X2, X3, X4, RZ, Y1, Y2, R2, R3, R4, R5, R6, R7, R8, and R9are as described in Formula (AT) or as otherwise described in any embodiments below. Formula (AT-D)

[0206] In certain embodiments, Lipids of the Disclosure have a structure of Formula (AT), wherein the Lipids of the Disclosure have a structure of Formula (AT-D): (AT-D), or a pharmaceutically acceptable salt thereof, wherein R1, R, X1, X2, X3, X4, RZ, R2, R3, R4, R5, R6, R7, R8, and R9are as described in Formula (AT) or as otherwise described in any embodiments below. Formula (AT-D’)

[0207] In certain embodiments, Lipids of the Disclosure have a structure of Formula (AT), wherein the Lipids of the Disclosure have a structure of Formula (AT-D’):(AT-D’), or a pharmaceutically acceptable salt thereof, wherein R1, R, X1, X2, X3, X4, RZ, R2, R3, R4, R5, R6, R7, R8, and R9are as described in Formula (AT) or as otherwise described in any embodiments below. Formula (AT-D’a)

[0208] In certain embodiments, Lipids of the Disclosure have a structure of Formula (AT), wherein the Lipids of the Disclosure have a structure of Formula (AT-D’a): (AT-D’a), or a pharmaceutically acceptable salt thereof, wherein R1, R, X2, X3, X4, RZ, R2, R3, R4, R5, R6, R7, R8, and R9are as described in Formula (AT) or as otherwise described in any embodiments below. Formula (AT-D’b)

[0209] In certain embodiments, Lipids of the Disclosure have a structure of Formula (AT), wherein the Lipids of the Disclosure have a structure of Formula (AT-D’b): (AT-D’b),Formula (AT-E)

[0210] In certain embodiments, Lipids of the Disclosure have a structure of Formula (AT), wherein the Lipids of the Disclosure have a structure of Formula (AT-E): (AT-E), or a pharmaceutically acceptable salt thereof, wherein R1, R, X1, Z, X2, X3, X4, RZ, Y1, Y2, R2, R3, R6, R7, R8, and R9are as described in Formula (AT) or as otherwise described in any embodiments below. Formula (AT-E’)

[0211] In certain embodiments, Lipids of the Disclosure have a structure of Formula (AT), wherein the Lipids of the Disclosure have a structure of Formula (AT-E’): (AT-E’), or a pharmaceutically acceptable salt thereof, wherein R1, R, X1, Z, X2, X3, X4, RZ, Y1, Y2, R2, R3, R6, R7, R8, and R9are as described in Formula (AT) or as otherwise described in any embodiments below. Formula (AT-E’’)

[0212] In certain embodiments, Lipids of the Disclosure have a structure of Formula (AT), wherein the Lipids of the Disclosure have a structure of Formula (AT-E’’): (AT-E’’),or a pharmaceutically acceptable salt thereof, wherein R1, R, X1, Z, X2, X3, X4, RZ, Y1, Y2, R2, R3, R6, R7, R8, and R9are as described in Formula (AT) or as otherwise described in any embodiments below. Formula (AT-F)

[0213] In certain embodiments, Lipids of the Disclosure have a structure of Formula (AT), wherein the Lipids of the Disclosure have a structure of Formula (AT-F): (AT-F), or a pharmaceutically acceptable salt thereof, wherein R1, R, X1, Z, X2, X3, X4, RZ, R2, R3, R6, R7, R8, and R9are as described in Formula (AT) or as otherwise described in any embodiments below. Formula (AT-F’)

[0214] In certain embodiments, Lipids of the Disclosure have a structure of Formula (AT), wherein the Lipids of the Disclosure have a structure of Formula (AT-F’): (AT-F’), or a pharmaceutically acceptable salt thereof, wherein R1, R, X1, Z, X2, X3, X4, RZ, R2, R3, R6, R7, R8, and R9are as described in Formula (AT) or as otherwise described in any embodiments below. Formula (AT-F’’)

[0215] In certain embodiments, Lipids of the Disclosure have a structure of Formula (AT), wherein the Lipids of the Disclosure have a structure of Formula (AT-F’’):(AT-F’’), or a pharmaceutically acceptable salt thereof, wherein R1, R, X1, Z, X2, X3, X4, RZ, R2, R3, R6, R7, R8, and R9are as described in Formula (AT) or as otherwise described in any embodiments below. Formula (AT-F’’’)

[0216] In certain embodiments, Lipids of the Disclosure have a structure of Formula (AT), wherein the Lipids of the Disclosure have a structure of Formula (AT-F’’’): (AT-F’’’), or a pharmaceutically acceptable salt thereof, wherein R1, R, X1, Z, X2, X3, X4, RZ, R2, R3, R6, R7, R8, and R9are as described in Formula (AT) or as otherwise described in any embodiments below. Formula (AT-F’’’’)

[0217] In certain embodiments, Lipids of the Disclosure have a structure of Formula (AT), wherein the Lipids of the Disclosure have a structure of Formula (AT-F’’’’):(AT-F’’’’), or a pharmaceutically acceptable salt thereof, wherein R1, R, X1, Z, X2, X3, X4, RZ, R2, R3, R6, R7, R8, and R9are as described in Formula (AT) or as otherwise described in any embodiments below. Formula (AT-F’’’’’)

[0218] In certain embodiments, Lipids of the Disclosure have a structure of Formula (AT), wherein the Lipids of the Disclosure have a structure of Formula (AT-F’’’’’): (AT-F’’’’’), or a pharmaceutically acceptable salt thereof, wherein R1, R, X1, Z, X2, X3, X4, RZ, R2, R3, R6, R7, R8, and R9are as described in Formula (AT) or as otherwise described in any embodiments below. Formula (AT-G)

[0219] In certain embodiments, Lipids of the Disclosure have a structure of Formula (AT), wherein the Lipids of the Disclosure have a structure of Formula (AT-G): (AT-G), or a pharmaceutically acceptable salt thereof, wherein R1, R, X1, X2, X3, Y1, Y2, X4, RZ, R2, R3, R6, R7, R8, and R9are as described in Formula (AT) or as otherwise described in any embodiments below. Formula (AT-G’)

[0220] In certain embodiments, Lipids of the Disclosure have a structure of Formula (AT), wherein the Lipids of the Disclosure have a structure of Formula (AT-G’):(AT-G’), or a pharmaceutically acceptable salt thereof, wherein R1, R, X1, X2, X3, Y1, Y2, X4, RZ, R2, R3, R6, R7, R8, and R9are as described in Formula (AT) or as otherwise described in any embodiments below. Formula (AT-H)

[0221] In certain embodiments, Lipids of the Disclosure have a structure of Formula (AT), wherein the Lipids of the Disclosure have a structure of Formula (AT-H): (AT-H), or a pharmaceutically acceptable salt thereof, wherein R1, R, X1, X2, X3, R2, R3, X4, RZ, R6, R7, R8, and R9are as described in Formula (AT) or as otherwise described in any embodiments below. Formula (AT-H’)

[0222] In certain embodiments, Lipids of the Disclosure have a structure of Formula (AT), wherein the Lipids of the Disclosure have a structure of Formula (AT-H’): (AT-H’),or a pharmaceutically acceptable salt thereof, wherein R1, R, X1, X2, X3, R2, R3, X4, RZ, R6, R7, R8, and R9are as described in Formula (AT) or as otherwise described in any embodiments below. Formula (AT-H’’)

[0223] In certain embodiments, Lipids of the Disclosure have a structure of Formula (AT), wherein the Lipids of the Disclosure have a structure of Formula (AT-H’’): (AT-H’’), or a pharmaceutically acceptable salt thereof, wherein R1, R, X1, X2, X3, R2, R3, X4, RZ, R6, R7, R8, and R9are as described in Formula (AT) or as otherwise described in any embodiments below. Formula (AT-H’’’)

[0224] In certain embodiments, Lipids of the Disclosure have a structure of Formula (AT), wherein the Lipids of the Disclosure have a structure of Formula (AT-H’’’): (AT-H’’’), or a pharmaceutically acceptable salt thereof, wherein R1, R, X1, X2, X3, R2, R3, X4, RZ, R6, R7, R8, and R9are as described in Formula (AT) or as otherwise described in any embodiments below. Formula (AT-I)

[0225] In certain embodiments, Lipids of the Disclosure have a structure of Formula (AT), wherein the Lipids of the Disclosure have a structure of Formula (AT-I):(AT-I), or a pharmaceutically acceptable salt thereof, wherein R1, R, X1, X2, X3, X4, RZ, Y1, Y2, R2, R3, R4, R5, R6, R7, R8, and R9are as described in Formula (AT) or as otherwise described in any embodiments below. Formula (AT-J)

[0226] In certain embodiments, Lipids of the Disclosure have a structure of Formula (AT), wherein the Lipids of the Disclosure have a structure of Formula (AT-J): (AT-J), or a pharmaceutically acceptable salt thereof, wherein R1, R, X1, X2, X3, X4, RZ, R2, R3, R4, R5, R6, R7, R8, and R9are as described in Formula (AT) or as otherwise described in any embodiments below. Formula (AT-J’)

[0227] In certain embodiments, Lipids of the Disclosure have a structure of Formula (AT), wherein the Lipids of the Disclosure have a structure of Formula (AT-J’): (AT-J’), or a pharmaceutically acceptable salt thereof, wherein R1, R, X1, X2, X3, X4, RZ, R2, R3, R4, R5, R6, R7, R8, and R9are as described in Formula (AT) or as otherwise described in any embodiments below.Formula (AT-K)

[0228] In certain embodiments, Lipids of the Disclosure have a structure of Formula (AT), wherein the Lipids of the Disclosure have a structure of Formula (AT-K):(AT-K), or a pharmaceutically acceptable salt thereof, wherein R R, X1, X2, X3, Y1, Y2, X4, Rz, R2, R3, R6, R', R8, and R9are as described in Formula (AT) or as otherwise described in any embodiments below.Formula (AT-K’)

[0229] In certain embodiments, Lipids of the Disclosure have a structure of Formula (AT), wherein the Lipids of the Disclosure have a structure of Formula (AT-K’):(AT-K’), or a pharmaceutically acceptable salt thereof, wherein R', R, X', X2, X3, Y’, Y2, X4, Rz, R2, R3, R6, R7, Rs, and R9are as described in Formula ( AT) or as otherwise described in any embodiments below.Formula (AT-L)

[0230] In certain embodiments, Lipids of the Disclosure have a structure of Formula (AT), wherein the Lipids of the Disclosure have a structure of Formula (AT-L):(AT-L),or a pharmaceutically acceptable salt thereof, wherein R1, R, X1, X2, X2, R2, R2, X4, Rz, R°, R7, R8, and R9are as described in Formula (AT) or as otherwise described in any embodiments below.Formula (AT-L’)

[0231] In certain embodiments, Lipids of the Disclosure have a structure of Formula (AT), wherein the Lipids of the Disclosure have a structure of Formula (AT-L’):(AT-L’), or a pharmaceutically acceptable salt thereof, wherein R‘, R, X1, X2, X2, R2, R2, X4, Rz, R°, R', R8, and R9are as described iti Formula (AT) or as otherwise described in any embodiments below.Formula (AT-L”)

[0232] In certain embodiments, Lipids of the Disclosure have a structure of Formula (AT), wherein the Lipids of the Disclosure have a structure of Formula (AT-L’’):(AT-L”), or a pharmaceutically acceptable salt thereof, wherein R!, R, X1, X2, X3, R2, R3, X4, Rz, Rb, R', R8, and R9are as described in Formula (AT) or as otherwise described in any embodiments below.Formula (AT-L’”)

[0233] In certain embodiments, Lipids of the Disclosure have a structure of Formula (AT), wherein the Lipids of the Disclosure have a structure of Formula (AT-L’”):(AT-L’’’), or a pharmaceutically acceptable salt thereof, wherein R1, R, X1, X2, X3, R2, R3, X4, RZ, R6, R7, R8, and R9are as described in Formula (AT) or as otherwise described in any embodiments below. Formula (AT-M)

[0234] In certain embodiments, Lipids of the Disclosure have a structure of Formula (AT), wherein the Lipids of the Disclosure have a structure of Formula (AT-M): (AT-M), or a pharmaceutically acceptable salt thereof, wherein R1, R, X2, X3, X4, RZ, Y1, Y2, R2, R3, R4, R5, R6, R7, R8, and R9are as described in Formula (AT) or as otherwise described in any embodiments below. Formula (AT-N)

[0235] In certain embodiments, Lipids of the Disclosure have a structure of Formula (AT), wherein the Lipids of the Disclosure have a structure of Formula (AT-N): (AT-N), or a pharmaceutically acceptable salt thereof, wherein R1, R, X1, X2, X3, X4, RZ, R2, R3, R4, R5, R6, R7, R8, and R9are as described in Formula (AT) or as otherwise described in any embodiments below.Formula (AT-N’)

[0236] In certain embodiments, Lipids of the Disclosure have a structure of Formula (AT), wherein the Lipids of the Disclosure have a structure of Formula (AT-N’): (AT-N’), or a pharmaceutically acceptable salt thereof, wherein R1, R, X1, X2, X3, X4, RZ, R2, R3, R4, R5, R6, R7, R8, and R9are as described in Formula (AT) or as otherwise described in any embodiments below. Formula (AT-O)

[0237] In certain embodiments, Lipids of the Disclosure have a structure of Formula (AT), wherein the Lipids of the Disclosure have a structure of Formula (AT-O): (AT-O), or a pharmaceutically acceptable salt thereof, wherein R1, R, X1, X2, X3, Y1, Y2, X4, RZ, R2, R3, R6, R7, R8, and R9are as described in Formula (AT) or as otherwise described in any embodiments below. Formula (AT-O’)

[0238] In certain embodiments, Lipids of the Disclosure have a structure of Formula (AT), wherein the Lipids of the Disclosure have a structure of Formula (AT-O’): (AT-O’),or a pharmaceutically acceptable salt thereof, wherein R1, R, X1, X2, X3, Y1, Y2, X4, RZ, R2, R3, R6, R7, R8, and R9are as described in Formula (AT) or as otherwise described in any embodiments below. Formula (AT-P)

[0239] In certain embodiments, Lipids of the Disclosure have a structure of Formula (AT), wherein the Lipids of the Disclosure have a structure of Formula (AT-P): (AT-P), or a pharmaceutically acceptable salt thereof, wherein R1, R, X1, X2, X3, R2, R3, X4, RZ, R6, R7, R8, and R9are as described in Formula (AT) or as otherwise described in any embodiments below. Formula (AT-P’)

[0240] In certain embodiments, Lipids of the Disclosure have a structure of Formula (AT), wherein the Lipids of the Disclosure have a structure of Formula (AT-P’): (AT-P’), or a pharmaceutically acceptable salt thereof, wherein R1, R, X1, X2, X3, R2, R3, X4, RZ, R6, R7, R8, and R9are as described in Formula (AT) or as otherwise described in any embodiments below. Formula (AT-P’’)

[0241] In certain embodiments, Lipids of the Disclosure have a structure of Formula (AT), wherein the Lipids of the Disclosure have a structure of Formula (AT-P’’):(AT-P’’), or a pharmaceutically acceptable salt thereof, wherein R1, R, X1, X2, X3, R2, R3, X4, RZ, R6, R7, R8, and R9are as described in Formula (AT) or as otherwise described in any embodiments below. Formula (AT-P’’’)

[0242] In certain embodiments, Lipids of the Disclosure have a structure of Formula (AT), wherein the Lipids of the Disclosure have a structure of Formula (AT-P’’’): (AT-P’’’), or a pharmaceutically acceptable salt thereof, wherein R1, R, X1, X2, X3, R2, R3, X4, RZ, R6, R7, R8, and R9are as described in Formula (AT) or as otherwise described in any embodiments below. Formula (AT-Q)

[0243] In certain embodiments, Lipids of the Disclosure have a structure of Formula (AT), wherein the Lipids of the Disclosure have a structure of Formula (AT-Q): (AT-Q), or a pharmaceutically acceptable salt thereof, wherein R1, R, X1, X2, X3, X4, RZ, Y1, Y2, R2, R3, R4, R5, R6, R7, R8, and R9are as described in Formula (AT) or as otherwise described in any embodiments below.Formula (AT-Q1)

[0244] In certain embodiments, Lipids of the Disclosure have a structure of Formula (AT), wherein the Lipids of the Disclosure have a structure of Formula (AT-Q1): (AT-Q1), or a pharmaceutically acceptable salt thereof, wherein Y1and Y2are independently selected from the group consisting of , , , , , and ; wherein the bond marked with an "*" is attached to R2for Y1or R3for Y2; and R1, R, X1, X2, X3, X4, RZ, R2, R3, R4, R5, R6, R7, R8, and R9are as described in Formula (AT) or as otherwise described in any embodiments below. Formula (AT-Q2)

[0245] In certain embodiments, Lipids of the Disclosure have a structure of Formula (AT), wherein the Lipids of the Disclosure have a structure of Formula (AT-Q2): (AT-Q2), or a pharmaceutically acceptable salt thereof, wherein R1is ; Y1and Y2are ; wherein the bond marked with an "*" is attached to R2for Y1or R3for Y2; and R, X1, X2, X3, X4, RZ, R2, R3, R4, R5, R6, R7, R8, and R9are as described in Formula (AT) or as otherwise described in any embodiments below. Formula (AT-R)

[0246] In certain embodiments, Lipids of the Disclosure have a structure of Formula (AT), wherein the Lipids of the Disclosure have a structure of Formula (AT-R):O R2X2R4R11N 3 O X X O R3R5O (AT-R), or a pharmaceutically acceptable salt thereof, wherein R1, R, X1, X2, X3, X4, RZ, R2, R3, R4, R5, R6, R7, R8, and R9are as described in Formula (AT) or as otherwise described in any embodiments below. Formula (AT-R’)

[0247] In certain embodiments, Lipids of the Disclosure have a structure of Formula (AT), wherein the Lipids of the Disclosure have a structure of Formula (AT-R’): (AT-R’), or a pharmaceutically acceptable salt thereof, wherein R1, R, X1, X2, X3, X4, RZ, R2, R3, R4, R5, R6, R7, R8, and R9are as described in Formula (AT) or as otherwise described in any embodiments below. Formula (AT-S)

[0248] In certain embodiments, Lipids of the Disclosure have a structure of Formula (AT), wherein the Lipids of the Disclosure have a structure of Formula (AT-S): (AT-S),or a pharmaceutically acceptable salt thereof, wherein R1, R, X1, X2, X3, X4, RZ, Y1, Y2, R2, R3, R6, R7, R8, and R9are as described in Formula (AT) or as otherwise described in any embodiments below. Formula (AT-S’)

[0249] In certain embodiments, Lipids of the Disclosure have a structure of Formula (AT), wherein the Lipids of the Disclosure have a structure of Formula (AT-S’): (AT-S’), or a pharmaceutically acceptable salt thereof, wherein R1, R, X1, X2, X3, X4, RZ, Y1, Y2, R2, R3, R6, R7, R8, and R9are as described in Formula (AT) or as otherwise described in any embodiments below. Formula (AT-S’’)

[0250] In certain embodiments, Lipids of the Disclosure have a structure of Formula (AT), wherein the Lipids of the Disclosure have a structure of Formula (AT-S’’): (AT-S’’), or a pharmaceutically acceptable salt thereof, wherein R1, R, X1, X2, X3, X4, RZ, Y1, Y2, R2, R3, R6, R7, R8, and R9are as described in Formula (AT) or as otherwise described in any embodiments below. Formula (AT-T)

[0251] In certain embodiments, Lipids of the Disclosure have a structure of Formula (AT), wherein the Lipids of the Disclosure have a structure of Formula (AT-T):(AT-T), or a pharmaceutically acceptable salt thereof, wherein R1, R, X1, X2, X3, X4, RZ, R2, R3, R6, R7, R8, and R9are as described in Formula (AT) or as otherwise described in any embodiments below. Formula (AT-T’)

[0252] In certain embodiments, Lipids of the Disclosure have a structure of Formula (AT), wherein the Lipids of the Disclosure have a structure of Formula (AT-T’): (AT-T’), or a pharmaceutically acceptable salt thereof, wherein R1, R, X1, X2, X3, X4, RZ, R2, R3, R6, R7, R8, and R9are as described in Formula (AT) or as otherwise described in any embodiments below. Formula (AT-T’’)

[0253] In certain embodiments, Lipids of the Disclosure have a structure of Formula (AT), wherein the Lipids of the Disclosure have a structure of Formula (AT-T’’):(AT-T’’), or a pharmaceutically acceptable salt thereof, wherein R1, R, X1, X2, X3, X4, RZ, R2, R3, R6, R7, R8, and R9are as described in Formula (AT) or as otherwise described in any embodiments below. Formula (AT-T’’’)

[0254] In certain embodiments, Lipids of the Disclosure have a structure of Formula (AT), wherein the Lipids of the Disclosure have a structure of Formula (AT-T’’’): (AT-T’’’), or a pharmaceutically acceptable salt thereof, wherein R1, R, X1, X2, X3, X4, RZ, R2, R3, R6, R7, R8, and R9are as described in Formula (AT) or as otherwise described in any embodiments below. Formula (AT-T’’’’)

[0255] In certain embodiments, Lipids of the Disclosure have a structure of Formula (AT), wherein the Lipids of the Disclosure have a structure of Formula (AT-T’’’’):(AT-T’’’’), or a pharmaceutically acceptable salt thereof, wherein R1, R, X1, X2, X3, X4, RZ, R2, R3, R6, R7, R8, and R9are as described in Formula (AT) or as otherwise described in any embodiments below. Formula (AT-T’’’’’)

[0256] In certain embodiments, Lipids of the Disclosure have a structure of Formula (AT), wherein the Lipids of the Disclosure have a structure of Formula (AT-T’’’’’): (AT-T’’’’’), or a pharmaceutically acceptable salt thereof, wherein R1, R, X1, X2, X3, X4, RZ, R2, R3, R6, R7, R8, and R9are as described in Formula (AT) or as otherwise described in any embodiments below. A

[0257] As disclosed in Formula (AT), in certain embodiments, A is CH or N. In certain embodiments, A is CH. In certain embodiments, A is N. Z

[0258] As disclosed in Formula (AT), in certain embodiments wherein A is CH, Z is , , , , , ,, , , , or ; wherein the bond marked with an "*" is attached to X1. In certain embodiments wherein A is CH, Z is , , , , , , , , or . In certain embodiments wherein A is CH, Z is or . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . As disclosed in Formula (AT), in certain embodiments wherein A is N, Z is a bond. X1

[0259] As disclosed in Formula (AT), in certain embodiments wherein A is N, X1is optionally substituted C1-C6 aliphatic. In certain embodiments wherein A is N, X1is unsubstituted C1- C6aliphatic. In certain embodiments, X1is optionally substituted C1-C6alkylene. In certain embodiments, X1is unsubstituted C1-C6alkylene. In certain embodiments, X1is unsubstituted C2-C6alkylene. In certain embodiments, X1is optionally substituted methylene. In certain embodiments, R2is optionally substituted C2 alkylene. In certain embodiments, X1is optionally substituted C3 alkylene. In certain embodiments, X1is optionally substituted C4 alkylene. In certain embodiments, X1is optionally substituted C5 alkylene. In certain embodiments, X1is optionally substituted C6 alkylene. In certain embodiments, X1is –(CH2)-. In certain embodiments, X1is –(CH2)2-. In certain embodiments, X1is –(CH2)3-. In certain embodiments, X1is –(CH2)4-. In certain embodiments, X1is – (CH2)5-. In certain embodiments, X1is –(CH2)6-.

[0260] As disclosed in Formula (AT), in certain embodiments wherein A is CH, X1is a bond or optionally substituted C1-C6 aliphatic. In certain embodiments, X1is a bond. In certain embodiments, X1is optionally substituted C1-C6 alkylene. In certain embodiments, X1is unsubstituted C1-C6 alkylene. In certain embodiments, X1is unsubstituted C2-C6 alkylene. In certain embodiments, X1is optionally substituted methylene. In certain embodiments, R2is optionally substituted C2alkylene. In certain embodiments, X1is optionally substituted C3alkylene. In certain embodiments, X1is optionally substituted C4alkylene. In certain embodiments, X1is optionally substituted C5alkylene. In certain embodiments, X1is optionally substituted C6alkylene. In certain embodiments, X1is –(CH2)-. In certain embodiments, X1is –(CH2)2-. In certain embodiments, X1is –(CH2)3-. In certain embodiments, X1is –(CH2)4-. In certain embodiments, X1is –(CH2)5-. In certain embodiments, X1is –(CH2)6-. R1

[0261] As disclosed in Formula (AT), in certain embodiments wherein A is N, R1is selected from the group consisting of , , and . As disclosed in Formula (AT), in certain embodiments wherein A is CH, R1is selected from the group consisting of , , , , , , , , and .

[0262] In certain embodiments, R1is . In certain embodiments, R1is . In certain embodiments, R1is . In certain embodiments, R1is . In certainembodiments, R1is . In certain embodiments, R1is . In certain embodiments, R1is . In certain embodiments, R1is . In certain embodiments, R1is .

[0263] In certain embodiments, R1is . In certain embodiments, R1is . In certain embodiments, R1is . In certain embodiments, R1is . X2and X3

[0264] As disclosed in Formula (AT), in certain embodiments, X2and X3are each independently optionally substituted C1-C12aliphatic. In certain embodiments, X2and X3are the same. In certain embodiments, X2and X3are different.

[0265] In certain embodiments, X2is an optionally substituted C1-C12 alkylene. In certain embodiments, X2is an optionally substituted C1-C12alkenylene. In certain embodiments, X2is an optionally substituted C1-C10aliphatic. In certain embodiments, X2is an optionally substituted C1-C10alkylene. In certain embodiments, X2is an optionally substituted C1-C10alkenylene. In certain embodiments, X2is an optionally substituted C1-C8aliphatic. In certain embodiments, X2is an optionally substituted C1-C8 alkylene. In certain embodiments, X2is an optionally substituted C1-C8 alkenylene. In certain embodiments, X2is an optionally substituted C1-C6 aliphatic. In certain embodiments, X2is an optionally substituted C1-C6 alkylene. In certain embodiments, X2is an optionally substituted C1-C6alkenylene. In certain embodiments, X2is an optionally substituted C2- C12aliphatic. In certain embodiments, X2is an optionally substituted C2-C12alkylene. In certain embodiments, X2is an optionally substituted C2-C12alkenylene. In certain embodiments, X2is an optionally substituted C4-C12 aliphatic. In certain embodiments, X2is an optionally substituted C4-C12alkylene. In certain embodiments, X2is an optionally substituted C4-C12alkenylene. In certain embodiments, X2is an optionally substituted C4-C10aliphatic. In certain embodiments, X2is an optionally substituted C4-C10 alkylene. In certain embodiments, X2is an optionally substituted C4-C10 alkenylene. In certain embodiments, X2is an optionally substituted C6-C8 aliphatic. In certain embodiments, X2is an optionally substituted C6-C8 alkylene. In certain embodiments, X2is an optionally substituted C6-C8alkenylene. In certain embodiments, X2is –(CH2)-. In certain embodiments, X2is –(CH2)2-. In certain embodiments, X2is –(CH2)3-. In certain embodiments, X2is – (CH2)4-. In certain embodiments, X2is –(CH2)5-. In certain embodiments, X2is –(CH2)6-. In certain embodiments, X2is –(CH2)7-. In certain embodiments, X2is –(CH2)8-. In certain embodiments, X2is – (CH2)9-. In certain embodiments, X2is –(CH2)10-.

[0266] In certain embodiments, X3is an optionally substituted C1-C12 alkylene. In certain embodiments, X3is an optionally substituted C1-C12alkenylene. In certain embodiments, X3is an optionally substituted C1-C10aliphatic. In certain embodiments, X3is an optionally substituted C1-C10alkylene. In certain embodiments, X3is an optionally substituted C1-C10alkenylene. In certain embodiments, X3is an optionally substituted C1-C8 aliphatic. In certain embodiments, X3is an optionally substituted C1-C8 alkylene. In certain embodiments, X3is an optionally substituted C1-C8 alkenylene. In certain embodiments, X3is an optionally substituted C1-C6 aliphatic. In certain embodiments, X3is an optionally substituted C1-C6 alkylene. In certain embodiments, X3is an optionally substituted C1-C6alkenylene. In certain embodiments, X3is an optionally substituted C2- C12aliphatic. In certain embodiments, X3is an optionally substituted C2-C12alkylene. In certain embodiments, X3is an optionally substituted C2-C12alkenylene. In certain embodiments, X3is an optionally substituted C4-C12 aliphatic. In certain embodiments, X3is an optionally substituted C4-C12 alkylene. In certain embodiments, X3is an optionally substituted C4-C12 alkenylene. In certain embodiments, X3is an optionally substituted C4-C10 aliphatic. In certain embodiments, X3is an optionally substituted C4-C10alkylene. In certain embodiments, X3is an optionally substituted C4-C10alkenylene. In certain embodiments, X3is an optionally substituted C6-C8aliphatic. In certain embodiments, X3is an optionally substituted C6-C8alkylene. In certain embodiments, X3is an optionally substituted C6-C8alkenylene. In certain embodiments, X3is –(CH2)-. In certain embodiments, X3is –(CH2)2-. In certain embodiments, X3is –(CH2)3-. In certain embodiments, X3is – (CH2)4-. In certain embodiments, X3is –(CH2)5-. In certain embodiments, X3is –(CH2)6-. In certain embodiments, X3is –(CH2)7-. In certain embodiments, X3is –(CH2)8-. In certain embodiments, X3is – (CH2)9-. In certain embodiments, X3is –(CH2)10-.

[0267] In certain embodiments, X2and X3are both –(CH2)8-. In certain embodiments, X2and X3are both –(CH2)6-. X4

[0268] As disclosed in Formula (AT), in certain embodiments, X4is a bond or C2-C6aliphatic. In certain embodiments, X4is a bond. In certain embodiments, X4is C2-C6 aliphatic. In certain embodiments, X4is C2 aliphatic. In certain embodiments, X4is C3 aliphatic. In certain embodiments, X4is C4 aliphatic. In certain embodiments, X4is C5 aliphatic. In certain embodiments, X4is C6aliphatic. Y1and Y2

[0269] As disclosed in Formula (AT), in certain embodiments, Y1and Y2are each independently , , , , , , , or , wherein the bond marked with an "*" is attached to X2for Y1or X3for Y2. In certain embodiments, Y1and Y2are the same. In certain embodiments, Y1and Y2are different.

[0270] In certain embodiments, Y1and Y2are each independently , , , , , or . In certain embodiments, Y1and Y2are each independently or . In certain embodiments, Y1is . In certain embodiments, Y1is . In certain embodiments, Y1is . In certain embodiments, Y1is . In certain embodiments, Y1is . In certain embodiments, Y1is . In certain embodiments, Y1is . In certain embodiments, Y1is . In certain embodiments, Y2is . In certain embodiments, Y2is . In certain embodiments, Y2is . In certain embodiments, Y2is . In certain embodiments, Y2is . In certain embodiments, Y2is . In certain embodiments,Y2is . In certain embodiments, Y2is . In certain embodiments, Y1and Y2are both . In certain embodiments, Y1and Y2are both . R2

[0271] As disclosed in Formula (AT), in certain embodiments, R2is optionally substituted C1-C6 aliphatic. In certain embodiments, R2is optionally substituted C1-C6 alkylene. In certain embodiments, R2is optionally substituted methylene. In certain embodiments, R2is optionally substituted C2alkylene. In certain embodiments, R2is optionally substituted C3alkylene. In certain embodiments, R2is optionally substituted C4alkylene. In certain embodiments, R2is optionally substituted C5alkylene. In certain embodiments, R2is optionally substituted C6alkylene. In certain embodiments, R2is –(CH2)-. In certain embodiments, R2is –(CH2)2-. In certain embodiments, R2is – (CH2)3-. In certain embodiments, R2is –(CH2)4-. In certain embodiments, R2is –(CH2)5-. In certain embodiments, R2is –(CH2)6-. R3

[0272] As disclosed in Formula (AT), in certain embodiments, R3is optionally substituted C1-C6aliphatic. In certain embodiments, R3is optionally substituted C1-C6alkylene. In certain embodiments, R3is optionally substituted methylene. In certain embodiments, R3is optionally substituted C2 alkylene. In certain embodiments, R3is optionally substituted C3 alkylene. In certain embodiments, R3is optionally substituted C4 alkylene. In certain embodiments, R3is optionally substituted C5 alkylene. In certain embodiments, R3is optionally substituted C6 alkylene. In certain embodiments, R3is –(CH2)-. In certain embodiments, R3is –(CH2)2-. In certain embodiments, R3is – (CH2)3-. In certain embodiments, R3is –(CH2)4-. In certain embodiments, R3is –(CH2)5-. In certain embodiments, R3is –(CH2)6-.

[0273] In certain embodiments, R2and R3are the same. In certain embodiments, R2and R3are different. R4

[0274] As disclosed in Formula (AT), in certain embodiments, R4is -CH(OR6)(OR7), - CH(SR6)(SR7), -CH(R6)(R7), or optionally substituted C1-C14aliphatic, wherein one or more methylene linkages are each optionally and independently replaced with an optionally substituted C3- C8 cycloalkylenyl, an optionally substituted bridged bicyclic or multicyclic C5-C12 cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-. In certain embodiments, R4is optionally substituted C1-C14aliphatic, wherein one or more methylene linkages are each optionally and independently replaced with an optionally substituted C3-C8cycloalkylenyl, an optionally substituted bridged bicyclic or multicyclic C5-C12cycloalkylenyl, phenyl, -O-, -NH-, -S- , -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-. In certain embodiments, R4is optionallysubstituted C1-C14aliphatic. In certain embodiments, R4is -CH(OR6)(OR7) . In certain embodiments, R4is -CH(R6)(R7). In certain embodiments, R4is -CH(SR6)(SR7).

[0275] In certain embodiments, one of the methylene linkages of R4is replaced with an optionally substituted C3-C8 cycloalkylenyl, an optionally substituted bridged bicyclic or multicyclic C5-C12cycloalkylenyl. In certain embodiments, the optionally substituted bridged bicyclic or multicyclic C5-C12cycloalkylenyl is selected from: , , , , , , , , and .

[0276] In certain embodiments, R4is selected from is selected from , , , , , , , , , , , , , , and .

[0277] In certain embodiments, R4is selected from is selected from and .R5

[0278] As disclosed in Formula (AT), in certain embodiments, R5is -CH(OR8)(OR9), - CH(SR8)(SR9), -CH(R8)(R9), or optionally substituted C1-C14 aliphatic, wherein one or more methylene linkages are each optionally and independently replaced with an optionally substituted C3- C8cycloalkylenyl, an optionally substituted bridged bicyclic or multicyclic C5-C12cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-. In certain embodiments, R5is optionally substituted C1-C14aliphatic, wherein one or more methylene linkages are each optionally and independently replaced with an optionally substituted C3-C8cycloalkylenyl, an optionally substituted bridged bicyclic or multicyclic C5-C12 cycloalkylenyl, phenyl, -O-, -NH-, -S- , -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-. In certain embodiments, R5is optionally substituted C1-C14 aliphatic. In certain embodiments, R5is -CH(OR8)(OR9) . In certain embodiments, R5is -CH(R8)(R9). In certain embodiments, R5is -CH(SR8)(SR9).

[0279] In certain embodiments, one of the methylene linkages of R5is replaced with an optionally substituted C3-C8cycloalkylenyl, an optionally substituted bridged bicyclic or multicyclic C5-C12 cycloalkylenyl. In certain embodiments, the optionally substituted bridged bicyclic or multicyclic C5-C12 cycloalkylenyl is selected from: , , , , , , , , and .

[0280] In certain embodiments, R4and R5are the same. In certain embodiments, R4and R5are different.

[0281] In certain embodiments, R5is selected from , , , ,, , , , , , , , and .

[0282] In certain embodiments, R5is selected from is selected from and . R6and R7

[0283] As disclosed in Formula (AT), in certain embodiments, R6and R7are each independently optionally substituted C1-C14aliphatic, wherein one or more methylene linkages are each optionally and independently replaced with an optionally substituted C3-C8cycloalkylenyl, an optionally substituted bridged bicyclic or multicyclic C5-C12cycloalkylenyl, phenyl, -O-, -NH-, -S-, - SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-.

[0284] In certain embodiments, R6and R7are the same. In certain embodiments, R6and R7are different.

[0285] In certain embodiments, R6is optionally substituted C1-C14aliphatic. In certain embodiments, R6is optionally substituted C1-C14alkyl. In certain embodiments, R6is optionally substituted C1-C14branched alkyl. In certain embodiments, R6is optionally substituted C1-C14straight chain alkyl. In certain embodiments, R6is optionally substituted C1-C14 alkenylene. In certain embodiments, R6is optionally substituted C1-C14 branched alkenyl. In certain embodiments, R6is optionally substituted C1-C14 straight chain alkenyl. In certain embodiments, R6is optionally substituted C6-C10alkyl. In certain embodiments, R6is optionally substituted –(CH2)5CH3. In certain embodiments, R6is optionally substituted –(CH2)6CH3. In certain embodiments, R6is optionally substituted –(CH2)7CH3. In certain embodiments, R6is optionally substituted –(CH2)8CH3. In certain embodiments, R6is optionally substituted –(CH2)9CH3.

[0286] In certain embodiments, one of the methylene linkages of R6is replaced with an optionally substituted C3-C8 cycloalkylenyl, an optionally substituted bridged bicyclic or multicyclic C5-C12cycloalkylenyl. In certain embodiments, the optionally substituted bridged bicyclic or multicyclic C5-C12cycloalkylenyl is selected from:, , , , , , , , and .

[0287] In certain embodiments, R7is optionally substituted C1-C14 aliphatic. In certain embodiments, R7is optionally substituted C1-C14 alkyl. In certain embodiments, R7is optionally substituted C1-C14branched alkyl. In certain embodiments, R7is optionally substituted C1-C14straight chain alkyl. In certain embodiments, R7is optionally substituted C1-C14alkenylene. In certain embodiments, R7is optionally substituted C1-C14branched alkenyl. In certain embodiments, R7is optionally substituted C1-C14straight chain alkenyl. In certain embodiments, R7is optionally substituted C6-C10 alkyl. In certain embodiments, R7is optionally substituted –(CH2)5CH3. In certain embodiments, R7is optionally substituted –(CH2)6CH3. In certain embodiments, R7is optionally substituted –(CH2)7CH3. In certain embodiments, R7is optionally substituted –(CH2)8CH3. In certain embodiments, R6is optionally substituted –(CH2)9CH3.

[0288] In certain embodiments, one of the methylene linkages of R7is replaced with an optionally substituted C3-C8cycloalkylenyl, an optionally substituted bridged bicyclic or multicyclic C5-C12 cycloalkylenyl. In certain embodiments, the optionally substituted bridged bicyclic or multicyclic C5-C12 cycloalkylenyl is selected from: , , , , , , , , and .

[0289] In certain embodiments, each R6and R7are selected from , , , , , , and .

[0290] In certain embodiments, each R6and R7are each independently selected from an optionally substituted bridged bicyclic C5-C12 cycloalkylenyl. In certain embodiments, R6is an optionally substituted bridged multicyclic C5-C12 cycloalkylenyl. In certain embodiments, R7is an optionally substituted bridged bicyclic C5-C12 cycloalkylenyl. In certain embodiments, the optionally substituted bridged bicyclic or multicyclic C5-C12cycloalkylenyl is selected from adamantyl, bicyclo[2.2.2]octyl, cubanyl, bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, and bicyclo[3.2.1]octyl. In certain embodiments, the optionally substituted bridged bicyclic or multicyclic C5-C12 cycloalkylenyl is selected from: , , , , , , , , and . In certain embodiments, the substituted bridged bicyclic or multicyclic C5-C12 cycloalkylenyl is a structure selected from , , , , , , , , and , wherein one or more C-H bonds are substituted.

[0291] In certain embodiments, R6and R7taken together form an optionally substituted bridged bicyclic or multicyclic C5-C12cycloalkylenyl. In certain embodiments, the optionally substituted bridged bicyclic or multicyclic C5-C12 cycloalkylenyl is selected from: , , , and .

[0292] R8and R9

[0293] As disclosed in Formula (AT), in certain embodiments, R8and R9are each independently optionally substituted C1-C14aliphatic, wherein one or more methylene linkages are each optionally and independently replaced with an optionally substituted C3-C8cycloalkylenyl, an optionally substituted bridged bicyclic or multicyclic C5-C12cycloalkylenyl, phenyl, -O-, -NH-, -S-, - SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-.

[0294] In certain embodiments, R8and R9are the same. In certain embodiments, R8and R9are different.

[0295] In certain embodiments, R8is optionally substituted C1-C14aliphatic. In certain embodiments, R8is optionally substituted C1-C14 alkyl. In certain embodiments, R8is optionally substituted C1-C14 branched alkyl. In certain embodiments, R8is optionally substituted C1-C14 straight chain alkyl. In certain embodiments, R8is optionally substituted C1-C14 alkenyl. In certain embodiments, R8is optionally substituted C1-C14branched alkenyl. In certain embodiments, R8is optionally substituted C1-C14straight chain alkenyl. In certain embodiments, R8is optionally substituted C6-C10alkyl. In certain embodiments, R8is optionally substituted –(CH2)5CH3. In certain embodiments, R8is optionally substituted –(CH2)6CH3. In certain embodiments, R8is optionally substituted –(CH2)7CH3. In certain embodiments, R8is optionally substituted –(CH2)8CH3. In certain embodiments, R8is optionally substituted –(CH2)9CH3.

[0296] In certain embodiments, one of the methylene linkages of R8is replaced with an optionally substituted C3-C8cycloalkylenyl, an optionally substituted bridged bicyclic or multicyclic C5-C12cycloalkylenyl. In certain embodiments, the optionally substituted bridged bicyclic or multicyclic C5-C12cycloalkylenyl is selected from: , , , , , , , , and .

[0297] In certain embodiments, R9is optionally substituted C1-C14aliphatic. In certain embodiments, R9is optionally substituted C1-C14alkyl. In certain embodiments, R9is optionally substituted C1-C14branched alkyl. In certain embodiments, R9is optionally substituted C1-C14straight chain alkyl. In certain embodiments, R9is optionally substituted C1-C14alkenyl. In certain embodiments, R9is optionally substituted C1-C14 branched alkenyl. In certain embodiments, R9is optionally substituted C1-C14 straight chain alkenyl. In certain embodiments, R9is optionally substituted C6-C10 alkyl. In certain embodiments, R9is optionally substituted –(CH2)5CH3. In certain embodiments, R9is optionally substituted –(CH2)6CH3. In certain embodiments, R9is optionally substituted –(CH2)7CH3. In certain embodiments, R9is optionally substituted –(CH2)8CH3. In certain embodiments, R9is optionally substituted –(CH2)9CH3.

[0298] In certain embodiments, one of the methylene linkages of R9is replaced with an optionally substituted C3-C8 cycloalkylenyl, an optionally substituted bridged bicyclic or multicyclic C5-C12 cycloalkylenyl. In certain embodiments, the optionally substituted bridged bicyclic or multicyclic C5-C12cycloalkylenyl is selected from:

[0300] In some embodiments, R8and R9taken together form an optionally substituted bridged bicyclic or multicyclic C4-C14 cycloalkyl or optionally substituted bridged bicyclic or multicyclic 4-14 membered heterocyclyl.

[0301] In certain embodiments, each R8and R9are each independently selected from an optionally substituted bridged bicyclic C5-C12 cycloalkylenyl. In certain embodiments, R8is an optionally substituted bridged multicyclic C5-C12 cycloalkylenyl. In certain embodiments, R9is an optionally substituted bridged bicyclic C5-C12 cycloalkylenyl. In certain embodiments, the optionally substituted bridged bicyclic or multicyclic C5-C12 cycloalkylenyl is selected from adamantyl, bicyclo[2.2.2]octyl, cubanyl, bicyclo[l.l.l]pcntyl, bicyclo[2.2.1]hcptyl, bicyclo[3.1.1]hcptyl, and bicyclo[3.2.1]octyL In certain embodiments, the optionally substituted bridged bicyclic or multicyclicC5-C12 cycloalkylenyl is selected from:In certain embodiments, the substituted bridged bicyclic or multicyclic C5-C12 cycloalkylenyl is a structure selected from, and , wherein one or more C-H bonds are substituted.

[0302] In certain embodiments, R8and R9taken together form an optionally substituted bridged bicyclic or multicyclic C5-C12 cycloalkylenyl. In certain embodiments, the optionally substituted bridged bicyclic or multicyclic C5-C12 cycloalkylenyl is selected from:

[0303] In some embodiments, Lipids of the Present Disclosure are selected from any lipid inTable (LB) below or a pharmaceutically acceptable salt thereof:Table (LB). Non-Limiting Examples of Ionizable Lipids of the Present DisclosureSeries “AC”

[0304] Described below are a number of exemplary ionizable lipids of the present disclosure. Formula (AC’)

[0305] In some embodiments, Lipids of the Disclosure have a structure of Formula (AC’) (AC’), or a pharmaceutically acceptable salt thereof, wherein: R1is selected from the group consisting of -NR2, , , , , , , , , , , , , , , , , , , , , , , and ; each R is independently -H or C1-C6 aliphatic; RZis NR2 or OH; XZis optionally substituted C2-C14alkylenyl or optionally substituted C2-C14alkenylenyl;each R3independently selected from is H and C1-6alkyl; X1is a bond or optionally substituted C2-C6aliphatic;Z is , , , , , , , or ; wherein the bond marked with an "*" is attached to X1; X2and X3are each independently optionally substituted C1-C12aliphatic; X4is a bond or C2-C6 aliphatic; Y1and Y2are independently selected from the group consisting of , , , , , , , and ; wherein the bond marked with an "*" is attached to X2for Y1or X3for Y2; R2is optionally substituted C1-C6aliphatic; R3is optionally substituted C1-C6aliphatic; (a) R4is -CH(OR6)(OR7); or (b) if R1is, , , , , , , , , , , , , , , or , R4is -CH(OR6)(OR7), or -CH(R6)(R7); R5is -CH(OR8)(OR9), -CH(R8)(R9), or optionally substituted C1-C14aliphatic, wherein one or more methylene linkages are each optionally and independently replaced with an optionally substituted C3-C8cycloalkylenyl, an optionally substituted bridged bicyclic or multicyclic C5-C12cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-;R6and R7are each independently optionally substituted C1-C14aliphatic, wherein one or more methylene linkages are each optionally and independently replaced with an optionally substituted C3-C8 cycloalkylenyl, an optionally substituted bridged bicyclic or multicyclic C5-C12 cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-; and R8and R9are each independently optionally substituted C1-C14aliphatic, wherein one or more methylene linkages are each optionally and independently replaced with an optionally substituted C3-C8cycloalkylenyl, an optionally substituted bridged bicyclic or multicyclic C5-C12cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-. Formula (AC)

[0306] In some embodiments, Lipids of the Disclosure have a structure of Formula (AC) (AC), or a pharmaceutically acceptable salt thereof, wherein: R1is selected from the group consisting of -NR2, , , , , , , , , , , and ; each R is independently -H or C1-C6 aliphatic; X1is a bond or optionally substituted C2-C6 aliphatic; Z is , , , , , , , or ; wherein the bond marked with an "*" is attached to X1; X2and X3are each independently optionally substituted C1-C12 aliphatic; X4is a bond or C2-C6aliphatic;Y1and Y2are independently selected from the group consisting of , , , , , , , and ; wherein the bond marked with an "*" is attached to X2for Y1or X3for Y2; R2is optionally substituted C1-C6 aliphatic; R3is optionally substituted C1-C6 aliphatic; R4is -CH(OR6)(OR7); R5is -CH(OR8)(OR9), -CH(R8)(R9), or optionally substituted C1-C14aliphatic, wherein one or more methylene linkages are each optionally and independently replaced with an optionally substituted C3- C8cycloalkylenyl, an optionally substituted bridged bicyclic or multicyclic C5-C12cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-; R6and R7are each independently optionally substituted C1-C14 aliphatic, wherein one or more methylene linkages are each optionally and independently replaced with an optionally substituted C3- C8cycloalkylenyl, an optionally substituted bridged bicyclic or multicyclic C5-C12cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-; and R8and R9are each independently optionally substituted C1-C14aliphatic, wherein one or more methylene linkages are each optionally and independently replaced with an optionally substituted C3- C8 cycloalkylenyl, an optionally substituted bridged bicyclic or multicyclic C5-C12 cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-. Formula (AC-A)

[0307] In certain embodiments, Lipids of the Disclosure have a structure of Formula (AC), wherein the Lipids of the Disclosure have a structure of Formula (AC-A): (AC-A), or a pharmaceutically acceptable salt thereof, wherein R1, R, X1, Z, X2, X3, Y1, Y2, R2, R3, R4, R5, R6, R7, R8, and R9are as described in Formula (AC) or (AC’) or as otherwise described in any embodiments below. Formula (AC-B)

[0308] In certain embodiments, Lipids of the Disclosure have a structure of Formula (AC), wherein the Lipids of the Disclosure have a structure of Formula (AC-B):(AC-B), or a pharmaceutically acceptable salt thereof, wherein R1, R, X1, Z, X2, X3, R2, R3, R4, R5, R6, R7, R8, and R9are as described in Formula (AC) or (AC’) or as otherwise described in any embodiments below. Formula (AC-C)

[0309] In certain embodiments, Lipids of the Disclosure have a structure of Formula (AC), wherein the Lipids of the Disclosure have a structure of Formula (AC-C): Y1R4O X2R22 51Y R X O X3R3R1(AC-C), or a pharmaceutically acceptable salt thereof, wherein R1, R, X1, X2, X3, Y1, Y2, R2, R3, R4, R5, R6, R7, R8, and R9are as described in Formula (AC) or (AC’) or as otherwise described in any embodiments below. Formula (AC-D)

[0310] In certain embodiments, Lipids of the Disclosure have a structure of Formula (AC), wherein the Lipids of the Disclosure have a structure of Formula (AC-D): (AC-D), or a pharmaceutically acceptable salt thereof, wherein R1, R, X1, X2, X3, R2, R3, R4, R5, R6, R7, R8, and R9are as described in Formula (AC) or (AC’) or as otherwise described in any embodiments below.Formula (AC-D1)

[0311] In certain embodiments, Lipids of the Disclosure have a structure of Formula (AC), wherein the Lipids of the Disclosure have a structure of Formula (AC-D1): o(AC-D1), or a pharmaceutically acceptable salt thereof, wherein R1, R, X1, R2, R3, R4, R5, R6, R7, R8, and R9are as described in Formula (AC) or (AC’) or as otherwise described in any embodiments below.Formula (AC-D2)

[0312] In certain embodiments, Lipids of the Disclosure have a structure of Formula (AC), wherein the Lipids of the Disclosure have a structure of Formula (AC-D2): o(AC-D2), or a pharmaceutically acceptable salt thereof, wherein R1, R, X1, R2, R3, R4, R5, R6, R7, R8, and R9are as described in Formula (AC) or (AC’) or as otherwise described in any embodiments below.Formula (AC-E)

[0313] In certain embodiments, Lipids of the Disclosure have a structure of Formula (AC), wherein the Lipids of the Disclosure have a structure of Formula (AC-E):(AC-E),or a pharmaceutically acceptable salt thereof, wherein R!, R, X1, Z, X2, X3, Y:, Y2, R2, R3, R°, R", R5, and Ryare as described in Formula (AC) or (AC’) or as otherwise described in any embodiments below.Formula (AC-F)

[0314] In certain embodiments, Lipids of the Disclosure have a structure of Formula (AC), wherein the Lipids of the Disclosure have a structure of Formula (AC-F):(AC-F), or a pharmaceutically acceptable salt thereof, wherein R', R, X1, Z, X2, X3, R2, R3, R6, R?, R8, and R9are as described in Formula (AC) or (AC’) or as otherwise described in any embodiments below.Formula (AC-G)

[0315] In certain embodiments, Lipids of the Disclosure have a structure of Formula (AC), wherein the Lipids of the Disclosure have a structure of Formula (AC-G):(AC-G), or a pharmaceutically acceptable salt thereof, wherein R1, R, X1, X2, X2’, Y!, Y2, R2, R3, R5. R7. R8, and R9are as described in Formula (AC) or (AC’) or as otherwise described in any embodiments below.Formula (AC-H)

[0316] In certain embodiments, Lipids of the Disclosure have a structure of Formula (AC), wherein the Lipids of the Disclosure have a structure of Formula (AC-H):(AC-H), or a pharmaceutically acceptable salt thereof, wherein R1, R, X1, X2, X3, R2, R3, R6, R7, R8, and R9are as described in Formula (AC) or (AC’) or as otherwise described in any embodiments below. Formula (AC-I)

[0317] In certain embodiments, Lipids of the Disclosure have a structure of Formula (AC), wherein the Lipids of the Disclosure have a structure of Formula (AC-I): O22R O X R6R1Z O O X1X4X3R7O R3O R8O O R9(AC-I), or a pharmaceutically acceptable salt thereof, wherein R1, R, X1, Z, X2, X3, X4, R2, R3, R6, R7, R8, and R9are as described in Formula (AC) or (AC’) or as otherwise described in any embodiments below.

[0318] In certain embodiments, R1is selected from the group consisting of -NR2,

[0319] In some embodiments, R1is selected from the group consisting of -NR2.

[0321] In certain embodiments, R1is -NR2. In certain embodiments, R1isIn certain embodiments, R . In certain embodiments, R1. In certain embodiments, R1is . In certain embodiments,R1is R . In certain embodiments, R1is R In certain embodiments, R1is. In certain embodiments, R1is In certain embodiments, R1isR . In certain embodiments, R1is R . In certain embodiments, R1is selected from the group consisting of -N(Et)2, -N(Me)(Et), I , and \ . In certain embodiments, R1is -N(Et)2.In certain embodiments, R1is -N(Me)2. In certain embodiments, R1is -N(Me)(Et In certain embodiments, R1is -NHz. In certain embodiments, R1is -N(nPr)2. In certain embodiments, R1is -N(iPr)2. In certain embodiments, R1is -N(Me)(Et). In certain embodiments, R1is I . In certainN<\ | embodiments, R1is \ In certain embodiments, R1is I^ / NH In some embodiments, R1is

[0322] X!

[0323] In certain embodiments, X1is optionally substituted C2-C6 aliphatic. In certain embodiments, X1is optionally substituted C2-C6 alkylene. In certain embodiments, R2is optionally substituted C2 alkylene. In certain embodiments, X1is optionally substituted C3 alkylene. In certain embodiments, X1is optionally substituted C4 alkylene. In certain embodiments, X1is optionally substituted Cs alkylene. In certain embodiments, X1is optionally substituted Ce alkylene. In certain embodiments, X1is -(012)2-. In certain embodiments, X1is -(012)3-. In certain embodiments, X1is - (012)4-. In certain embodiments, X1is -(012)5-. In certain embodiments, X1is -(CH2)6-. In certain embodiments, X1is a bond.Z

[0324] In certain embodiments, Lipids of the Disclosure have a structure of Formula (AC), with an is attached to X1. In certain embodiments, Lipids of the Disclosure have a structure ofOFormula (AC), (AC-A), (AC-B), (AC-E), (AC-F), or (AC-I), Z is . In certain embodiments,Lipids of the Disclosure have a structure of Formula (AC), (AC-A), (AC-B), (AC-E), (AC-F), or (AC-OI), Z is f . In certain embodiments. Lipids of the Disclosure have a structure of FormulaO(AC), (AC-A), (AC-B), (AC-E), (AC-F), or (AC-I), Z is . in certain embodiments, Lipids of the Disclosure have a structure of Formula (AC), (AC-A), (AC-B), (AC-E), (AC-F), or (AC-I), Z isOA A yO O in certain embodiments, Lipids of the Disclosure have a structure of Formula (AC),(AC-A), (AC-B), (AC-E), (AC-F), or (AC-I), Z is . In certain embodiments, Lipids of the Disclosure have a structure of Formula (AC), (AC-A), (AC-B), (AC-E), (AC-F), or (AC-I), Y1is . In certain embodiments, Lipids of the Disclosure have a structure of Formula (AC), (AC- A), (AC-B), (AC-E), (AC-F), or (AC-I), Z is . In certain embodiments, Lipids of the Disclosure have a structure of Formula (AC), (AC-A), (AC-B), (AC-E), (AC-F), or (AC-I), Z is . X2and X3

[0325] In certain embodiments, X2and X3are each independently optionally substituted C1- C12aliphatic. In certain embodiments, X2and X3are the same. In certain embodiments, X2and X3are different.

[0326] In certain embodiments, X2is an optionally substituted C1-C12 alkylene. In certain embodiments, X2is an optionally substituted C1-C12alkenylene. I In certain embodiments, X2is an optionally substituted C1-C10aliphatic. In certain embodiments, X2is an optionally substituted C1-C10alkylene. In certain embodiments, X2is an optionally substituted C1-C10alkenylene. In certain embodiments, X2is an optionally substituted C1-C8aliphatic. In certain embodiments, X2is an optionally substituted C1-C8 alkylene. In certain embodiments, X2is an optionally substituted C1-C8 alkenylene. In certain embodiments, X2is an optionally substituted C1-C6 aliphatic. In certain embodiments, X2is an optionally substituted C1-C6 alkylene. In certain embodiments, X2is an optionally substituted C1-C6alkenylene. In certain embodiments, X2is an optionally substituted C2- C12aliphatic. In certain embodiments, X2is an optionally substituted C2-C12alkylene. In certain embodiments, X2is an optionally substituted C2-C12alkenylene. In certain embodiments, X2is an optionally substituted C4-C12 aliphatic. In certain embodiments, X2is an optionally substituted C4-C12 alkylene. In certain embodiments, X2is an optionally substituted C4-C12 alkenylene. In certain embodiments, X2is an optionally substituted C4-C10 aliphatic. In certain embodiments, X2is an optionally substituted C4-C10 alkylene. In certain embodiments, X2is an optionally substituted C4-C10 alkenylene. In certain embodiments, X2is an optionally substituted C6-C8aliphatic. In certain embodiments, X2is an optionally substituted C6-C8alkylene. In certain embodiments, X2is an optionally substituted C6-C8alkenylene. In certain embodiments, X2is –(CH2)-. In certain embodiments, X2is –(CH2)2-. In certain embodiments, X2is –(CH2)3-. In certain embodiments, X2is – (CH2)4-. In certain embodiments, X2is –(CH2)5-. In certain embodiments, X2is –(CH2)6-. In certainembodiments, X2is –(CH2)7-. In certain embodiments, X2is –(CH2)8-. In certain embodiments, X2is – (CH2)9-. In certain embodiments, X2is –(CH2)10-.

[0327] In certain embodiments, X3is an optionally substituted C1-C12 alkylene. In certain embodiments, X3is an optionally substituted C1-C12 alkenylene. In certain embodiments, X3is an optionally substituted C1-C10aliphatic. In certain embodiments, X3is an optionally substituted C1-C10alkylene. In certain embodiments, X3is an optionally substituted C1-C10alkenylene. In certain embodiments, X3is an optionally substituted C1-C8aliphatic. In certain embodiments, X3is an optionally substituted C1-C8alkylene. In certain embodiments, X3is an optionally substituted C1-C8alkenylene. In certain embodiments, X3is an optionally substituted C1-C6 aliphatic. In certain embodiments, X3is an optionally substituted C1-C6 alkylene. In certain embodiments, X3is an optionally substituted C1-C6 alkenylene. In certain embodiments, X3is an optionally substituted C2- C12aliphatic. In certain embodiments, X3is an optionally substituted C2-C12alkylene. In certain embodiments, X3is an optionally substituted C2-C12alkenylene. In certain embodiments, X3is an optionally substituted C4-C12aliphatic. In certain embodiments, X3is an optionally substituted C4-C12alkylene. In certain embodiments, X3is an optionally substituted C4-C12 alkenylene. In certain embodiments, X3is an optionally substituted C4-C10 aliphatic. In certain embodiments, X3is an optionally substituted C4-C10 alkylene. In certain embodiments, X3is an optionally substituted C4-C10 alkenylene. In certain embodiments, X3is an optionally substituted C6-C8 aliphatic. In certain embodiments, X3is an optionally substituted C6-C8alkylene. In certain embodiments, X3is an optionally substituted C6-C8alkenylene. In certain embodiments, X3is –(CH2)-. In certain embodiments, X3is –(CH2)2-. In certain embodiments, X3is –(CH2)3-. In certain embodiments, X3is – (CH2)4-. In certain embodiments, X3is –(CH2)5-. In certain embodiments, X3is –(CH2)6-. In certain embodiments, X3is –(CH2)7-. In certain embodiments, X3is –(CH2)8-. In certain embodiments, X3is – (CH2)9-. In certain embodiments, X3is –(CH2)10-.

[0328] In certain embodiments, X2and X3are both –(CH2)8-. In certain embodiments, X2and X3are both –(CH2)6-. X4

[0329] In certain embodiments, Lipids of the Disclosure have a structure of Formula (AC) or (AC-I), wherein X4is a bond or C2-C6 aliphatic. In certain embodiments, Lipids of the Disclosure have a structure of Formula (AC) or (AC-I), wherein X4is a bond. In certain embodiments, Lipids of the Disclosure have a structure of Formula (AC) or (AC-I), wherein X4is C2-C6aliphatic. In certain embodiments, Lipids of the Disclosure have a structure of Formula (AC) or (AC-I), wherein X4is C2aliphatic. In certain embodiments, Lipids of the Disclosure have a structure of Formula (AC) or (AC- I), wherein X4is C3 aliphatic. In certain embodiments, Lipids of the Disclosure have a structure of Formula (AC) or (AC-I), wherein X4is C4 aliphatic. In certain embodiments, Lipids of the Disclosurehave a structure of Formula (AC) or (AC-I), wherein X4is C5aliphatic. In certain embodiments, Lipids of the Disclosure have a structure of Formula (AC) or (AC-I), wherein X4is C6aliphatic. Y1and Y2

[0330] In certain embodiments, Y1and Y2are each independently , , , , , , , or , wherein the bond marked with an "*" is attached to X2for Y1or X3for Y2.. In certain embodiments, Y1and Y2are the same. In certain embodiments, Y1and Y2are different.

[0331] In certain embodiments, Y1is . In certain embodiments, Y1is . In certain embodiments, Y1is . In certain embodiments, Y1is . In certain embodiments, Y1is . In certain embodiments, Y1is . In certain embodiments, Y1is . In certain embodiments, Y1is . In certain embodiments, Y2is . In certain embodiments, Y2is . In certain embodiments, Y2is . In certain embodiments, Y2is . In certain embodiments, Y2is . In certain embodiments, Y2is . In certain embodiments, Y2is . In certain embodiments, Y2is . In certain embodiments, Y1and Y2are both . In certain embodiments, Y1and Y2are both . R2

[0332] In certain embodiments, R2is optionally substituted C1-C6aliphatic. In certain embodiments, R2is optionally substituted C1-C6alkylene. In certain embodiments, R2is optionally substituted methylene. In certain embodiments, R2is optionally substituted C2 alkylene. In certainembodiments, R2is optionally substituted C3alkylene. In certain embodiments, R2is optionally substituted C4alkylene. In certain embodiments, R2is optionally substituted C5alkylene. In certain embodiments, R2is optionally substituted C6 alkylene. In certain embodiments, R2is –(CH2)-. In certain embodiments, R2is –(CH2)2-. In certain embodiments, R2is –(CH2)3-. In certain embodiments, R2is –(CH2)4-. In certain embodiments, R2is –(CH2)5-. In certain embodiments, R2is –(CH2)6-. R3

[0333] In certain embodiments, R3is optionally substituted C1-C6aliphatic. In certain embodiments, R3is optionally substituted C1-C6alkylene. In certain embodiments, R3is optionally substituted methylene. In certain embodiments, R3is optionally substituted C2 alkylene. In certain embodiments, R3is optionally substituted C3 alkylene. In certain embodiments, R3is optionally substituted C4 alkylene. In certain embodiments, R3is optionally substituted C5 alkylene. In certain embodiments, R3is optionally substituted C6alkylene. In certain embodiments, R3is –(CH2)-. In certain embodiments, R3is –(CH2)2-. In certain embodiments, R3is –(CH2)3-. In certain embodiments, R3is –(CH2)4-. In certain embodiments, R3is –(CH2)5-. In certain embodiments, R3is –(CH2)6-.

[0334] In certain embodiments, R2and R3are the same. In certain embodiments, R2and R3are different. R4

[0335] In certain embodiments, R4is -CH(OR6)(OR7). In certain embodiments, R4is - CH(R6)(R7).

[0336] In certain embodiments, R4is selected from , , , , and . R5

[0337] In certain embodiments, R5is optionally substituted C1-C14 aliphatic, - CH(OR8)(OR9); or -CH(R8)(R9). In certain embodiments, R5is optionally substituted C1-C14 aliphatic, wherein one or more methylene linkages are each optionally and independently replaced with an optionally substituted C3-C8cycloalkylenyl, an optionally substituted bridged bicyclic or multicyclic C5-C12cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or - C(O)O-. In certain embodiments, R5is optionally substituted C1-C14aliphatic. In certain embodiments, R5is -CH(OR8)(OR9) . In certain embodiments, R5is -CH(R8)(R9).

[0338] In certain embodiments, one of the methylene linkages of R5is replaced with an optionally substituted C3-C8 cycloalkylenyl, an optionally substituted bridged bicyclic or multicyclic C5-C12 cycloalkylenyl. In certain embodiments, the optionally substituted bridged bicyclic or multicyclic C5-C12 cycloalkylenyl is selected from:

[0339] , , , , , , , , and .

[0340] In certain embodiments, R4and R5are the same. In certain embodiments, R4and R5are different.

[0341] In certain embodiments, R5is selected from , , , , , , , , and .

[0342] In certain embodiments, R5is selected from , , , , and .R6and R7

[0343] In certain embodiments, R6and R7are each independently optionally substituted C1- C14 aliphatic, wherein one or more methylene linkages are each optionally and independently replaced with an optionally substituted C3-C8 cycloalkylenyl, an optionally substituted bridged bicyclic or multicyclic C5-C12cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, - NHC(O)- or -C(O)O-.

[0344] In certain embodiments, R6and R7are the same. In certain embodiments, R6and R7are different.

[0345] In certain embodiments, R6is optionally substituted C1-C14 aliphatic. In certain embodiments, R6is optionally substituted C1-C14 alkylene. In certain embodiments, R6is optionally substituted C1-C14branched alkylene. In certain embodiments, R6is optionally substituted C1-C14straight chain alkylene. In certain embodiments, R6is optionally substituted C1-C14alkenylene. In certain embodiments, R6is optionally substituted C1-C14branched alkenylene. In certain embodiments, R6is optionally substituted C1-C14 straight chain alkenylene. In certain embodiments, R6is optionally substituted C6-C10 alkylene. In certain embodiments, R6is optionally substituted – (CH2)5CH3. In certain embodiments, R6is optionally substituted –(CH2)6CH3. In certain embodiments, R6is optionally substituted –(CH2)7CH3. In certain embodiments, R6is optionally substituted – (CH2)8CH3. In certain embodiments, R6is optionally substituted –(CH2)9CH3.

[0346] In certain embodiments, one of the methylene linkages of R6is replaced with an optionally substituted C3-C8 cycloalkylenyl, an optionally substituted bridged bicyclic or multicyclic C5-C12 cycloalkylenyl. In certain embodiments, the optionally substituted bridged bicyclic or multicyclic C5-C12 cycloalkylenyl is selected from: , , , , , , , , and .

[0347] In certain embodiments, R7is optionally substituted C1-C14 aliphatic. In certain embodiments, R7is optionally substituted C1-C14alkylene. In certain embodiments, R7is optionally substituted C1-C14branched alkylene. In certain embodiments, R7is optionally substituted C1-C14straight chain alkylene. In certain embodiments, R7is optionally substituted C1-C14alkenylene. In certain embodiments, R7is optionally substituted C1-C14branched alkenylene. In certain embodiments, R7is optionally substituted C1-C14 straight chain alkenylene. In certain embodiments, R7is optionally substituted C6-C10 alkylene. In certain embodiments, R7is optionally substituted –(CH2)5CH3. In certain embodiments, R7is optionally substituted –(CH2)6CH3. In certain embodiments, R7is optionally substituted –(CH2)7CH3. In certain embodiments, R7is optionally substituted – (CH2)8CH3. In certain embodiments, R6is optionally substituted –(CH2)9CH3.

[0348] In certain embodiments, one of the methylene linkages of R7is replaced with an optionally substituted C3-C8cycloalkylenyl, an optionally substituted bridged bicyclic or multicyclic C5-C12cycloalkylenyl. In certain embodiments, the optionally substituted bridged bicyclic or multicyclic C5-C12cycloalkylenyl is selected from: , , , , , , , , and .

[0349] In certain embodiments, R6and R7are selected from , , , , , and . R8and R9

[0350] In certain embodiments, R8and R9are each independently optionally substituted C1- C14aliphatic, wherein one or more methylene linkages are each optionally and independently replaced with an optionally substituted C3-C8 cycloalkylenyl, an optionally substituted bridged bicyclic or multicyclic C5-C12 cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, - NHC(O)- or -C(O)O-.

[0351] In certain embodiments, R8and R9are the same. In certain embodiments, R8and R9are different.

[0352] In certain embodiments, R8is optionally substituted C1-C14 aliphatic. In certain embodiments, R8is optionally substituted C1-C14 alkylene. In certain embodiments, R8is optionally substituted C1-C14 branched alkylene. In certain embodiments, R8is optionally substituted C1-C14 straight chain alkylene. In certain embodiments, R8is optionally substituted C1-C14alkenylene. In certain embodiments, R8is optionally substituted C1-C14branched alkenylene. In certain embodiments, R8is optionally substituted C1-C14straight chain alkenylene. In certain embodiments,R8is optionally substituted C6-C10alkylene. In certain embodiments, R8is optionally substituted – (CH2)5CH3. In certain embodiments, R8is optionally substituted –(CH2)6CH3. In certain embodiments, R8is optionally substituted –(CH2)7CH3. In certain embodiments, R8is optionally substituted – (CH2)8CH3. In certain embodiments, R8is optionally substituted –(CH2)9CH3.

[0353] In certain embodiments, one of the methylene linkages of R8is replaced with an optionally substituted C3-C8cycloalkylenyl, an optionally substituted bridged bicyclic or multicyclic C5-C12cycloalkylenyl. In certain embodiments, the optionally substituted bridged bicyclic or multicyclic C5-C12cycloalkylenyl is selected from: , , , , , , , , and .

[0354] In certain embodiments, R9is optionally substituted C1-C14aliphatic. In certain embodiments, R9is optionally substituted C1-C14 alkylene. In certain embodiments, R9is optionally substituted C1-C14 branched alkylene. In certain embodiments, R9is optionally substituted C1-C14 straight chain alkylene. In certain embodiments, R9is optionally substituted C1-C14 alkenylene. In certain embodiments, R9is optionally substituted C1-C14 branched alkenylene. In certain embodiments, R9is optionally substituted C1-C14straight chain alkenylene. In certain embodiments, R9is optionally substituted C6-C10alkylene. In certain embodiments, R9is optionally substituted – (CH2)5CH3. In certain embodiments, R9is optionally substituted –(CH2)6CH3. In certain embodiments, R9is optionally substituted –(CH2)7CH3. In certain embodiments, R9is optionally substituted – (CH2)8CH3. In certain embodiments, R9is optionally substituted –(CH2)9CH3.

[0355] In certain embodiments, one of the methylene linkages of R9is replaced with an optionally substituted C3-C8cycloalkylenyl, an optionally substituted bridged bicyclic or multicyclic C5-C12cycloalkylenyl. In certain embodiments, the optionally substituted bridged bicyclic or multicyclic C5-C12cycloalkylenyl is selected from:

[0357] In some embodiments, Lipids of the Present Disclosure are selected from any lipid inTable (I-C) below or a pharmaceutically acceptable salt thereof:Table (I-C). Non-Limiting Examples of Ionizable Lipids of the Present DisclosureSeries “CO”

[0358] Described below are a number of exemplary ionizable lipids of the present disclosure.

[0359] The present disclosure provides compound of Formula (CO’):(CO’), or a pharmaceutically acceptable salt thereof, wherein:R1is selected from the group consisting of -OH, -N(R)2, , , , , , , , , , , , , , , , , , , , , , , and ; each R is independently -H or C1-C6aliphatic; RZis NR2 or OH; XZis optionally substituted C2-C14 alkylenyl or optionally substituted C2-C14 alkenylenyl;each R3independently selected from is H and C1-6alkyl; each R is independently -H or C1-C6aliphatic; X1is optionally substituted C2-C6aliphatic, wherein one or more methylene linkages are each optionally and independently replaced with -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-; X2is selected from the group consisting of a bond, -CH2- and -CH2CH2-; X3is selected from the group consisting of a bond, -CH2- and -CH2CH2-; X4and X5are each independently optionally substituted C1-C10 aliphatic; Y1and Y2are each independently , , , , , , , or ; wherein the bond marked with an "*" is attached to X4or X5; R2is optionally substituted C1-C6aliphatic;R3is optionally substituted C1-C6aliphatic; R4is -CH(OR6)(OR7); -CH(SR6)(SR7); -CH(R6)(R7); or optionally substituted C1-C14aliphatic, wherein one or more methylene linkages are each optionally and independently replaced with an optionally substituted C3-C8 cycloalkylenyl, an optionally substituted bridged bicyclic or multicyclic C5-C12 cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-; R5is -CH(OR8)(OR9); -CH(SR8)(SR9); -CH(R8)(R9) or optionally substituted C1-C14aliphatic, wherein one or more methylene linkages are each optionally and independently replaced with an optionally substituted C3-C8 cycloalkylenyl, an optionally substituted bridged bicyclic or multicyclic C5-C12 cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-; R6and R7are each independently optionally substituted C1-C14 aliphatic, wherein one or more methylene linkages are each optionally and independently replaced with an optionally substituted C3-C8cycloalkylenyl, an optionally substituted bridged bicyclic or multicyclic C5- C12cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or - C(O)O-; and R8and R9are each independently optionally substituted C1-C14 aliphatic, wherein one or more methylene linkages are each optionally and independently replaced with an optionally substituted C3-C8cycloalkylenyl, an optionally substituted bridged bicyclic or multicyclic C5- C12cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or - C(O)O-.

[0360] The present disclosure provides compound of Formula (CO): (CO), or a pharmaceutically acceptable salt thereof, wherein: R1is selected from the group consisting of -NR2,, , , , , , , , , , and ; each R is independently -H or C1-C6aliphatic; X1is optionally substituted C2-C6aliphatic, wherein one or more methylene linkages are each optionally and independently replaced with -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-; X2is selected from the group consisting of a bond, -CH2- and -CH2CH2-; X3is selected from the group consisting of a bond, -CH2- and -CH2CH2-; X4and X5are each independently optionally substituted C1-C10aliphatic; Y1and Y2are each independently , , , , , , , or ; wherein the bond marked with an "*" is attached to X4or X5; R2is optionally substituted C1-C6aliphatic; R3is optionally substituted C1-C6aliphatic; R4is -CH(OR6)(OR7); -CH(SR6)(SR7); -CH(R6)(R7); or optionally substituted C1-C14 aliphatic, wherein one or more methylene linkages are each optionally and independently replaced with an optionally substituted C3-C8 cycloalkylenyl, an optionally substituted bridged bicyclic or multicyclic C5-C12cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-; R5is -CH(OR8)(OR9); -CH(SR8)(SR9); -CH(R8)(R9) or optionally substituted C1-C14aliphatic, wherein one or more methylene linkages are each optionally and independently replaced with an optionally substituted C3-C8 cycloalkylenyl, an optionally substituted bridged bicyclic or multicyclic C5-C12 cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-; R6and R7are each independently optionally substituted C1-C14aliphatic, wherein one or more methylene linkages are each optionally and independently replaced with an optionally substituted C3-C8cycloalkylenyl, an optionally substituted bridged bicyclic or multicyclic C5-C12cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or - C(O)O-; and R8and R9are each independently optionally substituted C1-C14 aliphatic, wherein one or more methylene linkages are each optionally and independently replaced with an optionally substituted C3-C8 cycloalkylenyl, an optionally substituted bridged bicyclic or multicyclic C5- C12cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or - C(O)O-.

[0361] In certain embodiments, the compound of Formula (CO) is a compound of Formula (CO-A): (CO-A), or a pharmaceutically acceptable salt thereof, wherein R1, R, X1, X2, X3, X4, X5, Y1, Y2, R2, R3, R4, R5, R6, R7, R8, and R9are as described in Formula (CO) or (CO’) or as otherwise described in any embodiments below.

[0362] In certain embodiments, the compound of Formula (CO) is a compound of Formula (CO-B): (CO-B), or a pharmaceutically acceptable salt thereof, wherein R1, R, X1, X4, X5, Y1, Y2, R2, R3, R4, R5, R6, R7, R8, and R9are as described in Formula (CO) or (CO’) or as otherwise described in any embodiments below.

[0363] In certain embodiments, the compound of Formula (CO) is a compound of Formula (CO-C): (CO-C),or a pharmaceutically acceptable salt thereof, wherein R1, R, X1, X4, X5, Y1. Y2, R2, R3, R4, R3, R°, R', Rs, and R-' are as described in Formula (CO) or (CO’) or as otherwise described in any embodiments below.

[0364] In certain embodiments, the compound of Formula (CO) is a compound of Formula (CO-D):(CO-D), or a pharmaceutically acceptable salt thereof, wherein R', R, X1, Y’, Y2, R2, R’, R4, R\ Rs, R?, Rs, and R9are as described in Formula (CO) or (CO’) or as otherwise described in any embodiments below.

[0365] In certain embodiments, the compound of Formula (CO) is a compound of Formula (CO-E):(CO-E), or a pharmaceutically acceptable salt thereof, wherein R , R, X1, X2, X ’, X4, X’, Y1, Y2, R?, R?, R4, R5, R”, R', Ry and R4are as described in Formula (CO) or (CO’) or as otherwise described in any embodiments below.

[0366] In certain embodiments, the compound of Formula (CO) is a compound of Formula (CO-F):(CO-F),or a pharmaceutically acceptable salt thereof, wherein R!, R, X1, X4, X5, Y1. Y2, R2, R3, R°, R', R5, and R"' are as described in Formula (CO) or (CO’) or as otherwise described in any embodiments below.

[0367] In certain embodiments, the compound of Formula (CO) is a compound of Formula(CO-F’):(CO-F’), or a pharmaceutically acceptable salt thereof, wherein R1, R, X1, X4, Xs, Y’, Y2R2R3, R6, R?, R8, and Ryare as described in Formula (CO) or (CO’) or as otherwise described in any embodiments below.

[0368] In certain embodiments, the compound of Formula (CO) is a compound of Formula(CO-G):R7(CO-G), or a pharmaceutically acceptable salt thereof, wherein R1, R, X1, X4, X , Y!, Y2, R2, R3, R6, R7, R8, and R9are as described in Formula (CO) or (CO’) or as otherwise described in any embodiments below.

[0369] In certain embodiments, the compound of Formula (CO) is a compound of Formula(CO-G’):R7 / RS R6O \ o(CO-G’), or a pharmaceutically acceptable salt thereof, wherein R‘, R, X1, X4, X\ Y!, Y2, R2, R3, R6, R7. R8. and R’ are as described in Formula (CO) or (CO’) or as otherwise described in any embodiments below.

[0370] In certain embodiments, the compound of Formula (CO) is a compound of Formula (CO-H):R7d R6O. )-o V— R2d\ O-R8R3— R1 1 J O— / O-R9x1°xx0(CO-H), or a pharmaceutically acceptable salt thereof, wherein R', R, X1, Y1, Y2, R2, R’, R6, R7, Rs, and R9are as described in Formula (CO) or (CO’) or as otherwise described in any embodiments below.

[0371] In certain embodiments, the compound of Formula (CO) is a compound of Formula(CO-II’):(CO-H’), or a pharmaceutically acceptable salt thereof, wherein R1, R, X1, Y1, Y2, R2, R3, R6, R7, R8, and R9are as described in Formula (CO) or (CO’) or as otherwise described in any embodiments below.

[0372] In certain embodiments, the compound of Formula (CO) is a compound of Formula (CO-I): (CO-I), or a pharmaceutically acceptable salt thereof, wherein R, X1, X4, X5, Y1, Y2, R2, R3, R6, R7, R8, and R9are as described in Formula (CO) or (CO’) or as otherwise described in any embodiments below.

[0373] In certain embodiments, the compound of Formula (CO) is a compound of Formula (CO-I’):(CO-I’), or a pharmaceutically acceptable salt thereof, wherein R, X1, X4, X5, Y1, Y2, R2, R3, R6, R7, R8, and R9are as described in Formula (CO) or (CO’) or as otherwise described in any embodiments below.

[0374] In certain embodiments, the compound of Formula (CO) is a compound of Formula (CO-J): (CO-J), or a pharmaceutically acceptable salt thereof, wherein R, X1, Y1, Y2, R2, R3, R6, R7, R8, and R9are as described in Formula (CO) or (CO’) or as otherwise described in any embodiments below.

[0375] In certain embodiments, the compound of Formula (CO) is a compound of Formula (CO-J’):(CO-J’), or a pharmaceutically acceptable salt thereof, wherein R, X1, Y1, Y2, R2, R3, R6, R7, R8, and R9are as described in Formula (CO) or (CO’) or as otherwise described in any embodiments below.

[0376] In certain embodiments, the compound of Formula (CO) is a compound of Formula (CO-K): (CO-K), or a pharmaceutically acceptable salt thereof, wherein R, X1, Y1, Y2, R2, R3, R6, R7, R8, and R9are as described in Formula (CO) or (CO’) or as otherwise described in any embodiments below.

[0377] In certain embodiments, the compound of Formula (CO) is a compound of Formula (CO-L): (CO-L), or a pharmaceutically acceptable salt thereof, wherein R, X1, Y1, Y2, R2, R3, R6, R7, R8, and R9are as described in Formula (CO) or (CO’) or as otherwise described in any embodiments below.

[0378] In certain embodiments, the compound of Formula (CO) is a compound of Formula (CO-L’):(CO-L’), or a pharmaceutically acceptable salt thereof, wherein R, X1, Y1, Y2, R2, R3, R6, R7, R8, and R9are as described in Formula (CO) or (CO’) or as otherwise described in any embodiments below.

[0379] In certain embodiments, the compound of Formula (CO) is a compound of Formula (CO-M): (CO-M), or a pharmaceutically acceptable salt thereof, wherein R, X1, Y1, Y2, R2, R3, R6, R7, R8, and R9are as described in Formula (CO) or (CO’) or as otherwise described in any embodiments below.

[0380] In certain embodiments, the compound of Formula (CO) is a compound of Formula (CO-M’):(CO-M’), or a pharmaceutically acceptable salt thereof, wherein R, X1, Y1, Y2, R2, R3, R6, R7, R8, and R9are as described in Formula (CO) or (CO’) or as otherwise described in any embodiments below.

[0381] In certain embodiments, the compound of Formula (CO) is a compound of Formula (CO-N): (CO-N), or a pharmaceutically acceptable salt thereof, wherein R, X1, X4, X5, Y1, Y2, R2, R3, R6, R7, R8, and R9are as described in Formula (CO) or (CO’) or as otherwise described in any embodiments below.

[0382] In certain embodiments, the compound of Formula (CO) is a compound of Formula (CO-N’):R7(CO-N’), or a pharmaceutically acceptable salt thereof, wherein R, X1, X4, X\ Y!, Y R2, R3, R", R', R8, and R“ are. as described in Formula (CO) or (CO’) or as otherwise described in any embodiments below.

[0383] In certain embodiments, the compound of Formula (CO) is a compound of Formula(CO-O):(CO-O), or a pharmaceutically acceptable salt thereof, wherein R, X4, X2*, Y1, Y2, R2, R3, R6, R', R8, and R9are as described in Formula (CO) or (CO’) or as otherwise described in any embodiments below.

[0384] In certain embodiments, the compound of Formula (CO) is a compound of Formula (CO-O’):(CO-O’), or a pharmaceutically acceptable salt thereof, wherein R, X4, X3, Y1, Y2, R2, R3, R6, R7, R8, and R9are as described in Formula (CO) or (CO’) or as otherwise described in any embodiments below.

[0385] As disclosed in Formula (CO), in certain embodiments, R1is selected from the group

[0386] As disclosed in Formula (CO’), in certain embodiments, R1is selected from the group consisting ofIn certain embodiments, R1is -NR2. In certain embodiments, R1is . In certainSR'N^N^ embodiments, R1is R . In certain embodiments, R is R . In certain embodiments, R1is In certain embodiments,RR1is R . In certain embodiments, R1is . In certain embodiments, R1isIn certain embodiments, R1isR . In certain embodiments, R1is R

[0387] In certain embodiments, R1is -N(Et)2. In certain embodiments, R1is -N(Me)2. In certain embodiments, R1is -NH2. In certain embodiments, R1is -N(nPr)2. In certain embodiments,R1is -N(iPr)2. In certain embodiments, R1is -N(Me)(Et). In certain embodiments, R1is TH

[0388] As disclosed in Formula (CO), in certain embodiments, X1is optionally substituted CO-CG aliphatic, wherein one or more methylene linkages are each optionally and independently replaced with -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -NHC(O)- or -C(O)O-. In certain embodiments, X1is optionally substituted C2-C6 aliphatic. In certain embodiments, X1is optionally substituted CI-CG alkylene. In certain embodiments, X1is optionally substituted C2 alkylene. In certain embodiments, X1is optionally substituted C3 alkylene. In certain embodiments, X1is optionally substituted C4 alkylene. In certain embodiments, X1is optionally substituted C5 alkylene. In certain embodiments, X1is optionally substituted CG alkylene. In certain embodiments, X1is - (012)2-- In certain embodiments, X1is -(012)3-. In certain embodiments, X1is -(012)4-. In certain embodiments, X1is -(012)5-- In certain embodiments, X1is -(OOG--X2

[0389] As disclosed in Formula (CO), in certain embodiments, X2is selected from the group consisting of a bond, -CH2- and -CH2CH2-. In certain embodiments, X2is a bond. In certain embodiments, X2is -CH2-. In certain embodiments, X2is -CH2CH2-.X3

[0390] As disclosed in Formula (CO), in certain embodiments, X3is selected from the group consisting of a bond, -CH2- and -CH2CH2-. In certain embodiments, X3is a bond. In certain embodiments, X3is -CH2-. In certain embodiments, X3is -CH2CH2-. In certain embodiments, both X2and X3are -CH2-. In certain embodiments, both X2and X3are -CH2CH2-. In certain embodiments, X2is a bond and X3is -CH2-. In certain embodiments, X2is a bond and X3is -CH2CH2-. In certain embodiments, X3is a bond and X2is -CH2-. In certain embodiments, X3is a bond and X2is - CH2CH2-. X4and X5

[0391] As disclosed in Formula (CO), in certain embodiments, X4and X5are each independently optionally substituted C1-C10aliphatic. In certain embodiments, X4and X5are the same. In certain embodiments, X4and X5are different.

[0392] In certain embodiments, X4is an optionally substituted C1-C10alkylene. In certain embodiments, X4is an optionally substituted C1-C10 alkenylene. In certain embodiments, X4is an optionally substituted C1-C6 alkylene. In certain embodiments, X4is an optionally substituted C1-C6 alkenylene. In certain embodiments, X4is –(CH2)-. In certain embodiments, X4is –(CH2)2-. In certain embodiments, X4is –(CH2)3-. In certain embodiments, X4is –(CH2)4-. In certain embodiments, X4is – (CH2)5-. In certain embodiments, X4is –(CH2)6-.

[0393] In certain embodiments, X5is an optionally substituted C1-C10alkylene. In certain embodiments, X5is an optionally substituted C1-C10 alkenylene. In certain embodiments, X5is an optionally substituted C1-C6 alkylene. In certain embodiments, X5is an optionally substituted C1-C6 alkenylene. In certain embodiments, X5is –(CH2)-. In certain embodiments, X5is –(CH2)2-. In certain embodiments, X5is –(CH2)3-. In certain embodiments, X5is –(CH2)4-. In certain embodiments, X5is – (CH2)5-. In certain embodiments, X5is –(CH2)6-.

[0394] In certain embodiments, X4and X5are both –(CH2)-. In certain embodiments, X4and X5are both –(CH2)2-. Y1and Y2

[0395] As disclosed in Formula (CO), in certain embodiments, Y1and Y2are each independently , , , , , , , or , wherein the bond marked with an "*" is attached to X4or X5. In certain embodiments, Y1and Y2are the same. In certain embodiments, Y1and Y2are different.

[0396] In certain embodiments, Y1is . In certain embodiments, Y1is . In certain embodiments, Y1is . In certain embodiments, Y1is . In certain embodiments, Y1is . In certain embodiments, Y1is . In certain embodiments,Y1is . In certain embodiments, Y1is . In certain embodiments, Y2is . In certain embodiments, Y2is . In certain embodiments, Y2is . In certain embodiments, Y2is . In certain embodiments, Y2is . In certain embodiments, Y2is . In certain embodiments, Y2is . In certain embodiments, Y2is . In certain embodiments, Y1and Y2are both . In certain embodiments, Y1and Y2are both . R2

[0397] As disclosed in Formula (CO), in certain embodiments, R2is optionally substituted C1-C6aliphatic. In certain embodiments, R2is optionally substituted C1-C6alkylene. In certain embodiments, R2is optionally substituted methylene. In certain embodiments, R2is optionally substituted C2 alkylene. In certain embodiments, R2is optionally substituted C3 alkylene. In certain embodiments, R2is optionally substituted C4 alkylene. In certain embodiments, R2is optionally substituted C5 alkylene. In certain embodiments, R2is optionally substituted C6 alkylene. In certain embodiments, R2is –(CH2)-. In certain embodiments, R2is –(CH2)2-. In certain embodiments, R2is – (CH2)3-. In certain embodiments, R2is –(CH2)4-. In certain embodiments, R2is –(CH2)5-. In certain embodiments, R2is –(CH2)6-. R3

[0398] As disclosed in Formula (CO), in certain embodiments, R3is optionally substituted C1-C6 aliphatic. In certain embodiments, R3is optionally substituted C1-C6 alkylene. In certain embodiments, R3is optionally substituted methylene. In certain embodiments, R3is optionally substituted C2alkylene. In certain embodiments, R3is optionally substituted C3alkylene. In certain embodiments, R3is optionally substituted C4alkylene. In certain embodiments, R3is optionally substituted C5alkylene. In certain embodiments, R3is optionally substituted C6alkylene. In certain embodiments, R3is –(CH2)-. In certain embodiments, R3is –(CH2)2-. In certain embodiments, R3is – (CH2)3-. In certain embodiments, R3is –(CH2)4-. In certain embodiments, R3is –(CH2)5-. In certain embodiments, R3is –(CH2)6-.

[0399] In certain embodiments, R2and R3are the same. In certain embodiments, R2and R3are different. In certain embodiments, R2and R3are both –(CH2)2-.

[0400] As disclosed in Formula (CO), in certain embodiments, R4is -CH(OR6)(OR7); - CH(SR6)(SR7); -CH(RS)(R7); or optionally substituted C1-C14 aliphatic, wherein one or more methylene linkages are each optionally and independently replaced with an optionally substituted C3- Cx cycloalkylenyl, an optionally substituted bridged bicyclic or multicyclic C5-C12 cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-. In certain embodiments, R4is optionally substituted C1-C14 aliphatic, wherein one or more methylene linkages are each optionally and independently replaced with an optionally substituted C3-C8 cycloalkylenyl, an optionally substituted bridged bicyclic or multicyclic C5-C12 cycloalkylenyl, phenyl, -O-, -NH-, -S- , -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-. In certain embodiments, R4is optionally substituted C1-C14 aliphatic. In certain embodiments, R4is -CH(OR6)(OR7). In certain embodiments, R4is -CH(R6)(R7). In certain embodiments, R4is -CH(SR6)(SR7).

[0402] In certain embodiments, R4is selected fromJ?5

[0403] As disclosed in Formula (CO), in certain embodiments, R5is -CH(OR8)(OR9); - CH(SR8)(SR9); -CH(R8)(R9) or optionally substituted C1-C14 aliphatic, wherein one or more methylene linkages are each optionally and independently replaced with an optionally substituted C3- Q cycloalkylenyl, an optionally substituted bridged bicyclic or multicyclic C5-C12 cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-. In certain embodiments, R5is optionally substituted C1-C14 aliphatic, wherein one or more methylene linkages are each optionally and independently replaced with an optionally substituted C3-C8 cycloalkylenyl, an optionally substituted bridged bicyclic or multicyclic C5-C12 cycloalkylenyl, phenyl, -O-, -NH-, -S- , -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-. In certain embodiments, R5is optionally substituted C1-C14 aliphatic. In certain embodiments, R3is -CH(OR8)(OR9) . In certain embodiments, R3is -CH(R8)(R9). In certain embodiments, R5is -CH(SR8)(SR9).

[0404] In certain embodiments, R4and R3are the same. In certain embodiments, R4and R5are different., , , , , and .

[0406] In certain embodiments, R5is selected from , , , . R6and R7

[0407] As disclosed in Formula (CO), in certain embodiments, R6and R7are each independently optionally substituted C1-C14aliphatic, wherein one or more methylene linkages are each optionally and independently replaced with an optionally substituted C3-C8cycloalkylenyl, an optionally substituted bridged bicyclic or multicyclic C5-C12cycloalkylenyl, phenyl, -O-, -NH-, -S-, - SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-.

[0408] In certain embodiments, R6and R7are the same. In certain embodiments, R6and R7are different.

[0409] In certain embodiments, R6is optionally substituted C1-C14aliphatic. In certain embodiments, R6is optionally substituted C1-C14alkyl. In certain embodiments, R6is optionally substituted C1-C14branched alkyl. In certain embodiments, R6is optionally substituted C1-C14straight chain alkyl. In certain embodiments, R6is optionally substituted C1-C14 alkenyl. In certain embodiments, R6is optionally substituted C1-C14 branched alkenyl. In certain embodiments, R6is optionally substituted C1-C14 straight chain alkenyl. In certain embodiments, R6is optionally substituted C6-C10alkyl. In certain embodiments, R6is optionally substituted –(CH2)5CH3. In certain embodiments, R6is optionally substituted –(CH2)6CH3. In certain embodiments, R6is optionally substituted –(CH2)7CH3. In certain embodiments, R6is optionally substituted –(CH2)8CH3. In certain embodiments, R6is optionally substituted –(CH2)9CH3.

[0410] In certain embodiments, one of the methylene linkages of R6is replaced with an optionally substituted C3-C8 cycloalkylenyl, an optionally substituted bridged bicyclic or multicyclic C5-C12 cycloalkylenyl. In certain embodiments, the optionally substituted bridged bicyclic or multicyclic C5-C12 cycloalkylenyl is selected from: , , , , , , , , and .

[0411] In certain embodiments, R7is optionally substituted C1-C14 aliphatic. In certain embodiments, R7is optionally substituted C1-C14 alkyl. In certain embodiments, R7is optionally substituted C1-C14branched alkyl. In certain embodiments, R7is optionally substituted C1-C14straight chain alkyl. In certain embodiments, R7is optionally substituted C1-C14alkenyl. In certain embodiments, R7is optionally substituted C1-C14branched alkenyl. In certain embodiments, R7is optionally substituted C1-C14 straight chain alkenyl. In certain embodiments, R7is optionally substituted C6-C10 alkyl. In certain embodiments, R7is optionally substituted –(CH2)5CH3. In certain embodiments, R7is optionally substituted –(CH2)6CH3. In certain embodiments, R7is optionally substituted –(CH2)7CH3. In certain embodiments, R7is optionally substituted –(CH2)8CH3. In certain embodiments, R6is optionally substituted –(CH2)9CH3.

[0412] In certain embodiments, one of the methylene linkages of R7is replaced with an optionally substituted C3-C8 cycloalkylenyl, an optionally substituted bridged bicyclic or multicyclic C5-C12 cycloalkylenyl. In certain embodiments, the optionally substituted bridged bicyclic or multicyclic C5-C12 cycloalkylenyl is selected from: , , , , , , , , and .

[0413] In certain embodiments, R6and R7are selected from

[0414] In certain embodiments, each R6and R7are each independently selected from an optionally substituted bridged bicyclic C5-C12 cycloalkylenyL In certain embodiments, R6is an optionally substituted bridged multicyclic C5-C12 cycloalkylenyl. In certain embodiments, R7is an optionally substituted bridged bicyclic C5-C12 cycloalkylenyL In certain embodiments, the optionally substituted bridged bicyclic or multicyclic C5-C12 cycloalkylenyl is selected from adamantyl, bicyclo[2.2.2]octyl, cubanyl, bicyclo[l.l.l]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, and bicyclo[3.2.1]octyL In certain embodiments, the optionally substituted bridged bicyclic or multicyclicIn certain embodiments, the substituted bridged bicyclic or multicyclic C5-C12 cycloalkylenyl is a structure selected from or more C-H bonds are substituted.

[0415] In certain embodiments, R6and R7taken together form an optionally substituted bridged bicyclic or multicyclic C5-C12 cycloalkylenyL In certain embodiments, the optionally substituted bridged bicyclic or multicyclic C5-C12 cycloalkylenyl is selected from:Rsand R9

[0416] As disclosed in Formula (CO), in certain embodiments, R8and R9are each independently optionally substituted C1-C14 aliphatic, wherein one or more methylene linkages are each optionally and independently replaced with an optionally substituted C3-C8 cycloalkylenyl, an optionally substituted bridged bicyclic or multicyclic C5-C12 cycloalkylenyl, phenyl, -O-, -NH-, -S-, - SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-.

[0417] In certain embodiments, R8and R9are the same. In certain embodiments, R8and R9are different.

[0418] In certain embodiments, R8is optionally substituted C1-C14 aliphatic. In certain embodiments, R8is optionally substituted C1-C14 alkyl. In certain embodiments, R8is optionally substituted C1-C14 branched alkyl. In certain embodiments, R8is optionally substituted C1-C14 straight chain alkyl. In certain embodiments, R8is optionally substituted C1-C14alkenyl. In certain embodiments, R8is optionally substituted C1-C14branched alkenyl. In certain embodiments, R8is optionally substituted C1-C14straight chain alkenyl. In certain embodiments, R8is optionally substituted C6-C10 alkyl. In certain embodiments, R8is optionally substituted –(CH2)5CH3. In certain embodiments, R8is optionally substituted –(CH2)6CH3. In certain embodiments, R8is optionally substituted –(CH2)7CH3. In certain embodiments, R8is optionally substituted –(CH2)8CH3. In certain embodiments, R8is optionally substituted –(CH2)9CH3.

[0419] In certain embodiments, one of the methylene linkages of R8is replaced with an optionally substituted C3-C8 cycloalkylenyl, an optionally substituted bridged bicyclic or multicyclic C5-C12 cycloalkylenyl. In certain embodiments, the optionally substituted bridged bicyclic or multicyclic C5-C12 cycloalkylenyl is selected from: , , , , , , , , and .

[0420] In certain embodiments, R9is optionally substituted C1-C14 aliphatic. In certain embodiments, R9is optionally substituted C1-C14 alkyl. In certain embodiments, R9is optionally substituted C1-C14branched alkyl. In certain embodiments, R9is optionally substituted C1-C14straight chain alkyl. In certain embodiments, R9is optionally substituted C1-C14alkenyl. In certain embodiments, R9is optionally substituted C1-C14branched alkenyl. In certain embodiments, R9is optionally substituted C1-C14straight chain alkenyl. In certain embodiments, R9is optionally substituted C6-C10 alkyl. In certain embodiments, R9is optionally substituted –(CH2)5CH3. In certain embodiments, R9is optionally substituted –(CH2)6CH3. In certain embodiments, R9is optionallysubstituted –(CH2)7CH3. In certain embodiments, R9is optionally substituted –(CH2)8CH3. In certain embodiments, R9is optionally substituted –(CH2)9CH3.

[0421] In certain embodiments, one of the methylene linkages of R9is replaced with an optionally substituted C3-C8 cycloalkylenyl, an optionally substituted bridged bicyclic or multicyclic C5-C12cycloalkylenyl. In certain embodiments, the optionally substituted bridged bicyclic or multicyclic C5-C12cycloalkylenyl is selected from: , , , , , , , , and .

[0422] In certain embodiments, R8and R9are selected from , , , , , and .

[0423] In some embodiments, R8and R9taken together form an optionally substituted bridged bicyclic or multicyclic C4-C14 cycloalkyl or optionally substituted bridged bicyclic or multicyclic 4-14 membered heterocyclyl.

[0424] In certain embodiments, each R8and R9are each independently selected from an optionally substituted bridged bicyclic C5-C12cycloalkylenyl. In certain embodiments, R8is an optionally substituted bridged multicyclic C5-C12cycloalkylenyl. In certain embodiments, R9is an optionally substituted bridged bicyclic C5-C12 cycloalkylenyl. In certain embodiments, the optionally substituted bridged bicyclic or multicyclic C5-C12 cycloalkylenyl is selected from adamantyl, bicyclo[2.2.2]octyl, cubanyl, bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, and bicyclo[3.2.1]octyl. In certain embodiments, the optionally substituted bridged bicyclic or multicyclic C5-C12cycloalkylenyl is selected from: , , , , , , , , and . In certain embodiments, the substitutedbridged bicyclic or multicyclic C5-C12 cycloalkylenyl is a structure selected from, and , wherein one or more C-H bonds are substituted.

[0425] In certain embodiments, R8and R9taken together form an optionally substituted bridged bicyclic or multicyclic C5-C12 cycloalkylenyl. In certain embodiments, the optionally substituted bridged bicyclic or multicyclic C5-C12 cycloalkylenyl is selected from:

[0426] In some embodiments, Lipids of the Present Disclosure are selected from any lipid inTable (I-D) below or a pharmaceutically acceptable salt thereof:Table (I-D). Non-Limiting Examples of Ionizable Lipids of the Present DisclosureSeries “CC”

[0427] In some embodiments, an LNP disclosed herein comprises an ionizable lipid. In some embodiments, an LNP comprises two or more ionizable lipids.

[0428] Described below are a number of exemplary ionizable lipids of the present disclosure.

[0429] In certain embodiments, the present disclosure provides compound of Formula (CC’) (CC’), or a pharmaceutically acceptable salt thereof, wherein: R1is selected from the group consisting of -OH, -OAc, -NR2, , , , , , , , , , , , , , , , , , , , , , , and ; each R is independently -H or C1-C6 aliphatic; RZis NR2 or OH; XZis optionally substituted C2-C14 alkylenyl or optionally substituted C2-C14 alkenylenyl;each R3independently selected from is H and C1-6alkyl;X1is optionally substituted C2-C6aliphatic, wherein one or more methylene linkages are each optionally and independently replaced with -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-; X2is selected from the group consisting of a bond, -CH2- and -CH2CH2-; X2’is selected from the group consisting of a bond, -CH2- and -CH2CH2-; X3is selected from the group consisting of a bond, -CH2- and -CH2CH2-; X3’is selected from the group consisting of a bond, -CH2- and -CH2CH2-; X4and X5are independently optionally substituted C1-C10aliphatic; Y1and Y2are independently selected from the group consisting of , , , , , , , or ; wherein the bond marked with an "*" is attached to X4or X5; R2is optionally substituted C1-C6aliphatic; R3is optionally substituted C1-C6aliphatic; R4is -CH(OR6)(OR7); -CH(SR6)(SR7); -CH(SR8)(SR9); -CH(R6)(R7); -R10; or optionally substituted C1-C14 aliphatic-R10wherein one or more methylene linkages are each optionally and independently replaced with an optionally substituted C3-C8 cycloalkylenyl, phenyl, -O-, - NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-; R5is -CH(OR8)(OR9); -CH(SR8)(SR9); -CH(R8)(R9); optionally substituted C1-C14aliphatic, wherein one or more methylene linkages are each optionally and independently replaced with an optionally substituted C3-C8 cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, - OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-; -R11; or optionally substituted C1-C14 aliphatic- R11, wherein one or more methylene linkages are each optionally and independently replaced with an optionally substituted C3-C8 cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, - OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-; (a) R6and R7are each independently -R10; optionally substituted -C1-C14aliphatic-R10; wherein one or more methylene linkages are each optionally and independently replaced with an optionally substituted C3-C8 cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-; or(b) if R1is , , , , , , , , , , , , , , , or , R6and R7are each independently optionally substituted -C1-C14aliphatic wherein one or more methylene linkages are each optionally and independently replaced with an optionally substituted C3-C8 cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, - OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-; -R10; optionally substituted -C1-C14 aliphatic- R10; wherein one or more methylene linkages are each optionally and independently replaced with an optionally substituted C3-C8cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS- , -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-; R8and R9are each independently -R11; optionally substituted -C1-C14 aliphatic wherein one or more methylene linkages are each optionally and independently replaced with an optionally substituted C3-C8 cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, - NHC(O)- or -C(O)O-; or optionally substituted -C1-C14 aliphatic-R11wherein one or more methylene linkages are each optionally and independently replaced with an optionally substituted C3-C8cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, - NHC(O)- or -C(O)O-; and each R10and R11is independently an optionally substituted bridged bicyclic or multicyclic C5-C12 cycloalkylenyl, or two R10or two R11taken together form an optionally substituted bridged bicyclic or multicyclic C5-C12 cycloalkylenyl; or each R10and R11is independently an optionally substituted cyclic, bicyclic, bridged bicyclic, multicyclic or bridged multicyclic C4-C14cycloalkyl or optionally substituted cyclic, bicyclic, bridged bicyclic, multicyclic or bridged multicyclic 4-14 membered heterocyclyl, or two R10or two R11taken together form an optionally substituted bridged bicyclic or multicyclic C4- C14 cycloalkyl or optionally substituted bridged bicyclic or multicyclic 4-14 membered heterocyclyl.

[0430] In certain embodiments, the present disclosure also provides compounds of Formula (CC) (CC), or a pharmaceutically acceptable salt thereof, wherein: R1is selected from the group consisting of -OH, -OAc, -NR2, , , , , , , , , , , and ; each R is independently -H or C1-C6 aliphatic; X1is optionally substituted C2-C6 aliphatic, wherein one or more methylene linkages are each optionally and independently replaced with -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-; X2is selected from the group consisting of a bond, -CH2- and -CH2CH2-; X2’is selected from the group consisting of a bond, -CH2- and -CH2CH2-; X3is selected from the group consisting of a bond, -CH2- and -CH2CH2-; X3’is selected from the group consisting of a bond, -CH2- and -CH2CH2-; X4and X5are independently optionally substituted C1-C10 aliphatic; Y1and Y2are independently selected from the group consisting of , , , , , , , or ; wherein the bond marked with an "*" is attached to X4or X5; R2is optionally substituted C1-C6 aliphatic; R3is optionally substituted C1-C6aliphatic;R4is -CH(OR6)(OR7); -CH(SR6)(SR7); -CH(SR8)(SR9); -CH(R6)(R7); -R10; or optionally substituted C1-C14aliphatic-R10wherein one or more methylene linkages are each optionally and independently replaced with an optionally substituted C3-C8 cycloalkylenyl, phenyl, -O-, - NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-; R5is -CH(OR8)(OR9); -CH(SR8)(SR9); -CH(R8)(R9); optionally substituted C1-C14 aliphatic, wherein one or more methylene linkages are each optionally and independently replaced with an optionally substituted C3-C8cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, - OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-; -R11; or optionally substituted C1-C14aliphatic- R11, wherein one or more methylene linkages are each optionally and independently replaced with an optionally substituted C3-C8 cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, - OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-; R6and R7are each independently -R10; optionally substituted -C1-C14 aliphatic-R10; wherein one or more methylene linkages are each optionally and independently replaced with an optionally substituted C3-C8cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-; R8and R9are each independently -R11; optionally substituted -C1-C14 aliphatic wherein one or more methylene linkages are each optionally and independently replaced with an optionally substituted C3-C8 cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, - NHC(O)- or -C(O)O-; or optionally substituted -C1-C14aliphatic-R11wherein one or more methylene linkages are each optionally and independently replaced with an optionally substituted C3-C8cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, - NHC(O)- or -C(O)O-; and each R10and R11is independently an optionally substituted bridged bicyclic or multicyclic C5-C12 cycloalkylenyl, or two R10or two R11taken together form an optionally substituted bridged bicyclic or multicyclic C5-C12 cycloalkylenyl; or each R10and R11is independently an optionally substituted cyclic, bicyclic, bridged bicyclic, multicyclic or bridged multicyclic C4-C14cycloalkyl or optionally substituted cyclic, bicyclic, bridged bicyclic, multicyclic or bridged multicyclic 4-14 membered heterocyclyl, or two R10or two R11taken together form an optionally substituted bridged bicyclic or multicyclic C4- C14 cycloalkyl or optionally substituted bridged bicyclic or multicyclic 4-14 membered heterocyclyl.

[0431] In certain embodiments, the compound of Formula (CC) is a compound of Formula (CC-A):(CC-A), or a pharmaceutically acceptable salt thereof, wherein R‘, R, X‘, X4, X5, Y‘, Y2, R2, R4, R4, R4, R6, R', R8, R9,R10, R1 1, are as described in Formula (CC) or (CC*) or as otherwise described in any embodiments below.

[0432] In certain embodiments, the compound of Formula (CC) is a compound of Formula(CC-B):(CC-B), or a pharmaceutically acceptable salt thereof, wherein R '. R, X1, X4, X5, Y’, Y2, R2, R ’, R4, R ', Rft, R', Rs, R’ R10, R1 1, are as described in Formula (CC) or (CC’) or as otherwise described in any embodiments below.

[0433] In certain embodiments, the compound of Formula (CC) is a compound of Formula(CC-C):(CC-C), or a pharmaceutically acceptable salt thereof, wherein R‘, R, X1, Y1, Y2, R2, RJ, R1, R5, R6, R', Rb, RvRl u, R", are as described in Formula (CC) or (CC) or as otherwise described in any embodiments below.

[0434] In certain embodiments, the compound of Formula (CC) is a compound of Formula(CC-D):(CC-D), or a pharmaceutically acceptable salt thereof, wherein R!, R, X1, Y1, Y2, R2, RJ, R'1, R5, R6, R', Rb, R“ Ri 0, R", are as described in Formula (CC) or (CC’) or as otherwise described in any embodiments below.

[0435] In certain embodiments, the compound of Formula (CC) is a compound of Formula(CC-E):R4(CC-E), or a pharmaceutically acceptable salt thereof, wherein R', R, X!, X*, X\ R?, R1, R4, R R6, R'', R8, R9. R16, R11, are as described in Formula (CC) or (CC’) or as otherwise described in any embodiments below.

[0436] In certain embodiments, the compound of Formula (CC) is a compound of Formula (CC-F):R4(CC-F), or a pharmaceutically acceptable salt thereof, wherein R R, X!, X*, X5, R?, R5, R4, Rs, R\ R8, R9R!°, Rn. are as described in Formula (CC) or (CC’) or as otherwise described in any embodiments below.

[0437] In certain embodiments, the compound of Formula (CC) is a compound of Formula (CC-F’):R4(CC-F’), or a pharmaceutically acceptable salt thereof, wherein R‘, R, X1, X“, X3, R2, R3, R'f, R5, R', R2, R9R!°, R1are as described in Formula (CC) or (CC’) or as otherwise described in any embodiments below.

[0438] In certain embodiments, the compound of Formula (CC) is a compound of Formula (CC-G):R4(CC-G), or a pharmaceutically acceptable salt thereof, wherein X1, X'J, X3, R2, R5, R“, R3, R6, R;, Rs, R9R‘°, R1 !. are as described in Formula (CC) or (CC’) or as otherwise described in any embodiments below.

[0439] In certain embodiments, the compound of Formula (CC) is a compound of Formula (CC-H):R4(CC-H),or a pharmaceutically acceptable salt thereof, wherein X1, X4, X5, R2, R3, R4, R5, R6, R7, R8, R9,R10, R11,are as described in Formula (CC) or (CC’) or as otherwise described in any embodiments below.

[0440] In certain embodiments, the compound of Formula (CC) is a compound of Formula (CC-I): (CC-I), or a pharmaceutically acceptable salt thereof, wherein R1, R, X1, X4, X5, Y1, Y2, R2, R3, R8, R9, R11,are as described in Formula (CC) or (CC’) or as otherwise described in any embodiments below.

[0441] In certain embodiments, the compound of Formula (CC) is a compound of Formula (CC-J): (CC-J), or a pharmaceutically acceptable salt thereof, wherein R1, R, X1, X4, X5, R2, R3, R8, R9,R11,are as described in Formula (CC) or (CC’) or as otherwise described in any embodiments below.

[0442] In certain embodiments, the compound of Formula (CC) is a compound of Formula (CC-K):(CC-K), or a pharmaceutically acceptable salt thereof, wherein R1, R, X1, X4, X5, R2, R3, R8, R9,R11,are as described in Formula (CC) or (CC’) or as otherwise described in any embodiments below.

[0443] In certain embodiments, the compound of Formula (CC) is a compound of Formula (CC-L): (CC-L), or a pharmaceutically acceptable salt thereof, wherein X1, X4, X5, R2, R3, R8, R9,R11,are as described in Formula (CC) or (CC’) or as otherwise described in any embodiments below.

[0444] In certain embodiments, the compound of Formula (CC) is a compound of Formula (CC-M):(CC-M), or a pharmaceutically acceptable salt thereof, wherein X ', X4, X5, R2, R3, R8, R9R1 !, are as described in Formula (CC) or (CC’ ) or as otherwise described in any embodiments below.

[0445] In some embodiments, Lipids of the Disclosure have a structure of Formula (CC’),

[0446] As disclosed in Formula (CC), in certain embodiments, R1is selected from the group

[0447] In certain embodiments, R1is -OH. In certain embodiments, R1is -OAc. In certain embodiments, R1is -NRi. In certain embodiments, R1is In certain embodiments,SR'N I ^N l_l^R1is R . In certain embodiments, R1is certain embodiments, R1is In certain embodiments, R1isIn certain embodiments, R1is R . In certain embodiments, R1is R

[0448] In certain embodiments, R1is -N(Et)2. In certain embodiments, R1is -N(Me)2. In certain embodiments, R1is -NH2. In certain embodiments, R1is -N(nPr)2. In certain embodiments,R1is -N(iPr)2. In certain embodiments, R1is -N(Me)(Et). In certain embodiments, R1is OH. In certain embodiments, R1is . X1

[0449] As disclosed in Formula (CC), in certain embodiments, X1is optionally substituted C2-C6 aliphatic, wherein one or more methylene linkages are each optionally and independently replaced with -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -NHC(O)- or -C(O)O-. In certain embodiments, X1is optionally substituted C2-C6 aliphatic. In certain embodiments, X1is optionally substituted C2-C6alkylene. In certain embodiments, X1is optionally substituted C2alkylene. In certain embodiments, X1is optionally substituted C3alkylene. In certain embodiments, X1is optionally substituted C4alkylene. In certain embodiments, X1is optionally substituted C5alkylene. In certain embodiments, X1is optionally substituted C6alkylene. In certain embodiments, X1is – (CH2)2-. In certain embodiments, X1is –(CH2)3-. In certain embodiments, X1is –(CH2)4-. In certain embodiments, X1is –(CH2)5-. In certain embodiments, X1is –(CH2)6-. X2

[0450] As disclosed in Formula (CC), in certain embodiments, X2is selected from the group consisting of a bond, -CH2- and -CH2CH2-. In certain embodiments, X2is a bond. In certain embodiments, X2is -CH2-. In certain embodiments, X2is -CH2CH2-. X2’

[0451] As disclosed in Formula (CC), in certain embodiments, X2’is selected from the group consisting of a bond, -CH2- and -CH2CH2-. In certain embodiments, X2’is a bond. In certain embodiments, X2’is -CH2-. In certain embodiments, X2’is -CH2CH2-. X3

[0452] As disclosed in Formula (CC), in certain embodiments, X3is selected from the group consisting of a bond, -CH2- and -CH2CH2-. In certain embodiments, X3is a bond. In certain embodiments, X3is -CH2-. In certain embodiments, X3is -CH2CH2-. X3’

[0453] As disclosed in Formula (CC), in certain embodiments, X3’is selected from the group consisting of a bond, -CH2- and -CH2CH2-. In certain embodiments, X3’is a bond. In certain embodiments, X3’is -CH2-. In certain embodiments, X3’is -CH2CH2-.

[0454] In certain embodiments, each of X2, X2’, X3and X3’are each -CH2-. In certain embodiments, both X2and X3are each -CH2-; X3’is a bond, and X2’is -CH2CH2-. X4and X5

[0455] As disclosed in Formula (CC), in certain embodiments, X4and X5are each independently optionally substituted C1-C10 aliphatic. In certain embodiments, X4and X5are the same. In certain embodiments, X4and X5are different.

[0456] In certain embodiments, X4is an optionally substituted C1-C10alkylene. In certain embodiments, X4is an optionally substituted C1-C10 alkenylene. In certain embodiments, X4is an optionally substituted C1-C6 alkylene. In certain embodiments, X4is an optionally substituted C1-C6 alkenylene. In certain embodiments, X4is –(CH2)-. In certain embodiments, X4is –(CH2)2-. In certain embodiments, X4is –(CH2)3-. In certain embodiments, X4is –(CH2)4-. In certain embodiments, X4is – (CH2)5-. In certain embodiments, X4is –(CH2)6-.

[0457] In certain embodiments, X5is an optionally substituted C1-C10alkylene. In certain embodiments, X5is an optionally substituted C1-C10 alkenylene. In certain embodiments, X5is an optionally substituted C1-C6 alkylene. In certain embodiments, X5is an optionally substituted C1-C6 alkenylene. In certain embodiments, X5is –(CH2)-. In certain embodiments, X5is –(CH2)2-. In certain embodiments, X5is –(CH2)3-. In certain embodiments, X5is –(CH2)4-. In certain embodiments, X5is – (CH2)5-. In certain embodiments, X5is –(CH2)6-.

[0458] In certain embodiments, X4and X5are both –(CH2)-. In certain embodiments, X4and X5are both –(CH2)2-. Y1and Y2

[0459] As disclosed in Formula (CC), in certain embodiments, Y1and Y2are each independently , , , , , , , or , wherein the bond marked with an "*" is attached to X4or X5. In certain embodiments, Y1and Y2are the same. In certain embodiments, Y1and Y2are different.

[0460] In certain embodiments, Y1is . In certain embodiments, Y1is . In certain embodiments, Y1is . In certain embodiments, Y1is . In certain embodiments, Y1is . In certain embodiments, Y1is . In certain embodiments, Y1is . In certain embodiments, Y1is . In certain embodiments, Y2is . In certain embodiments, Y2is . In certain embodiments, Y2is . Incertain embodiments, Y2is . In certain embodiments, Y2is . In certain embodiments, Y2is . In certain embodiments, Y2is . In certain embodiments, Y2is . In certain embodiments, Y1and Y2are both . In certain embodiments, Y1and Y2are both . R2

[0461] As disclosed in Formula (CC), in certain embodiments, R2is optionally substituted C1-C6aliphatic. In certain embodiments, R2is optionally substituted C1-C6alkylene. In certain embodiments, R2is optionally substituted methylene. In certain embodiments, R2is optionally substituted C2alkylene. In certain embodiments, R2is optionally substituted C3alkylene. In certain embodiments, R2is optionally substituted C4 alkylene. In certain embodiments, R2is optionally substituted C5 alkylene. In certain embodiments, R2is optionally substituted C6 alkylene. In certain embodiments, R2is –(CH2)-. In certain embodiments, R2is –(CH2)2-. In certain embodiments, R2is – (CH2)3-. In certain embodiments, R2is –(CH2)4-. In certain embodiments, R2is –(CH2)5-. In certain embodiments, R2is –(CH2)6-. R3

[0462] As disclosed in Formula (CC), in certain embodiments, R3is optionally substituted C1-C6 aliphatic. In certain embodiments, R3is optionally substituted C1-C6 alkylene. In certain embodiments, R3is optionally substituted methylene. In certain embodiments, R3is optionally substituted C2alkylene. In certain embodiments, R3is optionally substituted C3alkylene. In certain embodiments, R3is optionally substituted C4alkylene. In certain embodiments, R3is optionally substituted C5alkylene. In certain embodiments, R3is optionally substituted C6alkylene. In certain embodiments, R3is –(CH2)-. In certain embodiments, R3is –(CH2)2-. In certain embodiments, R3is – (CH2)3-. In certain embodiments, R3is –(CH2)4-. In certain embodiments, R3is –(CH2)5-. In certain embodiments, R3is –(CH2)6-.

[0463] In certain embodiments, R2and R3are the same. In certain embodiments, R2and R3are different. In certain embodiments, R2and R3are both –(CH2)2-. R4

[0464] As disclosed in Formula (CC), in certain embodiments, R4is -CH(OR6)(OR7); - CH(SR6)(SR7); -CH(SR8)(SR9); -CH(R6)(R7); -R10; or optionally substituted C1-C14 aliphatic-R10wherein one or more methylene linkages are each optionally and independently replaced with an optionally substituted C3-C8cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-. In certain embodiments, R4is optionally substituted C1-C14 aliphatic-R10, wherein one or more methylene linkages are each optionally and independently replaced with an optionally substituted C3-C8 cycloalkylenyl, an optionally substituted bridged bicyclic or multicyclicC5-C12 cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or - C(O)O-. In certain embodiments, R4is optionally substituted C1-C14 aliphatic-R10. In certain embodiments, R4is -CH(OR6)(OR7). In certain embodiments, R4is -CH(R6)(R7). In certain embodiments, R4is -CH(SR6)(SR7). In certain embodiments, R4is -CH(SR8)(SR9). In certain embodiments, R4is R10.

[0465]

[0467] As disclosed in Formula ICC), in certain embodiments, R5is -CH(OR8)(OR9); - CH(SR8)(SR9); -CH(R8)(R9); optionally substituted C1-C14 aliphatic, wherein one or more methylene linkages are each optionally and independently replaced with an optionally substituted Cs-Cg cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -CIO)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-; - R11; or optionally substituted C1-C14 aliphatic-R11, wherein one or more methylene linkages are each optionally and independently replaced with an optionally substituted C3-C8 cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-. In certain embodiments, R5is optionally substituted C1-C14 aliphatic. In certain embodiments, R5is -CII(OR8)(OR9) . In certain embodiments, R5is -CH(R8)(R9). In certain embodiments, R5is -CH(SR8)(SR9). In certain embodiments, R5is R11.

[0468] In certain embodiments, R4and R5are the same. In certain embodiments, R4and R5are different.

[0470] In certain embodiments, R5is selected from

[0471] As disclosed in Formula ICC), in certain embodiments, R6and R7are each independently -R1U; optionally substituted -Ci-Cu aliphatic-R10; wherein one or more methylene linkages are each optionally and independently replaced with an optionally substituted Cs-Cg cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -CIO)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-.

[0472] In certain embodiments, R6and R7are the same. In certain embodiments, R6and R7are different.

[0473] In certain embodiments, R6is R10. In certain embodiments, R6is optionally substituted C1-C14 aliphatic-R10. In certain embodiments, R6is optionally substituted C1-C14 alkyl-R10. In certain embodiments, R6is optionally substituted C1-C14 branched alkyl-R10. In certain embodiments, R6is optionally substituted C1-C14 straight chain alkyl-R10. In certain embodiments, R6is optionally substituted C1-C14 alkenyl-R10. In certain embodiments, R6is optionally substituted Ci- C14 branched alkenyl-R10. In certain embodiments, R6is optionally substituted C1-C14 straight chain alkenyl-R10. In certain embodiments, R6is optionally substituted C1-C5 alkyl-R10. In certain embodiments, R6is optionally substituted -(CI bi-R10. In certain embodiments, R6is optionally substituted -(CFhh-R10. In certain embodiments, R6is optionally substituted -(CH2)3-R10- In certain embodiments, R6is optionally substituted -(CH2)4-R10- In certain embodiments, R6is optionally substituted -(CF^s-R10-

[0474] In certain embodiments, R7is R10. In certain embodiments, R7is optionally substituted CI-CH aliphatic-R10. In certain embodiments, R7is optionally substituted CI-CH alkyl-R10. In certain embodiments, R7is optionally substituted C -Ci ; branched alkyl-R10. In certain embodiments, R7is optionally substituted C1-C14 straight chain alkyl-R10. In certain embodiments, R7is optionally substituted C1-C14 alkenyl-R10. In certain embodiments, R7is optionally substituted CI- CH branched alkenyl-R10. In certain embodiments, R7is optionally substituted C1-C14 straight chain alkenyl-R10. In certain embodiments, R7is optionally substituted C1-C5 alkyl-R10. In certain embodiments, R7is optionally substituted -(CH2)-R10. In certain embodiments, R' is optionally substituted - (CH2)2-R10- In certain embodiments, R7is optionally substituted -(CH2)3-R10. In certain embodiments, R7is optionally substituted -(CH2)4-R10. In certain embodiments, R7is optionally substituted -(CH2)5-R10.

[0475] In certain embodiments, R6and R7are selected from andRsand R9

[0476] As disclosed in Formula (CC), in certain embodiments, R8and R9are each independently R11; optionally substituted -C1-C14 aliphatic wherein one or more methylene linkages arc each optionally and independently replaced with an optionally substituted C3-C8 cycloalkylcnyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-; or optionally substituted -C1-C14 aliphatic-R11wherein one or more methylene linkages are each optionally and independently replaced with an optionally substituted C3-C8 cycloalkylenyl, phenyl, -O-, -NH-, -S-, - SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-.

[0477] In certain embodiments, R8and R9are the same. In certain embodiments, R8and R9are different.

[0478] In certain embodiments, R8is R11. In certain embodiments, R8is optionally substituted C1-C14 aliphatic. In certain embodiments, R8is optionally substituted C1-C14 alkyl. In certain embodiments, R8is optionally substituted C1-C14 branched alkyl. In certain embodiments, R8is optionally substituted C1-C14 straight chain alkyl. In certain embodiments, R8is optionally substituted C1-C14alkenyl. In certain embodiments, R8is optionally substituted C1-C14branched alkenyl. In certain embodiments, R8is optionally substituted C1-C14straight chain alkenyl. In certain embodiments, R8is optionally substituted C6-C10alkyl. In certain embodiments, R8is optionally substituted –(CH2)5CH3. In certain embodiments, R8is optionally substituted –(CH2)6CH3. In certain embodiments, R8is optionally substituted –(CH2)7CH3. In certain embodiments, R8is optionally substituted –(CH2)8CH3. In certain embodiments, R8is optionally substituted –(CH2)9CH3.

[0479] In certain embodiments, R8is optionally substituted C1-C14aliphatic-R11. In certain embodiments, R8is optionally substituted C1-C14alkylene-R11. In certain embodiments, R8is optionally substituted C1-C14branched alkylene-R11. In certain embodiments, R8is optionally substituted C1-C14straight chain alkylene-R11. In certain embodiments, R8is optionally substituted C1- C14 alkenylene-R11. In certain embodiments, R8is optionally substituted C1-C14 branched alkenylene- R11. In certain embodiments, R8is optionally substituted C1-C14 straight chain alkenylene-R11. In certain embodiments, R8is optionally substituted C1-C5 alkylene-R11. In certain embodiments, R8is optionally substituted –(CH2)-R11. In certain embodiments, R8is optionally substituted –(CH2)2-R11. In certain embodiments, R8is optionally substituted –(CH2)3-R11. In certain embodiments, R8is optionally substituted –(CH2)4-R11. In certain embodiments, R8is optionally substituted –(CH2)5-R11.

[0480] In certain embodiments, R9is R11. In certain embodiments, R9is optionally substituted C1-C14 aliphatic. In certain embodiments, R9is optionally substituted C1-C14 alkyl. In certain embodiments, R9is optionally substituted C1-C14 branched alkyl. In certain embodiments, R9is optionally substituted C1-C14straight chain alkyl. In certain embodiments, R9is optionally substituted C1-C14alkenyl. In certain embodiments, R9is optionally substituted C1-C14branched alkenyl. In certain embodiments, R9is optionally substituted C1-C14straight chain alkenyl. In certain embodiments, R9is optionally substituted C6-C10 alkyl. In certain embodiments, R9is optionally substituted –(CH2)5CH3. In certain embodiments, R9is optionally substituted –(CH2)6CH3. In certain embodiments, R9is optionally substituted –(CH2)7CH3. In certain embodiments, R9is optionally substituted –(CH2)8CH3. In certain embodiments, R9is optionally substituted –(CH2)9CH3.

[0481] In certain embodiments, R9is optionally substituted C1-C14aliphatic-R11. In certain embodiments, R9is optionally substituted C1-C14alkylene-R11. In certain embodiments, R9is optionally substituted C1-C14 branched alkylene-R11. In certain embodiments, R9is optionally substituted C1-C14 straight chain alkylene-R11. In certain embodiments, R9is optionally substituted C1- C14 alkenylene-R11. In certain embodiments, R9is optionally substituted C1-C14 branched alkenylene- R11. In certain embodiments, R9is optionally substituted C1-C14straight chain alkenylene-R11. Incertain embodiments, R9is optionally substituted C1-C5alkylene-R11. In certain embodiments, R9is optionally substituted –(CH2)-R11. In certain embodiments, R9is optionally substituted –(CH2)2-R11. In certain embodiments, R9is optionally substituted –(CH2)3-R11. In certain embodiments, R9is optionally substituted –(CH2)4-R11. In certain embodiments, R9is optionally substituted –(CH2)5-R11.

[0482] In certain embodiments, R8and R9are selected from , , , , , and . In certain embodiments, R8and R9are selected from and . R10and R11

[0483] As disclosed in Formula (CC), in certain embodiments, each R10and R11are an optionally substituted bridged bicyclic or multicyclic C5-C12 cycloalkylenyl, or two R10or two R11taken together form an optionally substituted bridged bicyclic or multicyclic C5-C12cycloalkylenyl.

[0484] In certain embodiments, each R10and R11are the same. In certain embodiments, each R10and R11are different.

[0485] In some embodiments, each R10and R11is independently an optionally substituted cyclic, bicyclic, bridged bicyclic, multicyclic or bridged multicyclic C4-C14 cycloalkyl or optionally substituted cyclic, bicyclic, bridged bicyclic, multicyclic or bridged multicyclic 4-14 membered heterocyclyl, or two R10or two R11taken together form an optionally substituted bridged bicyclic or multicyclic C4-C14cycloalkyl or optionally substituted bridged bicyclic or multicyclic 4-14 membered heterocyclyl.

[0486] In certain embodiments, each R10is an optionally substituted bridged bicyclic C5-C12cycloalkylenyl. In certain embodiments, each R10is an optionally substituted bridged multicyclic C5- C12cycloalkylenyl. In certain embodiments, each R11is an optionally substituted bridged bicyclic C5- C12 cycloalkylenyl. In certain embodiments, each R11is an optionally substituted bridged multicyclic C5-C12 cycloalkylenyl. In certain embodiments, the optionally substituted bridged bicyclic or multicyclic C5-C12 cycloalkylenyl is selected from adamantyl, bicyclo[2.2.2]octyl, cubanyl, bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, and bicyclo[3.2.1]octyl. In certain embodiments, the optionally substituted bridged bicyclic or multicyclic C5-C12cycloalkylenyl isselected from:In certain embodiments, the substituted bridged bicyclic or multicyclic are substituted.

[0487] In certain embodiments, two R10taken together form an optionally substituted bridged bicyclic or multicyclic C5-C12 cycloalkylenyl. In certain embodiments, two R11taken together form an optionally substituted bridged bicyclic or multicyclic C5-C12 cycloalkylenyl. In certain embodiments, the optionally substituted bridged bicyclic or multicyclic C5-C12 cycloalkylenyl is

[0488] In some embodiments, Lipids of the Present Disclosure are selected from any lipid inTable (I-E) below or a pharmaceutically acceptable salt thereof:Table (I-E). Non-Limiting Examples of Ionizable Lipids of the Present Disclosure(I- A), (I-B), (I-C), (I-D), or (I-E) above, an enantiomer thereof, or any mixture of enantiomers thereof, or a pharmaceutically acceptable salt of any of the aforementioned. ii. Structural lipids

[0490] In some embodiments, an LNP comprises a structural lipid. In some embodiments, an LNP comprises two or more structural lipids. Structural lipids can be selected from the group consisting of, but are not limited to, cholesterol, fecosterol, fucosterol, beta sitosterol, sitosterol, ergosterol, campesterol, stigmasterol, brassicasterol, tomatidine, cholic acid, sitostanol, litocholic acid, tomatine, ursolic acid, alpha-tocopherol, Vitamin D3, Vitamin D2, Calcipotriol, botulin, lupeol,olcanolic acid, bcta-sitostcrol-acctatc and mixtures thereof. In some embodiments, the structural lipid is cholesterol. In some embodiments, the structural lipid is a cholesterol analogue disclosed by Patel, et aL, Nat Common., 11, 983 (2020), which is incorporated herein by reference in its entirety. In some embodiments, the structural lipid includes cholesterol and a corticosteroid (such as prednisolone, dexamethasone, prednisone, and hydrocortisone), or any combinations thereof. In some embodiments, a structural lipid is described in international patent application WO2019152557A1, which is incorporated herein by reference in its entirety.

[0491] In some embodiments, a structural lipid is a cholesterol analog. Using a cholesterol analog may enhance endosomal escape as described in Patel et al., Naturally-occurring cholesterol analogues in lipid nanoparticles induce polymorphic shape and enhance intracellular delivery of mRNA, Nature Communications (2020), which is incorporated herein by reference.

[0492] In some embodiments, a structural lipid is a phytosterol. Using a phytosterol may enhance endosomal escape as described in Herrera et al., Illuminating endosomal escape of polymorphic lipid nanoparticles that boost mRNA delivery, Biomaterials Science (2020), which is incorporated herein by reference.

[0493] In some embodiments, a structural lipid contains plant sterol mimetics for enhanced endosomal release.

[0494] In some embodiments, the structural lipid is cholesteryl hemisuccinate (CHEMS). In some embodiments, the structural lipid is 3-(4-((2-(4-morpholinyl)ethyl)amino)-4-oxobutanoate) (Mochol).Hi. PEGylated lipids

[0495] A PEGylated lipid is a lipid modified with polyethylene glycol.

[0496] In some embodiments, an LNP comprises one, two or more PEGylated lipid or PEG- modified lipid. A PEGylated lipid may be selected from the non-limiting group consisting of PEG- modified phosphatidylethanolamines, PEG-modified phosphatidic acids, PEG-modified ceramides, PEG-modified dialkylamines, PEG-modified diacylglycerols, PEG-modified dialkylglycerols, and mixtures thereof. For example, a PEG lipid may be PEG-c-DOMG, PEG-DMG, PEG-DLPE, PEG- DMPE, PEG-DPPC, or a PEG-DSPE lipid.

[0497] In some embodiments, the PEGylated lipid is selected from (R)-2,3- bis(octadecyloxy)propyl-l-(methoxypoly(ethyleneglycol)2000)propylcarbamate, PEG-S-DSG, PEG- S-DMG, PEG-PE, PEG-PAA, PEG-OH DSPE C18, PEG-DSPE, PEG-DSG, PEG-DPG, PEG- DOMG, PEG-DMPE Na, PEG-DMPE, PEG-DMG2000, PEG-DMG Cl 4, PEG-DMG, PEG-DMA, PEG-Ceramide C16, PEG-C-DOMG, PEG-c-DMOG, PEG-c-DMA, PEG-cDMA, PEGA, PEG750-C- DMA, PEG400, PEG2k-DMG, PEG2k-Cl l, PEG2000-PE, PEG2000P, PEG2000-DSPE, PEG2000- DOMG, PEG2000-DMG, PEG2000-C-DMA, PEG2000, PEG200, PEG(2k)-DMG, PEG DSPE Cl 8, PEG DMPE C14, PEG DLPE C12, PEG Click DMG C14, PEG Click C12, PEG Click CIO,N(Carbonyl-mcthoxypolycthylcnglycol-2000)-l,2-distcaroyl-sn-glyccro3-phosphocthanolaminc, Myrj52, mPEG-PLA, MPEG-DSPE, mPEG3000-DMPE, MPEG-2000-DSPE, MPEG2000-DSPE, mPEG2000-DPPE, mPEG2000-DMPE, mPEG2000-DMG, mDPPE-PEG2000, 1,2-distearoyl-sn- glycero-3-phosphoethanolamine-PEG2000, HPEG-2K-LIPD, Folate PEG-DSPE, DSPE-PEGMA 500, DSPE-PEGMA, DSPE-PEG6000, DSPE-PEG5000, DSPE-PEG2K-NAG, DSPE-PEG2k, DSPE- PEG2000maleimide, DSPE-PEG2000, DSPE-PEG, DSG-PEGMA, DSG-PEG5000, DPPE-PEG-2K, DPPE-PEG, DPPE-mPEG2000, DPPE-mPEG, DPG-PEGMA, DOPE-PEG2000, DMPE-PEGMA, DMPE-PEG2000, DMPE-Peg, DMPE-mPEG2000, DMG-PEGMA, DMG-PEG2000, DMG-PEG, distearoyl-glycerol-polyethyleneglycol, C18PEG750, C18PEG5000, C18PEG3000, C18PEG2000, C16PEG2000, C14PEG2000, C18-PEG5000, C18PEG, C16PEG, C16 mPEG (polyethylene glycol) 2000 Ceramide, C14-PEG-DSPE200, C14-PEG2000, C14PEG2000, C14-PEG 2000, C14-PEG, C14PEG, 14:0-PEG2KPE, l,2-distearoyl-sn-glycero-3-phosphoethanolamine-PEG2000, (R)-2,3- bis(octadecyloxy)propyl-l-(methoxypoly(ethyleneglycol)2000)propylcarbamate, (PEG)-C-DOMG, PEG-C-DMA, and DSPE-PEG-X.

[0498] In some embodiments, the LNP comprises a PEGylated lipid disclosed in one of US 2019 / 0240354; US 2010 / 0130588; US 2021 / 0087135; WO 2021 / 204179; US 2021 / 0128488; US 2020 / 0121809; US 2017 / 0119904; US 2013 / 0108685; US 2013 / 0195920; US 2015 / 0005363; US 2014 / 0308304; US 2013 / 0053572; WO 2019 / 232095A1; WO 2021 / 077067; WO 2019 / 152557; US 2015 / 0203446; US 2017 / 0210697; US 2014 / 0200257; or WO 2019 / 089828A1, each of which is incorporated by reference herein in their entirety.

[0499] In some embodiments, the LNP comprises a PEGylated lipid disclosed and described in PCT Publication WO2024044728A1 filed August 25, 2023, which is incorporated by reference herein, in its entirety. In certain embodiments, the PEGylated lipid is a lipid of any one of formulas PL-1’, PL-I”, PL-I, PL-Ia, PL-Ib, PL-Iaa, PL-Iab, PL-Iac, PL-Iad, PL-Iae, PL-Iaf, PL-Iag, PL-Iah, PL- Iba, PL-Ibb, PL-Ibc, PL-Ibd, PL-Ibe, PL-Ibf, PL-Ibg, PL-Ibh, PL-Ica, PL-Icb, PL-Icc, PL-Icd, PL-Id PL-Ie, PL-If, PL-Ig, PL-Ih, PL-Ii, PL-Iha, PL-Ihb, PL-Ihc, PL-Ihd, PL-Iia, PL-lib, PL-Iic, PL-Iid, PL- Ij, PL-Ik, L-Il, PL-Im, PL-In, PL-Io, PL-Ip, PL-Iq, PL-Ioa, PL-Iob, PL-Ioc, PL-Iod, PL-Ioe, PL-Iof, PL-Iog, PL-Ioh, PL-Ipa, PL-Ipb, PL-Ipc, PL-Ipd, PL-Ipe, PL-Ipf, PL-Ipg, PL-Iph, PL-Iqa, PL-Iqb, PL-Iqc, PL-Iqd, PL-Ir, PL-Is, PL-It, PL-Iu, PL-Iv, PL-Iw, PL-Iva, PL-Ivb, PL-Ivc, PL-Ivd, PL-Iwa, PL-Iwb, PL-Iwc, PL-Iwd, PL-Ix, PL-Ixx, PL-Iy, PL-Iyy, PL-Iyyy, PL-Iz, PL-Izz, PL-Izzz, PL-II', PL- II”, PL-II, PL-IIc, PL-IId, PL-IIe, PL-IIf, PL-IIg, PL-IIh, PL-IIa, PL-IIb, PL-IIk, PL-IIm or PL-IIn.

[0500] In some embodiments, the PEGylated lipid is a compound of formula PL-I’:L2-R2PL-I’or a pharmaceutically acceptable salt thereof, wherein: A1is a saturated 5-6 membered carbocyclic ring or a saturated 5-6 membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the carbocyclic ring and heterocyclic ring are substituted with t occurrences of R4; X1is -N(H)-, -N(C1-6 alkyl)-, -C1-6 aliphatic-N(H)-, -C1-6 aliphatic-N(C1-6 alkyl)-, -O- or -C1-6 aliphatic-O-; L1is -C(O)(C1-6aliphatic)C(O)-N(R)-, -C(O)(C1-6aliphatic)-N(R)C(O)-, -C(O)(C1-6aliphatic)C(O)O-, -C(O)(C1-6aliphatic)C(O)-, -C(O)(C1-6aliphatic)C(O)OCH2-, -C(O)(C1-6aliphatic)-, -C(O)(C1-6aliphatic)-N(R)-, or -C(O)-; L2and L3are independently a covalent bond or C1-6 alkylene wherein one methylene unit of the C1-6 alkylene is optionally replaced with -O-, -NR-, -S-, -S-S-, -S(O)-, -S(O)2-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -OC(O)N(R)-, -N(R)C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -N(R)C(O)N(R)-, -C(R5)=N-, or - C(R5)=N-O-; R1is H, C1-6alkyl, -(C1-6alkyl)-N3, -(C1-6alkyl)-SH, or C3-8alkynyl; R2and R3are independently a straight or branched C6-30alkyl, straight or branched C6-30alkenyl, or straight or branched C6-30 alkynyl; wherein 1, 2, or 3 methylene units are independently and optionally replaced by a saturated or partially unsaturated C3-6 carbocyclic ring or phenylene; wherein the alkyl, alkenyl, and alkynyl and any carbocyclic ring or phenylene is substituted with m instances of Rx; R4is C1-4alkyl; R5is C1-6alkyl or C2-14alkenyl; each R is independently hydrogen or an optionally substituted group selected from C1-6aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each Rxis independently halogen, -CN, -OR, -SR, -C(O)R, -C(O)OR, or -OC(O)OR; n is an integer from 10-75, inclusive; m is 0, 1, 2, 3, or 4; and t is 0, 1, or 2.

[0501] In some embodiments, the PEGylated lipid is a compound of formula PL-II’:PL-II’ or a pharmaceutically acceptable salt thereof, wherein: X1is -N(H)-, -N(C1-6 alkyl)-, -C1-6 aliphatic-N(H)-, -C1-6 aliphatic-N(C1-6 alkyl)-, -O- or -C1-6 aliphatic-O-; L1is -C(O)(C1-6 aliphatic)C(O)-, -C(O)(C1-6 aliphatic)-, or -C(O)-; L2and L3are a covalent bond or C1-6alkylene wherein one methylene unit of the C1-6alkylene is optionally replaced with -O-, -NR-, -S-, -S-S-, -S(O)-, -S(O)2-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)O-, -OC(O)N(R)-, -N(R)C(O)O-, -C(O)N(R)-, -N(R)C(O)-, -N(R)C(O)N(R)-, -C(R6)=N-, or -C(R6)=N- O-; R1is H, C1-6 alkyl, -(C1-6 alkyl)-N3, -(C1-6 alkyl)-SH, or C3-8 alkynyl; R2and R3are independently straight or branched C6-30 alkyl, straight or branched C6-30 alkenyl, or straight or branched C6-30 alkynyl; wherein 1, 2, or 3 methylene units are independently and optionally replaced by a saturated or partially unsaturated C3-6carbocyclic ring or phenylene; wherein the alkyl, alkenyl, and alkynyl and any carbocyclic ring or phenylene is substituted with m instances of Rx; R6is C1-6alkyl or C2-14alkenyl; each R is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each Rxis independently halogen, -CN, -OR, -SR, -C(O)R, -C(O)OR, or OC(O)OR; n is an integer from 10-75, inclusive; and m is 0, 1, 2, 3, or 4.

[0502] In some embodiments, the PEGylated lipid compound is one of those shown in Table (I-X), or a pharmaceutically acceptable salt thereof. Table (I-X). Exemplary PEGylated Compounds Compound Structure

[0503] In some embodiments, the LNP comprises a PEGylated lipid substitute in place of the PEGylated lipid. All embodiments disclosed herein that contemplate a PEGylated lipid should be understood to also apply to PEGylated lipid substitutes. In some embodiments, the LNP comprises a polysarcosine-lipid conjugate, such as those disclosed in US 2022 / 0001025 Al, which is incorporated by reference herein in its entirety. In some embodiments the LNP comprises a polyoxazoline-lipid conjugate, such as those disclosed in US 2022 / 0249695 Al, which is incorporated by reference herein in its entirety. iv. Phospholipids

[0504] In some embodiments, an LNP of the present disclosure comprises a phospholipid. In some embodiments, an LNP of the present disclosure comprises two or more phospholipids.Phospholipids useful in the compositions and methods may be selected from the non-limiting group consisting of l,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), l,2-dioleoyl-sn-glycero-3- phosphoethanolamine (DOPE), l,2-dilinoleoyl-sn-glycero-3-phosphocholine (DLPC), 1,2- dimyristoyl-sn-glycero-phosphocholine (DMPC), 1.2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), l,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-diundecanoyl-sn-glycero-phosphocholine (DUPC), l-palmitoyl-2-oleoyl-sn-glycero-3-phosphocho line (POPC), 1,2-di-O-octadecenyl-sn- glycero-3-phosphocholine (18:0 Diether PC), l-oleoyl-2-cholesterylhemisuc cinoyl-sn-glycero-3- phosphocholine (OChemsPC), l-hexadecyl-sn-glycero-3-phosphocholine (C16 Lyso PC), 1,2- dilinolenoyl-sn-glycero-3-phosphocholine, 1 ,2-diarachidonoyl-sn-glycero-3-phosphocholine, 1 ,2-didocosahcxacnoyl-sn-glyccro-3-phosphocholinc, l,2-diphytanoylsn-glyccro-3-phosphocthanolaminc (ME 16.0 PE), l,2-distearoyl-sn-glycero-3-phosphoethanolamine, l,2-dilinoleoyl-sn-glycero-3- phosphoethanolamine, 1 ,2-dilinolenoyl-sn-glycero-3-phosphoethanolamine, 1 ,2-diarachidonoyl-sn- glycero-3-phosphoethanolamine, l,2-didocosahexaenoyl-sn-glycero-3-phosphoethanolamine, 1,2- dioleoyl-sn-glycero-3-phospho-rac-(l-glycerol) sodium salt (DOPG), sodium (S)-2-ammonio-3- ((((R)-2-(oleoyloxy)-3-(stearoyloxy)propoxy)oxidophosphoryl)oxy)propanoate (L-cc- phosphatidylserine; Brain PS), dimyristoyl phosphatidylcholine (DMPC), dimyristoyl phosphoethanolamine (DMPE), dimyristoylphosphatidylglycerol (DMPG), dioleoyl- phosphatidylethanolamine4-(N -maleimidomethyl)-cyclohexane- 1 -carboxylate (DOPE-mal), dioleoylphosphatidylglycerol (DOPG), l,2-dioleoyl-sn-glycero-3-(phospho-L-serine) (DOPS), acell- fusogenicphospholipid (DPhPE), dipalmitoylphosphatidylethanolamine (DPPE), 1,2-Dielaidoyl-sn- phosphatidylethanolamine (DEPE), dipalmitoylphosphatidylglycerol (DPPG), dipalmitoylphosphatidylserine (DPPS), distearoylphosphatidylcholine (DSPC), distearoyl- phosphatidyl-ethanolamine (DSPE), distearoyl phosphoethanolamineimidazole (DSPEI), 1,2- diundecanoyl-sn-glycero-phosphocholine (DUPC), egg phosphatidylcholine (EPC), 1,2-dioleoyl-sn- glycero-3-phosphate (18: 1 PA; DOPA), ammonium bis((S)-2-hydroxy-3-(oleoyloxy)propyl) phosphate (18: 1 DMP; LBPA), l,2-dioleoyl-sn-glycero-3-phospho-(l’-myo-inositol) (DOPI; 18:1 PI), l,2-distearoyl-sn-glycero-3-phospho-L-serine (18:0 PS), l,2-dilinoleoyl-sn-glycero-3-phospho-L- serine (18:2 PS), l-palmitoyl-2-oleoyl-sn-glycero-3-phospho-L-serine (16:0-18:1 PS; POPS), 1- stearoyl-2-oleoyl-sn-glycero-3-phospho-L-serine (18:0-18:1 PS), l-stearoyl-2-linoleoyl-sn-glycero-3- phospho-L-serine (18:0-18:2 PS), l-oleoyl-2-hydroxy-sn-glycero-3-phospho-L-serine (18:1 Lyso PS),1-stearoyl-2-hydroxy-sn-glycero-3-phospho-L-serine (18:0 Lyso PS), and sphingomyelin. In some embodiments, an LNP includes DSPC. In certain embodiments, an LNP includes DOPE. In some embodiments, an LNP includes both DSPC and DOPE.

[0505] In some embodiments, the LNP comprises a phospholipid selected from 1- pentadecanoyl-2-oleoyl-sn-glycero-3-phosphocholine, l-myristoyl-2-palmitoyl-sn-glycero-3- phosphocholine, l-myristoyl-2-stearoyl-sn-glycero-3-phosphocholine, l-palmitoyl-2-myristoyl-sn- glycero-3-phosphocholine, l-palmitoyl-2-stearoyl-sn-glycero-3-phosphocholine, l-palmitoyl-2- oleoyl-glycero-3-phosphocholine, l-palmitoyl-2-linoleoyl-sn-glycero-3-phosphocholine, 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine, l-palmitoyl-2-docosahexaenoyl-sn-glycero-3- phosphocholine, l-stearoyl-2-myristoyl-sn-glycero-3-phosphocholine, l-stearoyl-2-palmitoyl-sn- glycero-3-phosphocholine, l-stearoyl-2-oleoyl-sn-glycero-3-phosphocholine, l-stearoyl-2-linoleoyl- sn-glycero-3-phosphocholine, l-stearoyl-2-arachidonoyl-sn-glycero-3-phosphocholine, l-stearoyl-2- docosahexaenoyl-sn-glycero-3-phosphocholine, l-oleoyl-2-myristoyl-sn-glycero-3-phosphocholine, l-oleoyl-2-palmitoyl-sn-glycero-3-phosphocholine, l-oleoyl-2-stearoyl-sn-glycero-3-phosphocholine, l-palmitoyl-2-acetyl-sn-glycero-3-phosphocholine, l,2-dioleoyl-sn-glycero-3-phospho-(l’-myo- inositol-3 ’ ,4’ -bisphosphate), 1 ,2-dioleoyl-sn-glycero-3-phospho-( 1 ’ -myo-inositol-3 ’ ,5 ’ -bisphosphate),l,2-diolcoyl-sn-glyccro-3-phospho-(r-myo-inositol-4’,5’-bisphosphatc), l,2-diolcoyl-sn-glyccro-3- phospho-( r-myo-irK)sitol-3'.4'.5'-trisphosphate). l,2-dioleoyl-sn-glycero-3-phospho-(l’ -myo-inositol- s' -phosphate), l,2-dioleoyl-sn-glycero-3-phospho-(r-myo-inositol-4’ -phosphate), 1,2-dioleoyl-sn- glycero-3-phospho-(l'-myo-inositol-5'-phosphate), l,2-dioleoyl-sn-glycero-3-phospho-(l' -myo- inositol), l,2-dioleoyl-sn-glycero-3-phospho-L-serine, and l-(8Z-octadecenoyl)-2-pahnitoyl-sn- gly cero - 3-phosphocholine.

[0506] In some embodiments, the LNP comprises a phospholipid selected from DSPS (Distearoylphosphatidylserine), DSPG (l,2-distearoyl-sn-glycero-3-phospho-(l'-rac-glycerol)), DSPA (l,2-Distearoyl-sn-glycero-3-phosphate), diPhyPC (l,2-diphytanoyl-sn-glycero-3-phosphocholine), diPhy-diether-PC ( 1 ,2-di-O-phy tanyl-sn-glycero-3-phosphocholine), diPhy PE ( 1 ,2-diphytanoy 1-sn- glycero-3-phosphoethanolamine), diPhy-diether-PE (l,2-di-O-phytanyl-sn-glycero-3- phosphoethanolamine), diPhyPS (l,2-diphytanoyl-sn-glycero-3-phospho-L-serine), diPhyPG (1,2- diphytanoyl-sn-glycero-3-phospho-(l'-rac-glycerol)), diPhyPA (l,2-diphytanoyl-sn-glycero-3- phosphate), Egg PA (L-a-phosphatidic acid), and Soy PA (L-a-phosphatidic acid).

[0507] In some embodiments, the LNP comprises a phospholipid selected from 18:1 (A9- Cis) PE (DOPE), 18:0-18:1 PE (SOPE), C16-18:l PE, 16:0-18:1 PE (POPE), 18:1 BMP (S,R), 18:0- 18:1 PC (SOPC), 16:0-18:1 PC (POPC), 4ME 16:0 Diether PE (4Me), 18:1 (A9-Trans) PE (DEPE), 16:1 PE (DPPE), and CL. In certain embodiments, the LNP comprises a phospholipid described or disclosed in Alvarez-Benedicto, et aL (Biomater. Sci., 2022, 10, 549) and Li, et al. (Asian Journal of Pharmaceutical Sciences, 2015, 10, 81-98).

[0508] In certain embodiments, the phospholipid is a sphingoid lipid or sphingolipid, such as, but not limited to sphingomyelin. As used herein, the terms “sphingoid lipid” and “sphingolipid” are meant to refer to a class of lipids containing a backbone comprising a sphingoid base. An exemplary sphingoid base is sphingosine. In certain embodiments, the LNP comprises a sphingolipid selected from Egg Sphingomyelin (Egg SM / ESM / (2S,3R,E)-3-hydroxy-2-palmitamidooctadec-4- en-l-yl (2-(trimethylammonio)ethyl) phosphate), Brain or Porcine Sphingomyelin (Brain SM / (2S,3R,E)-3-hydroxy-2-stearamidooctadec-4-en-l-yl (2-(trimethylammonio)ethyl) phosphate), Milk or Bovine Sphingomyelin (Milk SM / (2S,3R,E)-3-hydroxy-2-tricosanamidooctadec-4-en-l-yl (2- (trimethylammonio)ethyl) phosphate), 28:0 SM (N-octacosanoyl-D-erythro- sphingosylphosphorylcholine), 14:0 SM (N-myristoyl-D-erythro-sphingosylphosphorylcholine), 16:1 SM (N-palmitoleoyl-D-erythro-sphingosylphosphorylcholine), 12:0 Dihydro SM (N-lauroyl-D- erythro-sphinganylphosphorylcholine), Lyso SM (Sphingosylphosphorylcholine), Lyso SM (Sphingosylphosphorylcholine), Lyso SM (dihydro) (Sphinganine Phosphorylcholine), 24:1 SM (N- nervonoyl-D-erythro-sphingosylphosphorylcholine), 24:0 SM (N-lignoceroyl-D-erythro- sphingosylphosphorylcholine), 18:1 SM (N-oleoyl-D-erythro-sphingosylphosphorylcholine), 18:0 SM (N-stearoyl-D-erythro-sphingosylphosphorylcholine), 17:0 SM (N-heptadecanoyl-D-erythro-sphingosylphosphorylcholinc), 16:0 SM (N-palmitoyl-D-crythro-sphingosylphosphorylcholinc), 12:0 SM (N-lauroyl-D-erythro-sphingosylphosphorylcholine), 06:0 SM (N-hexanoyl-D-erythro- sphingosylphosphorylcholine), 02:0 SM (N-acetyl-D-erythro-sphingosylphosphorylcholine), 3-O- methyl Lyso SM (3-O-methyl-spingosylphosphorylcholine), 3-O-methyl-N-methyl Lyso SM (3-O- methyl-N-methyl-spingosylphosphorylcholine), and 3-N-methyl Lyso SM (3-N-melhyl- spingosylphosphorylcholine).

[0509] In some embodiments, the LNP comprises at least two phospholipids. In certain embodiments, at least a portion of the overall phospholipid content comprises a non- phosphatidylcholine phospholipid, wherein a “non-phosphatidylcholine phospholipid” is a phospholipid that does not comprise a phosphatidylcholine moiety. Exemplary non- phosphatidylcholine phospholipids include, but are not limited to, DOPE, DSPS, and DSPG. In certain embodiments, the LNP comprises at least 5 mol% of a non-phosphatidylcholine phospholipid. In certain embodiments, the LNP comprises at least 6 mol% of a non-phosphatidylcholine phospholipid. In certain embodiments, the LNP comprises at least 10 mol% of a non- phosphatidylcholine phospholipid.

[0510] In some embodiments, the LNP comprises a phospholipid comprising at least one constrained tail, such as those described by Gan, et al. (Bioeng Transl Med. 2020 Sep; 5(3): elO16L). In certain embodiments, the phospholipid is one selected from:

[0511] In some embodiments, the LNP comprises a phospholipid comprising a ceramide analogue having a triazole linkage, such as those described by Kim et al., Bioorg. Med. Chem. Lett., 17(16), 2007, 4584-4587.

[0512] In some embodiments, the LNP comprises a phospholipid disclosed in WO 2023 / 141470, which is incorporated by reference herein, in its entirety. In certain embodiments, the

[0513] In some embodiments, the LNP comprises a phospholipid disclosed in WO 2022 / 040641, which is incorporated by reference herein, in its entirety.

[0514] In some embodiments, a phospholipid tail may be modified in order to promote endosomal escape as described in U.S. 2021 / 0121411, which is incorporated herein by reference.

[0515] In some embodiments, the LNP comprises a phospholipid disclosed in one of US 2019 / 0240354; US 2010 / 0130588; US 2021 / 0087135; WO 2021 / 204179; US 2021 / 0128488; US 2020 / 0121809; US 2017 / 0119904; US 2013 / 0108685; US 2013 / 0195920; US 2015 / 0005363; US 2014 / 0308304; US 2013 / 0053572; WO 2019 / 232095A1; WO 2021 / 077067; WO 2019 / 152557; US 2017 / 0210697; or WO 2019 / 089828A1, each of which is incorporated by reference herein in their entirety.

[0516] In some embodiments, phospholipids disclosed in US 2020 / 0121809 have the following structure: o wherein R1 and R2 are each independently a branched or straight, saturated or unsaturated carbon chain (e.g., alkyl, alkenyl, alkynyl). v. Targeting moieties

[0517] In some embodiments, the lipid nanoparticle further comprises a targeting moiety. The targeting moiety may be an antibody or a fragment thereof. The targeting moiety may be capable of binding to a target antigen. In certain embodiments, the lipid nanoparticle comprises more than one targeting moiety. In certain embodiments, the lipid nanoparticle comprises more than one targeting moiety, wherein the targeting moieties target at least two different receptors, and in some embodiments, the at least two different receptors are prevalent on different types of cells or tissues.

[0518] In some embodiments, the pharmaceutical composition comprises a targeting moiety that is operably connected to a lipid nanoparticle. In some embodiments, the targeting moiety is capable of binding to a target antigen. In some embodiments, the target antigen is expressed in a target organ. In some embodiments, the target antigen is expressed more in the target organ than it is in the liver.

[0519] In some embodiments, the targeting moiety is an antibody as described in WO2016189532A1, which is incorporated herein by reference. For example, in some embodiments, the targeted particles are conjugated to a specific anti-CD38 monoclonal antibody (mAb), which allows specific delivery of the siRNAs encapsulated within the particles at a greater percentage to B- cell lymphocytes malignancies (such as MCL) than to other subtypes of leukocytes.

[0520] In some embodiments, the targeting moiety targets a receptor selected from CD20, CCR7, CD3, CD4, CD5, CD8, CD16, CD19, CD20, CD21, CD22, CD25, CD28, CD35, CD40, CD45RA, CD45RO, CD52, CD62L, CD80, CD95, CD127, and CD137. In some embodiments, the targeting moiety targets a receptor selected from CD1, CD2, CD3, CD5, CD7, CD8, CD16, CD25, CD26, CD27, CD28, CD30, CD38, CD39, CD40L, CD44, CD45, CD62L, CD69, CD73, CD80, CD83, CD86, CD95, CD103, CD119, CD126, CD150, CD153, CD154, CD161, CD183, CD223, CD254, CD275, CD45RA, CXCR3, CXCR5, FasL, IL18R1, CTLA-4, 0X40, GITR, LAG3, ICOS, PD-1, leu-12, TCR, TLR1, TLR2, TLR3, TLR4, TLR6, NKG2D, CCR, CCR1, CCR2, CCR4, CCR6, and CCR7. In some embodiments, the targeting moiety targets a receptor selected from CD2, CD3, CD5 and CD7. In some embodiments, the targeting moiety targets a receptor selected from CD2, CD3, CD5, CD7, CD8, CD4, beta 7 integrin, beta 2 integrin, and Clq. In some embodiments, the targeting moiety targets CD117. In some embodiments, the targeting moiety targets CD90. In some embodiments, the targeting moiety targets a receptor selected from a mannose receptor, CD206 and Clq. In some embodiments, the targeting moiety is selected from T-cell receptor motif antibodies, T- cell a chain antibodies, T-cell P chain antibodies, T-cell y chain antibodies, T-cell 8 chain antibodies, CCR7 antibodies, CD3 antibodies, CD4 antibodies, CD5 antibodies, CD7 antibodies, CD8 antibodies, CDl lb antibodies, CDl lc antibodies, CD16 antibodies, CD19 antibodies, CD20 antibodies, CD21 antibodies, CD22 antibodies, CD25 antibodies, CD28 antibodies, CD34 antibodies, CD35 antibodies, CD40 antibodies, CD45RA antibodies, CD45RO antibodies, CD52 antibodies, CD56 antibodies, CD62L antibodies, CD68 antibodies, CD80 antibodies, CD95 antibodies, CD117 antibodies, CD127 antibodies, CD133 antibodies, CD137 (4-1BB) antibodies, CD163 antibodies, F4 / 80 antibodies, IL- 4Ra antibodies, Sca-1 antibodies, CTLA-4 antibodies, GITR antibodies GARP antibodies, LAP antibodies, granzyme B antibodies, LFA-1 antibodies, transferrin receptor antibodies, and fragments thereof. In certain embodiments, the targeting moiety is any one described or contemplated in US20230312713A1, US20230203538A1, US20230320995A1, US20160145348, and US20110038941, each of which is incorporated by reference herein in its entirety.

[0521] In some embodiments, the targeting moiety is a small molecule. In some embodiments, the small molecule binds to an ectoenzyme on an immune cell, wherein the ectoenzyme is selected from the group consisting of CD38, CD73, adenosine 2a receptor, and adenosine 2b receptor. In some embodiments, the small molecule is mannose, a lectin, acivicin, biotin, or digoxigenin.

[0522] In some embodiments, the lipid nanoparticles may be targeted when conjugated / attached / associated with a targeting moiety such as an antibody, or a fragment thereof. vi. Zwitterionic amino lipids

[0523] In some embodiments, an LNP comprises a zwitterionic lipid. In some embodiments, an LNP comprising a zwitterionic lipid does not comprise a phospholipid.

[0524] Zwitterionic amino lipids have been shown to be able to self- assemble into LNPs without phospholipids to load, stabilize, and release mRNAs intracellularly as described in U.S. Patent Application 20210121411, which is incorporated herein by reference in its entirety.Zwitterionic, ionizable cationic and permanently cationic helper lipids enable tissue-selective mRNA delivery and CRISPR-Cas9 gene editing in spleen, liver and lungs as described in Liu et aL, Membrane-destablizing ionizable phospholipids for organ-selective mRNA delivery and CRISPR-Cas gene editing, Nat Mater. (2021), which is incorporated herein by reference in its entirety.

[0525] The zwitterionic lipids may have head groups containing a cationic amine and an anionic carboxylate as described in Walsh et al.. Synthesis, Characterization and Evaluation of Ionizable Lysine-Based Lipids for siRNA Delivery, Bioconjug Chem. (2013), which is incorporated herein by reference in its entirety. Ionizable lysine-based lipids containing a lysine head group linked to a long-chain dialkylamine through an amide linkage at the lysine a-amine may reduce immunogenicity as described in Walsh et al., Synthesis, Characterization and Evaluation of Ionizable Lysine-Based Lipids for siRNA Delivery, Bioconjug Chem. (2013). vii. Additional lipid components

[0526] In some embodiments, the LNP compositions of the present disclosure further comprise one or more additional lipid components capable of influencing the tropism of the LNP. In some embodiments, the LNP further comprises at least one lipid selected from DDAB, EPC, 14PA, 18BMP, DODAP, DOTAP, and C12-200 (see Cheng, et al. Nat Nanotechnol. 2020 April; 15(4): 313— 320.; Dillard, et al. PNAS 2021 Vol. 118 No. 52.).

[0527] In some embodiments, an LNP of the present disclosure further comprises one or more additional ionizable lipids, such as, but not limited to those disclosed in one of US 2023 / 0053437; US 2019 / 0240354; US 2010 / 0130588; US 2021 / 0087135; WO 2021 / 204179; US 2021 / 0128488; US 2020 / 0121809; US 2017 / 0119904; US 2013 / 0108685; US 2013 / 0195920; US 2015 / 0005363; US 2014 / 0308304; US 2013 / 0053572; WO 2019 / 232095A1; WO 2021 / 077067; WO 2019 / 152557; US 2017 / 0210697; or WO 2019 / 089828A1, each of which is incorporated by reference herein in their entirety. In certain embodiments, an LNP of the present disclosure further comprises one or more additional ionizable lipids selected from those disclosed in WO2023044343A1 or WO2023044333A1, both of which are incorporated by reference herein in their entirety.

[0528] In some embodiments, the LNP compositions of the present disclosure comprise, or further comprise one or more lipids selected from l,2-di-O-octadecenyl-sn-glycero-3-phosphocholine (18:0 Diether PC), l,2-dilinolenoyl-sn-glycero-3-phosphocholine (18:3 PC), Acylcarnosine (AC), 1- hexadecyl-sn-glycero-3-phosphocholine (C16 Lyso PC), N-oleoyl-sphingomyelin (SPM) (C18:l), N- lignoceryl SPM (C24:0), N-nervonoylshphingomyelin (C24:l), Cardiolipin (CL), l,2-bis(tricosa- 10,12-diynoyl)-sn-glycero-3-phosphocholine (DC8-9PC), dicetyl phosphate (DCP), dihexadecyl phosphate (DCP1), l,2-Dipalmitoylglycerol-3-hemisuccinate (DGSucc), short-chain bis-n-hcptadccanoyl phosphatidylcholine (DHPC), dihcxadccoyl-phosphocthanolaminc (DHPE), 1,2- dilinoleoyl-sn-glycero-3-phosphocholine (DLPC), l,2-dilauroyl-sn-glycero-3-PE (DLPE), dimyristoyl glycerol hemisuccinate (DMGS), dimyristoyl phosphatidylcholine (DMPC), dimyristoyl phosphoethanolamine (DMPE), dimyristoylphosphatidylglycerol (DMPG), dioleyloxybenzylalcohol (DOBA), l,2-dioleoylglyceryl-3-hemisuccinate (DOGHEMS), N-[2-(2-{2-[2-(2,3-Bis-octadec-9- enyloxy-propoxy)-ethoxy]-ethoxy}-ethoxy)-ethyl]-3-(3,4,5-dihydroxy-6-hydroxymethyl-tetrahydro- pyran-2-ylsulfanyl)-propionamide (DOGP4aMan), dioleoylphosphatidylcholine (DOPC), dioleoylphosphatidylethanolamine (DOPE), dioleoyl-phosphatidylethanolamine4-(N- maleimidomethyl)-cyclohexane-l -carboxylate (DOPE-mal), dioleoylphosphatidylglycerol (DOPG), l,2-dioleoyl-sn-glycero-3-(phospho-L-serine) (DOPS), acell-fusogenicphospholipid (DPhPE), dipalmitoylphosphatidylethanolamine (DPPE), dipalmitoylphosphatidylglycerol (DPPG), dipalmitoylphosphatidylserine (DPPS), distearoylphosphatidylcholine (DSPC), distearoyl- phosphatidyl-ethanolamine (DSPE), distearoyl phosphoethanolamineimidazole (DSPEI), 1,2- diundecanoyl-sn-glycero-phosphocholine (DUPC), egg phosphatidylcholine (EPC), histaminedistearoylglycerol (HDSG), 1,2-Dipalmitoylglycerol-hemisuccinate-Na-Histidinyl- Hemisuccinate (HistSuccDG), N-(5'-hydroxy-3'-oxypentyl)-10-12-pentacosadiynamide (h-Pegi- PCDA), 2-[l-hexyloxyethyl]-2-devinylpyropheophorbide-a (HPPH), hydrogenatedsoybeanphosphatidylcholine (HSPC), 1 ,2-Dipalmitoylglycerol-O-a-histidinyl-Na- hemisuccinate (IsohistsuccDG), mannosialized dipalmitoylphosphatidylethanolamine (ManDOG), 1,2- Dioleoyl-sn-Glycero-3-Phosphoethanolamine-N-[4-(p-maleimidomethyl)cyclohexane-carboxamide] (MCC-PE), l,2-diphytanoyl-sn-glycero-3-phosphoe...

Claims

CLAIMS 1. A compound of Formula (CC): (CC), or a pharmaceutically acceptable salt thereof, wherein: R1is selected from the group consisting of -OH, -OAc, -NR2, , , , , , , , , , , and ; each R is independently -H or C1-C6 aliphatic; X1is optionally substituted C2-C6 aliphatic, wherein one or more methylene linkages are each optionally and independently replaced with -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, - NHC(O)- or -C(O)O-; X2is selected from the group consisting of a bond, -CH2- and -CH2CH2-; X2’is selected from the group consisting of a bond, -CH2- and -CH2CH2-; X3is selected from the group consisting of a bond, -CH2- and -CH2CH2-; X3’is selected from the group consisting of a bond, -CH2- and -CH2CH2-; X4and X5are independently optionally substituted C1-C10 aliphatic; Y1and Y2are independently selected from the group consisting of , , , , , , , or ; wherein the bond marked with an "*" is attached to X4or X5;R2is optionally substituted C1-C6aliphatic; R3is optionally substituted C1-C6aliphatic; R4is -CH(OR6)(OR7); -CH(SR6)(SR7); -CH(SR8)(SR9); -CH(R6)(R7); -R10; or optionally substituted C1-C14 aliphatic-R10wherein one or more methylene linkages are each optionally and independently replaced with an optionally substituted C3-C8 cycloalkylenyl, phenyl, -O-, -NH-, - S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-; R5is -CH(OR8)(OR9); -CH(SR8)(SR9); -CH(R8)(R9); optionally substituted C1-C14aliphatic, wherein one or more methylene linkages are each optionally and independently replaced with an optionally substituted C3-C8 cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, - OC(O)-, -NHC(O)- or -C(O)O-; -R11; or optionally substituted C1-C14 aliphatic-R11, wherein one or more methylene linkages are each optionally and independently replaced with an optionally substituted C3-C8 cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, - NHC(O)- or -C(O)O-; R6and R7are each independently -R10; or optionally substituted -C1-C14aliphatic-R10; wherein one or more methylene linkages are each optionally and independently replaced with an optionally substituted C3-C8 cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, - NHC(O)- or -C(O)O-; R8and R9are each independently -R11; optionally substituted -C1-C14 aliphatic wherein one or more methylene linkages are each optionally and independently replaced with an optionally substituted C3-C8cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or - C(O)O-; or optionally substituted -C1-C14aliphatic-R11wherein one or more methylene linkages are each optionally and independently replaced with an optionally substituted C3-C8cycloalkylenyl, phenyl, -O-, -NH-, -S-, -SS-, -C(O)-, -OC(O)O-, -OC(O)-, -NHC(O)- or -C(O)O-; and each R10and R11are independently an optionally substituted bridged bicyclic or multicyclic C4-C12 cycloalkylenyl, or two R10or two R11taken together form an optionally substituted bridged bicyclic or multicyclic C4-C12cycloalkylenyl.

2. The compound of claim 1, wherein (CC-A), or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1, wherein the compound is of Formula (CC-B): (CC-B), or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1, wherein the compound is of Formula (CC-C): (CC-C), or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1, wherein the compound is of Formula (CC-D): (CC-D), or a pharmaceutically acceptable salt thereof.

6. The compound of claim 1, wherein the compound is of Formula (CC-E): (CC-E), or a pharmaceutically acceptable salt thereof.

7. The compound of claim 1, wherein the compound is of Formula (CC-F):R4(CC-F), or a pharmaceutically acceptable salt thereof.

8. The compound of claim 1, wherein the compound is of Formula (CC-F’):R4(CC-F’), or a pharmaceutically acceptable salt thereof.

9. The compound of claim 1, wherein the compound is of Formula (CC-G):R4(CC-G), or a pharmaceutically acceptable salt thereof.

10. The compound of claim 1, wherein the compound is of Formula (CC-H):(CC-H), or a pharmaceutically acceptable salt thereof.

11. The compound of claim 1, wherein the compound is of Formula (CC-I):(CC-I), or a pharmaceutically acceptable salt thereof.

12. The compound of claim 1, wherein the compound is of Formula (CC-J):(CC-J), or a pharmaceutically acceptable salt thereof.

13. The compound of claim 1, wherein the compound is of Formula (CC-K):(CC-K), or a pharmaceutically acceptable salt thereof.

14. The compound of claim 1, wherein the compound is of Formula (CC-L):(CC-L), or a pharmaceutically acceptable salt thereof.

15. The compound of claim 1, wherein the compound is of Formula (CC-M):(CC-M), or a pharmaceutically acceptable salt thereof.

16. The compound of any of claims 1-9, 11-14, wherein R1is -OH or .

17. The compound of claim 16, wherein R1is -OH.

18. The compound of claim 16, wherein R1is .

19. The compound of claim 16, wherein R1is .

20. The compound of any of claims 1-19, wherein X1is optionally substituted C2-C6alkylene.

21. The compound of claim 20, wherein X1is optionally substituted C2-C4alkylene.

22. The compound of claim 20, wherein X1is selected from the group consisting of -(CH2)2-, -(CH2)3- and -(CH2)4-.

23. The compound of claim 22, wherein X1is -(CH2)2-.

24. The compound of claim 22, wherein X1is -(CH2)3-.

25. The compound of claim 22, wherein X1is -(CH2)4-.

26. The compound of any of claims 1-3, 6-12, or 15-25, wherein X4is optionally substituted C2-C7 aliphatic.

27. The compound of claim 26, wherein X4is optionally substituted C2-C3 alkylene.

28. The compound of claim 27, wherein X4is -(CH2)2-.

29. The compound of claim 27, wherein X4is -(CH2)3-.

30. The compound of any of claims 1-3, 6-12, or 15-29, wherein X5is optionally substituted C2-C7aliphatic.

31. The compound of claim 30, wherein X5is optionally substituted C2-C3alkylene.

32. The compound of claim 31, wherein X5is -(CH2)2-.

33. The compound of claim 31, wherein X5is -(CH2)3-.

34. The compound of any of claims 1-5, 11, or 16-33, wherein Y1is , wherein the bond marked with an "*" is attached to X4.

35. The compound of any of claims 1-5, 11, or 16-34, wherein Y2is , wherein the bond marked with an "*" is attached to X5.

36. The compound of any of claims 1-35, wherein R2is optionally substituted C1-C3 alkylene.

37. The compound of any of claims 1-35, wherein R2is optionally substituted C1 alkylene.

38. The compound of claim 37, wherein R2is –(CH2)-.

39. The compound of any of claims 1-35, wherein R3is optionally substituted C2alkylene.

40. The compound of claim 39, wherein R2is –(CH2)2-.

41. The compound of any of claims 1-40, wherein R3is optionally substituted C1-C3alkylene.

42. The compound of any of claims 1-41, wherein R3is optionally substituted C1alkylene.

43. The compound of claim 42, wherein R3is –(CH2)-.

44. The compound of any of claims 1-41, wherein R3is optionally substituted C2 alkylene.

45. The compound of claim 44, wherein R3is –(CH2)2-.

46. The compound of any of claims 1-10 or 16-45, R4is -CH(OR6)(OR7).

47. The compound of any of claims 1-10 or 16-45, R4is -CH(SR6)(SR7).

48. The compound of any of claims 1-10 or 16-45, R4is -R10.

49. The any of claims 1-10 or 16-45, R4is selected from the group consisting of51. The compound of any of claims 1-10 or 16-50, R5is -CH(OR6)(OR7).

52. The compound of any of claims 1-10 or 16-50, R5is -CH(OR8)(OR9).

53. The compound of any of claims 1-10 or 16-50, R5is -CH(SR6)(SR7).

54. The compound of any of claims 1-10 or 16-50, R5is -CH(OR8)(OR9).

55. The compound of any of claims 1-10 or 16-50, R5is -R11.O'56. The compound of any of claims 1-10 or 16-50, R5is selected from, , , , , , and .

57. The compound of any of claims 1-10 or 16-50, R5is selected from , , , and .

58. The compound of any of claims 1-55, wherein R6is -R10or optionally substituted -C1-C14aliphatic-R10.

59. The compound claim 58, wherein R6is optionally substituted -C1-C14 aliphatic-R10.

60. The compound claim 58, wherein R6is -CH2R10.

61. The compound claim 58, wherein R6is -R10.

62. The compound of any of claims 1-61, wherein R7is -R10or optionally substituted -C1-C14aliphatic-R10.

63. The compound claim 62, wherein R7is optionally substituted -C1-C14aliphatic-R10.

64. The compound claim 62, wherein R7is -CH2R10.

65. The compound claim 62, wherein R7is -R10.

66. The compound of any of claims 1-65, wherein R10is optionally substituted bridged bicyclic C5- C10 cycloalkylenyl.

67. The compound claim 66, wherein R10is an optionally substituted group selected from bicyclo[2.2.2]octyl or adamantyl.

68. The compound claim 66, wherein R10is selected from the group consisting of69. The compound of any of claims 1-68, wherein R8is optionally substituted -C1-C14 aliphatic.

70. The compound claim 69, wherein R8is optionally substituted -C7-C10 aliphatic.

71. The compound claim 69, wherein R8is selected from the group consisting of72. The compound of any of claims 1-71, wherein R9is optionally substituted -C1-C14 aliphatic.

73. The compound claim 72, wherein R9is optionally substituted -C7-C10 aliphatic.

74. The compound claim 72, wherein R9is selected from the group consisting of75. The compound of any of claims 1-74, wherein R11is optionally substituted bridged bicyclic C5- C10 cycloalkylenyl.

76. The compound claim 75, wherein R11is an optionally substituted group selected from bicyclo[2.2.2]octyl or adamantyl.

77. The compound claim 76, wherein R11is selected from the group consisting of78. A compound selected from the group consisting of those disclosed in Table (I-E) or a pharmaceutically acceptable salt therefore.

79. A pharmaceutical composition comprising: a) at least one lipid nanoparticle comprising at least one compound of any one of claims 1-78; and b) at least one nucleobase editing system.

80. The pharmaceutical composition of claim 79, wherein the nucleobase editing system comprises a CRISPR-Cas gene editing system.

81. The pharmaceutical composition of claim 79, wherein the nucleobase editing system comprises a prime editing system or components thereof.

82. The pharmaceutical composition of claim 79, wherein the nucleobase editing system comprises a retron editing system.

83. The pharmaceutical composition of claim 79, wherein the nucleobase editing system comprises a TnpB editing system.

84. The pharmaceutical composition of claim 79, wherein the nucleobase editing system comprises an integrase editing system.

85. The pharmaceutical composition of claim 79, wherein the nucleobase editing system comprises an integrase editing system.

86. The pharmaceutical composition of claim 79, wherein the nucleobase editing system comprises an epigenetic editing system.

87. The pharmaceutical composition of claim 79, wherein the nucleobase editing system comprises a gene writing system.

88. The pharmaceutical composition of claim 79, wherein the nucleobase editing system comprises a gene inactivating system.

89. The pharmaceutical composition of claim 79, wherein the nucleobase editing system comprises zinc finger nuclease.

90. The pharmaceutical composition of claim 79, wherein the nucleobase editing system comprises aTALE Nuclease, a TALE nickase, Zinc Finger (ZF) Nuclease, ZF Nickase, mcganuclcasc, or a combination thereof.

91. The pharmaceutical composition of claim 79, wherein the nucleobase editing system comprises a meganuclease.

92. The pharmaceutical composition of any one of claims 79-91, wherein the at least one lipid nanoparticle further comprises: i) at least one structural lipid; ii) at least one phospholipid; and iii) at least one PEGylated lipid.

93. The pharmaceutical composition of any one of claims 79-92, wherein the at least one structural lipid is selected from cholesterol, fecosterol, fucosterol, beta sitosterol, sitosterol, ergosterol, campesterol, stigmasterol, brassicasterol, tomatidine, cholic acid, sitostanol, litocholic acid, tomatine, ursolic acid, alpha-tocopherol, Vitamin D3, Vitamin D2, CalcipotrioL botulin, lupeol, oleanolic acid, beta-sitosterol-acetate and any combinations thereof.

94. The pharmaceutical composition of any one of claims 79-93, wherein the at least one phospholipid is selected from l,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 1,2-dioleoyl- sn-glycero-3-phosphoethanolamine (DOPE), l,2-dilinoleoyl-sn-glycero-3-phosphocholine (DLPC), 1,2-dimyristoyLsn-glycero-phosphocholine (DMPC), 1.2-dioleoyl-sn-glycero-3- phosphocholine (DOPC), l,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2- diundecanoyl-sn-glycero-phosphocholine (DUPC), l-palmitoyl-2-oleoyl-sn-glycero-3- phosphocho line (POPC), l,2-di-O-octadcccnyl-sn-glyccro-3-phosphocholinc (18:0 Dicthcr PC), l-oleoyl-2-cholesterylhemisuc cinoyl-sn-glycero-3-phosphocholine (OChemsPC), 1-hexadecyl- sn-glycero-3-phosphocholine (C16 Lyso PC), l,2-dilinolenoyl-sn-glycero-3-phosphocholine, 1,2- diarachidonoyl-sn-glycero-3-phosphocholine, l,2-didocosahexaenoyl-sn-glycero-3- phosphocholine, l,2-diphytanoylsn-glycero-3-phosphoethanolamine (ME 16.0 PE), 1,2- distearoyl-sn-glycero-3-phosphoethanolamine, l,2-dilinoleoyl-sn-glycero-3- phosphoethanolamine, l,2-dilinolenoyl-sn-glycero-3-phosphoethanolamine, 1,2-diarachidonoyl- sn-glycero-3-phosphoethanolamine, l,2-didocosahexaenoyl-sn-glycero-3-phosphoethanolamine, l,2-dioleoyl-sn-glycero-3-phospho-rac-(l -glycerol) sodium salt (DOPG), sodium (S)-2-ammonio- 3-((((R)-2-(oleoyloxy)-3-(stearoyloxy)propoxy)oxidophosphoryl)oxy)propanoate (L-a- phosphatidylserine; Brain PS), dimyristoyl phosphatidylcholine (DMPC), dimyristoyl phosphoethanolamine (DMPE), dimyristoylphosphatidylglycerol (DMPG), dioleoyl- phosphatidylethanolamine4-(N-maleimidomethyl)-cyclohexane-l -carboxylate (DOPE-mal), dioleoylphosphatidylglycerol (DOPG), L2-dioleoyl-sn-glycero-3-(phospho-L-serine) (DOPS),accll-fusogcnicphospholipid (DPhPE), dipalmitoylphosphatidylcthanolaminc (DPPE), 1,2- Dielaidoyl-sn-phosphatidylethanolamine (DEPE), dipalmitoylphosphatidylglycerol (DPPG), dipalmitoylphosphatidylserine (DPPS), distearoylphosphatidylcholine (DSPC), distearoyl- phosphatidy 1-ethanolamine (DSPE), distearoyl phosphoethanolamineimidazole (DSPEI), 1,2- diundecanoyl-sn-glycero-phosphocholine (DUPC), egg phosphatidylcholine (EPC), 1,2-dioleoyl- sn-glycero-3-phosphate (18:1 PA; DOPA), ammonium bis((S)-2-hydroxy-3-(oleoyloxy)propyl) phosphate (18:1 DMP; LBPA), l,2-dioleoyl-sn-glycero-3-phospho-(l’-myo-inositol) (DOPI; 18:1 PI), l,2-distearoyl-sn-glycero-3-phospho-L-serine (18:0 PS), l,2-dilinoleoyl-sn-glycero-3- phospho-L-serine (18:2 PS), l-palmitoyl-2-oleoyl-sn-glycero-3-phospho-L-serine (16:0-18:1 PS; POPS), l-stearoyl-2-oleoyl-sn-glycero-3-phospho-L-serine (18:0-18:1 PS), l-stearoyl-2-linoleoyl- sn-glycero-3-phospho-L-serine (18:0-18:2 PS), l-oleoyl-2-hydroxy-sn-glycero-3-phospho-L- serine (18:1 Lyso PS), l-stearoyl-2-hydroxy-sn-glycero-3-phospho-L-serine (18:0 Lyso PS), and sphingomyelin.

95. The pharmaceutical composition of any one of claims 79-94, wherein the at least one PEGylated lipid is selected from (R)-2,3-bis(octadecyloxy)propyl-l- (methoxypoly(ethyleneglycol)2000)propylcarbamate, PEG-S-DSG, PEG-S-DMG, PEG-PE, PEG- PAA, PEG-OH DSPE C18, PEG-DSPE, PEG-DSG, PEG-DPG, PEG-DOMG, PEG-DMPE Na, PEG-DMPE, PEG-DMG2000, PEG-DMG Cl 4, PEG-DMG 2000, PEG-DMG, PEG-DMA, PEG- Ceramide C16, PEG-C-DOMG, PEG-c-DMOG, PEG-c-DMA, PEG-cDMA, PEGA, PEG750-C- DMA, PEG400, PEG2k-DMG, PEG2k-Cll, PEG2000-PE, PEG2000P, PEG2000-DSPE, PEG2000-DOMG, PEG2000-DMG, PEG2000-C-DMA, PEG2000, PEG200, PEG(2k)-DMG, PEG DSPE C18, PEG DMPE C14, PEG DLPE C12, PEG Click DMG C14, PEG Click C12, PEG Click CIO, N(Carbonyl-methoxypolyethylenglycol-2000)-l,2-distearoyl-sn-glycero3- phosphoethanolamine, Myrj52, mPEG-PLA, MPEG-DSPE, mPEG3000-DMPE, MPEG-2000- DSPE, MPEG2000-DSPE, mPEG2000-DPPE, mPEG2000-DMPE, mPEG2000-DMG, mDPPE- PEG2000, l,2-distearoyl-sn-glycero-3-phosphoethanolamine-PEG2000, HPEG-2K-LIPD, Folate PEG-DSPE, DSPE-PEGMA 500, DSPE-PEGMA, DSPE-PEG6000, DSPE-PEG5000, DSPE- PEG2K-NAG, DSPE-PEG2k, DSPE-PEG2000maleimide, DSPE-PEG2000, DSPE-PEG, DSG- PEGMA, DSG-PEG5000, DPPE-PEG-2K, DPPE-PEG, DPPE-mPEG2000, DPPE-mPEG, DPG- PEGMA, DOPE-PEG2000, DMPE-PEGMA, DMPE-PEG2000, DMPE-Peg, DMPE-mPEG2000, DMG-PEGMA, DMG-PEG2000, DMG-PEG, distearoyl-glycerol-polyethyleneglycol, C18PEG750, CI8PEG5000, CI8PEG3000, CI8PEG2000, CI6PEG2000, CI4PEG2000, C18- PEG5000, C18PEG, C16PEG, C16 mPEG (polyethylene glycol) 2000 Ceramide, C14-PEG- DSPE200, C14-PEG2000, C14PEG2000, C14-PEG 2000, C14-PEG, C14PEG, 14:0-PEG2KPE, l,2-distearoyl-sn-glycero-3-phosphoethanolamine-PEG2000, (R)-2,3-bis(octadecyloxy)propyl-l- (methoxypoly(ethyleneglycol)2000)propylcarbamate, (PEG)-C-DOMG, PEG-C-DMA, andDSPE-PEG-X.

96. The pharmaceutical composition of any one of claims 79-95, wherein the LNP further comprises at least one additional lipid component selected from l,2-di-O-octadecenyl-sn-glycero-3- phosphocholine (18:0 Diether PC), l,2-dilinolenoyl-sn-glycero-3-phosphocholine (18:3 PC), Acylcarnosine (AC), l-hexadecyl-sn-glycero-3-phosphocholine (C16 Lyso PC), N-oleoyl- sphingomyelin (SPM) (C18:l), N-lignoceryl SPM (C24:0), N-nervonoylshphingomyelin (C24:l), Cardiolipin (CL), l,2-bis(tricosa-10,12-diynoyl)-sn-glycero-3-phosphocholine (DC8-9PC), dicetyl phosphate (DCP), dihexadecyl phosphate (DCP1), l,2-Dipalmitoylglycerol-3-hemisuccinate (DGSucc), short-chain bis-n-heptadecanoyl phosphatidylcholine (DHPC), dihexadecoyl- phosphoethanolamine (DHPE), 1 ,2-dilinoleoyl-sn-glycero-3-phosphocholine (DLPC), 1,2- dilauroyl-sn-glycero-3-PE (DLPE), dimyristoyl glycerol hemisuccinate (DMGS), dimyristoyl phosphatidylcholine (DMPC), dimyristoyl phosphoethanolamine (DMPE), dimyristoylphosphatidylglycerol (DMPG), dioleyloxybenzylalcohol (DOBA), 1,2- dioleoylglyceryl-3-hemisuccinate (DOGHEMS), N-[2-(2-{2-[2-(2,3-Bis-octadec-9-enyloxy- propoxy)-ethoxy]-ethoxy }-ethoxy)-ethyl]-3-(3,4,5-lrihydroxy-6-hydroxymethyl-letrahydro- pyran-2-ylsulfanyl)-propionamide (DOGP4aMan), dioleoylphosphatidylcholine (DOPC), dioleoylphosphatidylethanolamine (DOPE), dioleoyl-phosphatidylethanolamine4-(N- malcimidomcthyl) -cyclohexane- 1-carboxylatc (DOPE-mal), diolcoylphosphatidylglyccrol (DOPG), l,2-dioleoyl-sn-glycero-3-(phospho-L-serine) (DOPS), acell-fusogenicphospholipid (DPhPE), dipalmitoylphosphatidylethanolamine (DPPE), dipalmitoylphosphatidylglycerol (DPPG), dipalmitoylphosphatidylserine (DPPS), distearoylphosphatidylcholine (DSPC), distearoyl-phosphatidyl-ethanolamine (DSPE), distearoyl phosphoethanolamineimidazole (DSPEI), 1,2-diundecanoyl-sn-glycero-phosphocholine (DUPC), egg phosphatidylcholine (EPC), histaminedistearoylglycerol (HDSG), 1 ,2-Dipalmitoylglycerol-hemisuccinate-Na-Histidinyl- Hemisuccinate (HistSuccDG), N-(5'-hydroxy-3'-oxypentyl)-10-12-pentacosadiynamide (h-Pegi- PCDA), 2-[l-hexyloxyethyl]-2-devinylpyropheophorbide-a (HPPH), hydrogenatedsoybeanphosphatidylcholine (HSPC), 1,2-Dipalmitoylglycerol-O-a-histidinyl-Na- hemisuccinate (IsohistsuccDG), mannosialized dipalmitoylphosphatidylethanolamine (ManDOG), l,2-Dioleoyl-sn-Glycero-3-Phosphoethanolamine-N-[4-(p-maleimidomethyl)cyclohexane- carboxamide] (MCC-PE), l,2-diphytanoyl-sn-glycero-3-phosphoethanolamine (ME 16:0 PE), 1- myristoyl-2-hydroxy-sn-glycero-phosphocholine (MHPC), a thiol-reactive maleimide headgroup lipid e.g.1 ,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N- [4-(p-maleimidophenyl)but-yramid (MPB-PE), Nervonic Acid (NA), sodium cholate (NaChol), l,2-dioleoyl-sn-glycero-3- [phosphoethanolamine-N-dodecanoyl (NC12-DOPE), l-oleoyl-2-cholesteryl hemisuccinoyl-sn- glycero-3-phosphocholine (OChemsPC), phosphatidylethanolamine lipid (PE), PE lipid conjugated with polyethylene glycol(PEG) (e.g., polyethylene glycol-distcaroylphosphatidylcthanolaminc lipid (PEG-PE)), phosphatidylglyccrol (PG), partially hydrogenated soy phosphatidylchloline (PIISPC), phosphatidylinositol lipid (PI), phosphotidylinositol-4-phosphate (PIP), palmitoyloleoylphosphatidylcholine (POPC), phosphatidylethanolamine (POPE), palmitoyloleyolphosphatidylglycerol (POPG), phosphatidylserine (PS), lissamine rhodamineB-phosphatidylethanolamine lipid (Rh-PE), purifiedsoy-derivedmixtureofphospholipids (SIOO), phosphatidylcholine (SM), 18-l-trans-PE,l- stearoyl-2-oleoyl-phosphatidyethanolamine (SOPE), soybean phosphatidylcholine (SPC), sphingomyelins (SPM), alpha, alpha-trehalose-6,6'-dibehenate (TDB), L2-dielaidoyl-sn-glycero-3- phophoethanolamine (transDOPE), ((23S,5R)-3-(bis(hexadecyloxy)methoxy)-5-(5-methyl-2,4- dioxo-3,4-dihydropyrimidin- 1 (2H)-yl)tetrahydrofuran-2-yl)methylmethylphosphate, 1 ,2- diarachidonoyl-sn-glycero-3-phosphocholine, l,2-diarachidonoyl-sn-glycero-3- phosphoethanolamine, l,2-didocosahexaenoyl-sn-glycero-3-phosphocholine, 1,2- didocosahexaenoyl-sn-glycero-3-phosphoethanolamine, l,2-dilinolenoyl-sn-glycero-3- phosphocholine, l,2-dilinolenoyl-sn-glycero-3-phosphoethanolamine, 1,2-dilinoleoyl-sn-glycero- 3-phosphoethanolamine, l,2-dioleyl-sn-glycero-3-phosphoethanolamine, 1,2-distearoyl-sn- glycero-3-phosphoethanolamine, 16-O-monomethyl PE, 16-O-dimethyl PE, and dioleylphosphatidylethanolamine.

97. A method of delivering a nuclcobasc editing system to a subject in need thereof, the method comprising administering to the subject the pharmaceutical composition of any one of claims 79- 96.

98. The pharmaceutical composition of any one of claims 79-97 for use as a medicament.

99. Use of a pharmaceutical composition of any one of claims 79-97 for the manufacture of a medicament for delivery of a nucleobase editing system.

100. A lipid nanoparticle (LNP) comprising a compound of any one of claims 1-78, or a pharmaceutically acceptable salt thereof.

101. The LNP of claim 100, further comprising:(a) a PEG- lipid(b) a structural lipid; and(c) a non-ionizable lipid and / or a zwitterionic lipid.

102. The LNP of claim 101, wherein the lipid nanoparticle further comprises an additional ionizable lipid, besides a compound of Formula (CC).

103. The LNP of claim 101 or 102, wherein the PEG-lipid is selected from the group consisting ofPEG-c-DOMG, PEG-DMG, PEG-DLPE, PEG-DMPE, PEG-DPPC, and PEG-DSPE.

104. The LNP of any one of claims 101-103, wherein the structural lipid is selected from the group consisting of cholesterol, fecosterol, sitosterol, ergosterol, campesterol, stigmasterol, brassicasterol, tomatidine, ursolic acid, an alpha-tocopherol.

105. The LNP of any one of claims 101-104, wherein the non-ionizable lipid is a phospholipid selected from the group consisting of l,2-distearoyl-sn-glycero-3 -phosphocholine (DSPC), 1,2- dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), 1 ,2-dilinoleoyl-sn-glycero-3- phosphocholine (DLPC), 1,2-dimyristoyl-sn-glycero-phosphocholine (DMPC), 1.2-dioleoyLsn- glycero-3 -phosphocholine (DOPC), l,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2- diundecanoyl-sn-gly cero-phosphocholine (DUPC), 1 -palmitoy 1-2-oleoyl-sn-gly cero-3 - phosphocho line (POPC), l,2-di-O-octadcccnyl-sn-glyccro-3-phosphocholinc (18:0 Dicthcr PC), l-oleoyl-2-cholesterylhemisuc cinoyl-sn-glycero-3-phosphocholine (OChemsPC), 1-hexadecyl- sn-glycero-3-phosphocholine (C16 Lyso PC), l,2-dilinolenoyl-sn-glycero-3-phosphocholine, 1,2- diarachidonoyl-sn-glycero-3-phosphocholine, l,2-didocosahexaenoyl-sn-glycero-3- phosphocholine, l,2-diphytanoylsn-glycero-3-phosphoethanolamine (ME 16.0 PE), 1,2- distearoyl-sn-glycero-3-phosphoethanolamine, l,2-dilinoleoyl-sn-glycero-3- phosphoethanolamine, l,2-dilinolenoyl-sn-glycero-3-phosphoethanolamine, 1,2-diarachidonoyl- sn-glycero-3-phosphoethanolamine, l,2-didocosahexaenoyl-sn-glycero-3-phosphoethanolamine, l,2-dioleoyl-sn-glycero-3-phospho-rac-(l -glycerol) sodium salt (DOPG), sodium (S)-2-ammonio- 3-((((R)-2-(oleoyloxy)-3-(stearoyloxy)propoxy)oxidophosphoryl)oxy)propanoate (L-a- phosphatidylserine; Brain PS), dimyristoyl phosphatidylcholine (DMPC), dimyristoyl phosphoethanolamine (DMPE), dimyristoylphosphatidylglycerol (DMPG), dioleoyl- phosphatidylethanolamine4-(N-maleimidomethyl)-cyclohexane-l -carboxylate (DOPE-mal), dioleoylphosphatidylglycerol (DOPG), l,2-dioleoyl-sn-glycero-3-(phospho-L-serine) (DOPS), acell-fusogenicphospholipid (DPhPE), dipalmitoylphosphatidylethanolamine (DPPE), dipalmitoylphosphatidylglycerol (DPPG), dipalmitoylphosphatidylserine (DPPS), distearoylphosphatidylcholine (DSPC), distearoyl-phosphatidyl-ethanolamine (DSPE), distearoyl phosphoethanolamineimidazole (DSPEI), 1,2-diundecanoyl-sn-glycero-phosphocholine (DUPC), egg phosphatidylcholine (EPC), l,2-dioleoyl-sn-glycero-3-phosphate (18:1 PA; DOPA), ammonium bis((S)-2-hydroxy-3-(oleoyloxy)propyl) phosphate (18:1 DMP; LBPA), 1,2-dioleoyl- sn-glycero-3-phospho-(r -myo-inositol) (DOPI; 18:1 PI), l,2-distearoyl-sn-glycero-3-phospho-L- serine (18:0 PS), l,2-dilinoleoyl-sn-glycero-3-phospho-L-serine (18:2 PS), l-palmitoyl-2-oleoyl- sn-glycero-3-phospho-L-serine (16:0-18:1 PS; POPS), l-stearoyl-2-oleoyl-sn-glycero-3-phospho- L-serine (18:0-18:1 PS), l-stearoyl-2-linoleoyl-sn-glycero-3-phospho-L-serine (18:0-18:2 PS), 1- oleoyl-2-hydroxy-sn-glycero-3-phospho-L-serine (18:1 Lyso PS), l-stearoyl-2-hydroxy-sn-glyccro-3-phospho-L-scrinc (18:0 Lyso PS), and sphingomyelin.

106. The LNP of any one of claims 101-105, further comprising a targeting moiety.

107. The LNP of claim 106, wherein the targeting moiety is an antibody or a fragment thereof.

108. The LNP of any one of claims 101-107, further comprising an active agent.

109. The LNP of claim 108, wherein the active agent is a nucleic acid.1 10. The LNP of claim 109, wherein the nucleic acid is a ribonucleic acid.

111. The LNP of claim 110, wherein the ribonucleic acid is at least one ribonucleic acid selected from the group consisting of a small interfering RNA (siRNA), an asymmetrical interfering RNA (aiRNA), a microRNA (miRNA), a Dicer-substrate RNA (dsRNA), a small hairpin RNA (shRNA), a messenger RNA (mRNA), and a long non-coding RNA (IncRNA).

112. The LNP of claim 111, wherein the nucleic acid is a messenger RNA (mRNA) or a circular RNA.

113. The LNP of claim 112, wherein the mRNA includes an open reading frame encoding a cancer antigen.

114. The LNP of claim 112, wherein the mRNA includes an open reading frame encoding an immune checkpoint modulator.

115. The LNP of any one of claims 112-114, wherein the mRNA includes at least one motif selected from the group consisting of a stem loop, a chain terminating nucleoside, a polyA sequence, a polyadenylation signal, and a 5' cap structure.

116. The LNP of claim 109, wherein the nucleic acid is suitable for a genome editing technique.

117. The LNP of claim 116, wherein the genome editing technique is clustered regularly interspaced short palindromic repeats (CRISPR) or transcription activator-like effector nuclease (TALEN).

118. The LNP of claim 109, wherein the nucleic acid is at least one nucleic acid suitable for a genome editing technique selected from the group consisting of a CRISPR RNA (crRNA), a trans-activating crRNA (tracrRNA), a single guide RNA (sgRNA), and a DNA repair template.

119. The LNP of claim 112, wherein the mRNA is at least 30 nucleotides in length.

120. The LNP of claim 112, wherein the mRNA is at least 300 nucleotides in length.

121. A pharmaceutical composition comprising a LNP of any one of claims 101-120, and a pharmaceutically acceptable carrier.

122. The pharmaceutical composition of claim 121, formulated for intravenous or intramuscular administration.

123. The pharmaceutical composition of claim 121, which is formulated for intravenous administration.

124. A method for delivering a nucleic acid to a cell comprising contacting the cell with a LNP of any one of claims 101-120 or a pharmaceutical composition of any one of claims 99-101.

125. A method for treating a disease characterized by a deficiency of a functional protein, the method comprising administering to a subject having the disease, a LNP formulation comprising a LNP of any one of claims 101-120, wherein the mRNA encodes the functional protein or a protein having the same biological activity as the functional protein.

126. A method for treating a disease characterized by overexpression of a polypeptide, comprising administering to a subject having the disease a LNP formulation comprising a LNP of any one of claims 101-120 and a siRNA, wherein the siRNA targets expression of the overexpressed polypeptide.

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