Lipids and lipid-like compounds for therapeutic lipid nanoparticle (LNP) delivery

Abstract

The current disclosure relates to lipid-based compositions and methods of administering therapeutic agents relating thereto. In particular, the disclosure relates to lipid-like substituted aryl and / or heteroaryl compounds, substituted piperazines, and / or other aryl and / or heteroaryl lipid compounds as LNP delivery materials that may be incorporated into lipid-based compositions to increase efficiency of delivery of a therapeutic agent(s) to tissues of a subject.

Description

[0001] LIPIDS AND LIPID-LIKE COMPOUNDS FOR THERAPEUTIC LIPID NANOPARTICLE (LNP) DELIVERY CROSS-REFERENCE TO RELATED APPLICATIONS The present application is related to and claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Patent Application No. 63 / 494,871, entitled “LIPID-LIKE SUBSTITUTED ARYL AND HETEROARYL COMPOUNDS AS LIPID NANOPARTICLE (LNP) DELIVERY MATERIALS AND THERAPEUTIC USES THEREOF,” filed April 7, 2023, U.S. Provisional Patent Application No. 63 / 494,872, entitled "SUBSTITUTED PIPERAZINE IONIZABLE LIPIDS USEFUL FOR THERAPEUTIC LIPID NANOPARTICLE (LNP) DELIVERY", filed April 7, 2023, U.S. Provisional Patent Application No. 63 / 624,550, entitled " SUBSTITUTED PIPERAZINE IONIZABLE LIPIDS USEFUL FOR THERAPEUTIC LIPID NANOPARTICLE (LNP) DELIVERY", filed January 24, 2024, U.S. Provisional Patent Application No.63 / 501,566, entitled "ARYL AND HETEROARYL LIPID COMPOUNDS, LIPID NANOPARTICLE (LNP) FORMULATIONS, AND THERAPEUTIC USES THEREOF" filed May 11, 2023 and U.S. Provisional Patent Application No. 63 / 624,073, entitled "ARYL AND HETEROARYL LIPID COMPOUNDS, LIPID NANOPARTICLE (LNP) FORMULATIONS, AND THERAPEUTIC USES THEREOF", filed January 23, 2024. The entire contents of the aforementioned patent applications are incorporated herein by this reference. FIELD The current disclosure relates to lipid-based compositions. In particular, the disclosure relates to (1) lipid-like ionizable substituted aryl and heteroaryl compounds as lipid nanoparticle (LNP) delivery materials, (2) substituted piperazines as ionizable lipids, and (3) other aryl and heteroaryl lipid compounds, that may be incorporated into lipid-based compositions to increase efficiency of delivery of a therapeutic agent(s) to one or more tissues of a subject. BACKGROUND Nucleic acid therapies offer tremendous potential for treatment of diseases at the level of individual, targeted genes. However, safe and effective delivery systems are essential for realizing the full promise of nucleic acid therapeutics. Non-specific delivery of nucleic acid therapeutics to all organs and tissues can often result in off-site (non-targeted and / or off-target) effects and toxicity. Preferential delivery of nucleic acid therapeutics to an organ or tissue of interest in which a specific action is desirable is a continuing goal for drug delivery in general, and delivery of nucleic acid-based agents in particular. Unfortunately, there are effectively no options for nanoparticle delivery systems that are capable of targeting specific tissues without introducing ligand-based targeting strategies (i.e., active targeting). Accordingly, there is an unmet need in the art for delivery modalities that are capable of achieving tissue-specific delivery of nucleic acid cargoes based only upon the structural components of such delivery modalities (e.g., via non-active targeting modalities). BRIEF SUMMARY The present disclosure provides various novel lipids and lipid-like compounds. Certain aspects of the disclosure provide novel ionizable lipid-like chemicals (e.g., lipid- like substituted aryl and heteroaryl compounds as represented by Formula I) that were designed and synthesized according to the techniques disclosed herein. These novel ionizable lipid-like substituted aryl and heteroaryl compounds were formulated into lipid nanoparticles (LNPs), and shown to provide a stable and efficient LNP formulation, which was comparable to, or better than, benchmark lipids of the prior art. Some aspects of the disclosure provide novel ionizable lipid-like chemicals (e.g., substituted piperazine ionizable lipids as represented by Formula VII) that were designed and synthesized according to the techniques disclosed herein. These novel ionizable lipid-like chemicals were also formulated into lipid nanoparticles (LNPs), and shown to provide a stable and efficient LNP formulation, which was comparable to, or better than, benchmark lipids of the prior art. Further aspects of the disclosure provide novel ionizable lipid-like chemicals (e.g., aryl and heteroaryl lipid compounds as represented by Formula IX) that were designed and synthesized according to the techniques disclosed herein. These novel aryl and heteroaryl lipid compounds were also formulated into lipid nanoparticles (LNPs), and shown to provide a stable and efficient LNP formulation, which was comparable to, or better than, benchmark lipids of the prior art. The present disclosure is based, at least in part, upon the discovery that lipid-like substituted aryl and heteroaryl compounds may be used to form novel ionizable lipids having advantageous properties when used in lipid particles for the in vivo delivery of a therapeutic agent(s). In particular, the techniques herein provide lipid-based nanoparticle compositions and formulations capable of specifically targeting a cargo moiety (e.g., a nucleic acid cargo) to specific tissues of a subject, without requiring a ligand-based targeting strategy. Lipid-like substituted aryl and heteroaryl compounds as disclosed herein may comprise the following general structure: In one aspect, the disclosure provides a compound of Formula I: (I) or a salt or isomer thereof, where X is CH or N; a and b are independently 2-5; m1, m2, m3, and m4are independently 4-10; E1, E2, E3, and E4 are independently -O(CO)O-, -(CO)O- or -O(CO)-; T1, T2, T3, and T4 are independently branched or unbranched C5-C22 alkyl, C5-C22 alkenyl, or C5-C22alkynyl; R1and R2are independently H or C1-C6alkyl, C2-C6alkenyl, or C2-C6alkynyl; R3 is independently H or C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl or ; G is O, -(CO)NR3-, -NR3(CO)-, -(CO)O-, or -CH2(CO)NR3-; L is a bond or optionally substituted C1-C4alkyl; Z is CH or N, and R4 and R5 are independently H, C1-C3 alkyl, C2-C3 alkenyl, or C2-C3 alkynyl, or optionally substituted 3-7 membered ring comprising 0-2 heteroatoms, or R4and R5together with L form a substituted 3-7 membered ring. In some embodiments, one or more of R1 and R2, a and b, m1-m4, E1-E4, and T1-T4 are the same. In some embodiments, one or more of R1 and R2, a and b, m1-m4, E1-E4, and T1-T4 are different. In some embodiments, R1and R2, a and b, m1-m4, E1-E4, and T1-T4are all the same. In some embodiments, R1and R2are H. In some embodiments, a and b are independently 3, 4, or 5. In some embodiments, a and b are 3. In some embodiments, m1, m2, m3, and m4are independently 6, 7, 8, or 9. In some embodiments, m1, m2, m3, and m4 are 8. In some embodiments, E1, E2, E3, and E4 are -(CO)O-. In some embodiments, E1, E2, E3, and E4 are -O(CO)- or -O(CO)O-. In some embodiments, T1, T2, T3, or T4are independently selected from the group consisting of C5-C18 alkyl, C5-C18 alkenyl, and C5-C18 alkynyl, each of which is optionally substituted, optionally where T1, T2, T3, and T4 are independently selected from the group consisting of C5-C18alkyl, C5-C18alkenyl, and C5-C18alkynyl, each of which is optionally substituted. In some embodiments, T1, T2, T3, or T4 are independently selected from the group consisting of C5-C12alkyl, C5-C12alkenyl, and C5-C12alkynyl, each of which is optionally substituted, optionally T1, T2, T3, and T4are independently selected from the group consisting of C5-C12 alkyl, C5-C12 alkenyl, and C5-C12 alkynyl, each of which is optionally substituted. In some embodiments, T1, T2, T3, or T4 are independently selected from the group consisting of C5-C10alkyl, C5-C10alkenyl, and C5-C10alkynyl, each of which is optionally substituted, optionally T1, T2, T3, and T4 are independently selected from the group consisting of C5-C10 alkyl, C5-C10 alkenyl, and C5-C10 alkynyl, each of which is optionally substituted. In some embodiments, T1, T2, T3, or T4are independently selected from the group consisting of C5-C8alkyl, C5-C8alkenyl, and C5-C8alkynyl, each of which is optionally substituted, optionally T1, T2, T3, and T4 are independently selected from the group consisting of C5-C8alkyl, C5-C8alkenyl, and C5-C8alkynyl, each of which is optionally substituted. In some embodiments, T1, T2, T3, or T4are independently selected from the group consisting of C6-C8 alkyl, C6-C8 alkenyl, and C6-C8 alkynyl, each of which is optionally substituted, optionally T1, T2, T3, and T4are independently selected from the group consisting of C6-C8alkyl, C6-C8alkenyl, and C6-C8alkynyl, each of which is optionally substituted. In some embodiments, T1, T2, T3, or T4 are independently selected from the group consisting of C7 or C8 alkyl, C7 or C8 alkenyl, and C7 or C8 alkynyl, each of which is optionally substituted, optionally T1, T2, T3, and T4are independently selected from the group consisting of C7 or C8 alkyl, C7 or C8 alkenyl, and C7 or C8 alkynyl, each of which is optionally substituted. In some embodiments, G is O, -(CO)NR3-, and -NR3(CO)-. In some embodiments, R3is H or methyl. In some embodiments, In some embodiments, L is a bond. In some embodiments, L is C1alkyl. In some embodiments, L is C2 alkyl. In some embodiments, L is C3alkyl. In some embodiments, L is C4alkyl. In some embodiments, R4, R5, or R4 and R5 are absent or H. In some embodiments, R4, R5, or R4and R5are . In some embodiments, R4and R5are independently C1, C2, or C3alkyl. In some embodiments, R4and R5form an optionally substituted 6 membered ring comprising 1 or 2 heteroatoms. In some embodiments, at least one of the 1 or 2 heteroatoms is N. In some embodiments, a hydrogen of at least one atom of the 6 membered ring is substituted with a methyl group. In some embodiments, the at least one atom is a N atom. In some embodiments, the 6 membered ring includes 1, 2, or 3 double bonds, optionally wherein the 6 membered ring includes three double bonds. In some embodiments, R4 and R5 are methyl. In some embodiments, R4and R5form an optionally substituted 5 membered ring comprising 1 or 2 heteroatoms and 1 or 2 double bonds. In some embodiments, at least one of the 1 or 2 heteroatoms is N. In some embodiments, T1, T2, T3, and T4 are independently an alkyl selected from the group consisting of butane, pentane, hexane, heptane, octane, nonane, decane, undecane, dodecane, and tridecane, each of which is optionally substituted. In some embodiments, T1, T2, T3, and T4 are octane or tridecane. In some embodiments, T1, T2, T3, and T4 are independently an alkenyl selected from the group consisting of but-1-ene, but-2-ene, pent-1-ene, pent-2-ene, hex-1-ene, hex-2-ene, hex3-ene, hept-1-ene, hept-2-ene, hept-3-ene, oct-1-ene, oct-2-ene, oct-3-ene, oct-4-ene, non-1-ene, non-2- ene, non-3-ene, non-4-ene, non-5-ene, dec-1-ene, dec-2-ene, dec-3-ene, dec-4-ene, dec-5-ene, dec- 6-ene, undec-1-ene, undec-2-ene, undec-3-ene, undec-4-ene, undec-5-ene, undec-6-ene, undec-7- ene, dodec-1-ene, dodec-2-ene, dodec-3-ene, dodec-4-ene, dodec-5-ene, dodec-6-ene, dodec-8- ene, and an alkenyl group comprising two or more double bonds, each of which is optionally substituted. In some embodiments, T1, T2, T3, and T4are independently an alkynyl selected from the group consisting of but-1-yne, but-2-yne, pent-1-yne, pent-2-yne, hex-1-yne, hex-2-yne, hex3-yne, hept-1-yne, hept-2-yne, hept-3-yne, oct-1-yne, oct-2-yne, oct-3-yne, oct-4-yne, non-1-yne, non-2- yne, non-3-yne, non-4-yne, non-5-yne, dec-1-yne, dec-2-yne, dec-3-yne, dec-4-yne, dec-5-yne, dec-6-yne, undec-1-yne, undec-2-yne, undec-3-yne, undec-4-yne, undec-5-yne, undec-6-yne, undec-7-yne, dodec-1-yne, dodec-2-yne, dodec-3-yne, dodec-4-yne, dodec-5-yne, dodec-6-yne, dodec-8-yne, and an alkynyl group comprising two or more triple bonds, each of which is optionally substituted. In some embodiments, X is N. In one aspect, the disclosure provides a compound of Formula II:

[0002] (II), or a salt or isomer thereof, where X is CH or N; L1, L2, and L3 are independently -O-, -(CO)NRx-, -NRx(CO)-, -(CO)O-, -CH2(CO)NRx-, provided that when A is CH not all of L1, L2, and L3are -(CO)NRx-; Rxis H, C1-C6alkyl, or C3-C6cycloalkyl; G1 and G2 are Formula III: or salt or isomer thereof, where n1 is 3, 45, 6, 7, 8, 9, or 10; L4 is -(CO)O- or -O(CO)-; R6is branched C5-C20alkyl; G3 is Formula (III), Formula (IV), Formula (V), or Formula (VI): R7 and R8 are independently, optionally functionalized, C1-C5 alkyl; n2, n3, and n4are independently 0, 1, 2, or 3; X1 is C, N, or O; and R9 and R10 are independently H or optionally functionalized C1-C5 alkyl. In one aspect, the disclosure provides a compound selected from the group consisting of: (SM-066),

[0003] ( ( (SM-082),

[0004] ( (SM-089),

[0005] ( ( (SM-092),

[0006] ( ( (SM-095),

[0007] ( ( (SM-101),

[0008] O ( ( (SM-114),

[0009] ( ( (SM-120),

[0010]

[0011] ( ( ( (SM-163),

[0012] ( (SM-173). In one aspect, the disclosure provides a pharmaceutical composition comprising a lipid of Formula I:

[0013] ( or a salt or isomer thereof, where X is CH or N; a and b are independently 2-5; m1, m2, m3, and m4are independently 4-10; E1, E2, E3, and E4 are independently -O(CO)O-, -(CO)O- or -O(CO)-; T1, T2, T3, and T4 are independently branched or unbranched C5-C22 alkyl, C5-C22 alkenyl, or C5-C22alkynyl; R1 and R2 are independently H or C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; R3 is independently H or C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl or G is O, -(CO)NR3-, -NR3(CO)-, -(CO)O-, or -CH2(CO)NR3-; L is a bond or optionally substituted C1-C4alkyl; Z is CH or N, and R4 and R5 are independently H, C1-C3 alkyl, C2-C3 alkenyl, or C2-C3 alkynyl, or optionally substituted 3-7 membered ring comprising 0-2 heteroatoms, or R4 and R5 together with L form a substituted 3-7 membered ring. In some embodiments, one or more of R1and R2, a and b, m1-m4, E1-E4, and T1-T4are the same. In some embodiments, one or more of R1 and R2, a and b, m1-m4, E1-E4, and T1-T4 are different. In some embodiments, R1and R2, a and b, m1-m4, E1-E4, and T1-T4are all the same. In some embodiments, R1 and R2 are H. In some embodiments, a and b are independently 1, 2, or 3. In some embodiments, a and b are 1. In some embodiments, m1, m2, m3, and m4 are independently 4, 5, 6, or 7. In some embodiments, m1, m2, m3, and m4 are 6. In some embodiments, E1, E2, E3, and E4are -(CO)O-. In some embodiments, E1, E2, E3, and E4 are -O(CO)- or -O(CO)O-. In some embodiments, T1, T2, T3, or T4 are independently selected from the group consisting of C5-C18 alkyl, C5-C18 alkenyl, and C5-C18 alkynyl, each of which is optionally substituted, optionally T1, T2, T3, and T4are independently selected from the group consisting of C5-C18 alkyl, C5-C18 alkenyl, and C5-C18 alkynyl, each of which is optionally substituted. In some embodiments, T1, T2, T3, or T4 are independently selected from the group consisting of C5-C12alkyl, C5-C12alkenyl, and C5-C12alkynyl, each of which is optionally substituted, optionally T1, T2, T3, and T4are independently selected from the group consisting of C5-C12 alkyl, C5-C12 alkenyl, and C5-C12 alkynyl, each of which is optionally substituted. In some embodiments, T1, T2, T3, or T4are independently selected from the group consisting of C5-C10alkyl, C5-C10alkenyl, and C5-C10alkynyl, each of which is optionally substituted, optionally T1, T2, T3, and T4 are independently selected from the group consisting of C5-C10 alkyl, C5-C10 alkenyl, and C5-C10 alkynyl, each of which is optionally substituted. In some embodiments, T1, T2, T3, or T4are independently selected from the group consisting of C5-C8 alkyl, C5-C8 alkenyl, and C5-C8 alkynyl, each of which is optionally substituted, optionally T1, T2, T3, and T4 are independently selected from the group consisting of C5-C8alkyl, C5-C8alkenyl, and C5-C8alkynyl, each of which is optionally substituted. In some embodiments, T1, T2, T3, or T4are independently selected from the group consisting of C6-C8 alkyl, C6-C8 alkenyl, and C6-C8 alkynyl, each of which is optionally substituted, optionally wherein T1, T2, T3, and T4are independently selected from the group consisting of C6-C8alkyl, C6-C8alkenyl, and C6-C8alkynyl, each of which is optionally substituted. In some embodiments, T1, T2, T3, or T4are independently selected from the group consisting of C7or C8alkyl, C7or C8alkenyl, and C7or C8alkynyl, each of which is optionally substituted, optionally wherein T1, T2, T3, and T4 are independently selected from the group consisting of C7 or C8 alkyl, C7 or C8 alkenyl, and C7 or C8 alkynyl, each of which is optionally substituted. In some embodiments, G is O, -(CO)NR3-, and -NR3(CO)-. In some embodiments, R3 is H or methyl. In some embodiments, . In some embodiments, L is a bond. In some embodiments, L is C1 alkyl. In some embodiments, L is C2alkyl. In some embodiments, L is C3 alkyl. In some embodiments, L is C4 alkyl. In some embodiments, R4, R5, or R4and R5are absent or H. In some embodiments, R4, R5, or R4 and R5 are . In some embodiments, R4and R5are independently C1, C2, or C3 alkyl. In some embodiments, R4and R5form an optionally substituted 6 membered ring comprising 1 or 2 heteroatoms. In some embodiments, at least one of the 1 or 2 heteroatoms is N. In some embodiments, a hydrogen of at least one atom of the 6 membered ring is substituted with a methyl group. In some embodiments, the at least one atom is a N atom. In some embodiments, the 6 membered ring includes 1, 2, or 3 double bonds, optionally wherein the 6 membered ring includes three double bonds. In some embodiments, R4 and R5 are methyl. In some embodiments, R4 and R5 form an optionally substituted 5 membered ring comprising 1 or 2 heteroatoms and 1 or 2 double bonds. In some embodiments, at least one of the 1 or 2 heteroatoms is N. In some embodiments, T1, T2, T3, and T4 are independently an alkyl selected from the group consisting of butane, pentane, hexane, heptane, octane, nonane, decane, undecane, dodecane, and tridecane, each of which is optionally substituted. In some embodiments, T1, T2, T3, and T4 are octane or tridecane. In some embodiments, T1, T2, T3, and T4 are independently an alkenyl selected from the group consisting of but-1-ene, but-2-ene, pent-1-ene, pent-2-ene, hex-1-ene, hex-2-ene, hex3-ene, hept-1-ene, hept-2-ene, hept-3-ene, oct-1-ene, oct-2-ene, oct-3-ene, oct-4-ene, non-1-ene, non-2- ene, non-3-ene, non-4-ene, non-5-ene, dec-1-ene, dec-2-ene, dec-3-ene, dec-4-ene, dec-5-ene, dec- 6-ene, undec-1-ene, undec-2-ene, undec-3-ene, undec-4-ene, undec-5-ene, undec-6-ene, undec-7- ene, dodec-1-ene, dodec-2-ene, dodec-3-ene, dodec-4-ene, dodec-5-ene, dodec-6-ene, dodec-8- ene, and an alkenyl group comprising two or more double bonds, each of which is optionally substituted. In some embodiments, T1, T2, T3, and T4are independently an alkynyl selected from the group consisting of but-1-yne, but-2-yne, pent-1-yne, pent-2-yne, hex-1-yne, hex-2-yne, hex3-yne, hept-1-yne, hept-2-yne, hept-3-yne, oct-1-yne, oct-2-yne, oct-3-yne, oct-4-yne, non-1-yne, non-2- yne, non-3-yne, non-4-yne, non-5-yne, dec-1-yne, dec-2-yne, dec-3-yne, dec-4-yne, dec-5-yne, dec-6-yne, undec-1-yne, undec-2-yne, undec-3-yne, undec-4-yne, undec-5-yne, undec-6-yne, undec-7-yne, dodec-1-yne, dodec-2-yne, dodec-3-yne, dodec-4-yne, dodec-5-yne, dodec-6-yne, dodec-8-yne, and an alkynyl group comprising two or more triple bonds, each of which is optionally substituted. In some embodiments, X is N. In one aspect, the disclosure provides a pharmaceutical composition comprising a lipid of Formula II:

[0014] (II), or a salt or isomer thereof, where X is CH or N; L1, L2, and L3are independently -O-, -(CO)NRx-, -NRx(CO)-, -(CO)O-, -CH2(CO)NRx-, provided that when A is CH not all of L1, L2, and L3 are -(CO)NRx-; Rx is H, C1-C6 alkyl, or C3-C6 cycloalkyl; G1 and G2 are Formula III: or salt or isomer thereof, where n1 is 3, 45, 6, 7, 8, 9, or 10; L4 is -(CO)O- or -O(CO)-; R6is branched C5-C20alkyl; G3 is Formula (III), Formula (IV), Formula (V), or Formula (VI): R7 and R8 are independently, optionally functionalized, C1-C5 alkyl; n2, n3, and n4are independently 0, 1, 2, or 3; X1 is C, N, or O; and R9 and R10 are independently H or optionally functionalized C1-C5 alkyl. In an aspect, the disclosure provides a lipid particle comprising any of the above compounds. In some embodiments, the disclosure further provides a therapeutic agent. In some embodiments, the therapeutic agent is a nucleic acid. In an aspect, the disclosure provides a pharmaceutical composition comprising the above lipid particle and a pharmaceutically acceptable excipient, carrier, or diluent. Other aspects of the present disclosure are based, at least in part, upon the discovery that substituted piperazines may be used to form novel ionizable lipids having advantageous properties when used in lipid particles for the delivery of a therapeutic agent(s). In particular, the techniques herein provide lipid-based nanoparticle compositions and formulations capable of specifically targeting a cargo moiety (e.g., a nucleic acid cargo) to specific tissues of a subject, without requiring a ligand-based targeting strategy. Substituted piperazines ionizable lipids as disclosed herein comprise a head group having the following structure: , where the protonatable piperazine (e.g., pH-titratable) head group is connected to C5-C20 hydrocarbon chains e.g., alkyl or alkenyl chains, where each hydrocarbon chain independently has 0 to 5 (e.g., 0, 1, 2, 3, 4, or 5) double bonds, via a linker having the following structure: L , where L5 is -O(CO)-, -CH2-O(CO)-, -CH2(CO)O-, or -O(CO)-NH-, n5is 2, 3, 4, 5, 6, 7, or 8, and G4is a bond, -(CO)O-, or -O(CO)-. The C5-C20hydrocarbon chains may be attached to the G4 atom of the linker. Substituted piperazines ionizable lipids disclosed herein provide stable and efficient lipid nanoparticle (LNP) formulations for delivery of therapeutic oligonucleotides to specific target tissues of interest. An aspect of the disclosure provides a chemical compound of Formula VII:

[0015] (VII) or a salt or isomer thereof, where L6is -O(CO)-, -CH2-O(CO)-, -CH2(CO)O-, or -O(CO)-NH-; n6 and n7 are independently 1, 2, 3, 4, 5, 6, 7, or 8; G5 and G6 are independently a bond; -(CO)O-; or -O(CO)-; and R11and R12are each independently, optionally substituted, C5-C20alkyl or C5-C20alkenyl. In some embodiments, R11and R12are the same. In some embodiments, R11 and R12 are different. In some embodiments, R11or R12are independently selected from the group consisting of optionally substituted C8-C20alkyl and C8-C20alkenyl, optionally R11and R12are independently selected from the group consisting of optionally substituted C8-C20 alkyl and C8-C20 alkenyl. In some embodiments, n6 and n7 are independently 4, 5, 6, 7, or 8. In some embodiments, R11or R12include 1, 2, 3, 4, 5, 6, or more sites of unsaturation. In some embodiments, R11 or R12 are independently selected from the group consisting of optionally substituted C8-C17 alkyl and C8-C17 alkenyl, optionally wherein R11 and R12 are independently selected from the group consisting of optionally substituted C8-C17alkyl and C8-C17alkenyl. In some embodiments, n6 and n7 are independently 5, 6, or 7. In some embodiments, R11 or R12 include 1, 2, 3, 4, 5, 6, or more sites of unsaturation. In some embodiments, R11 or R12 are independently selected from the group consisting of optionally substitutedC10-C17alkyl and C10-C17alkenyl, optionally wherein R11and R12are independently selected from the group consisting of optionally substituted C10-C17 alkyl and C10- C17 alkenyl. In some embodiments, n6and n7are independently 5, 6, or 7. In some embodiments, R11or R12include 1, 2, 3, 4, 5, 6, or more sites of unsaturation. In some embodiments, R11 or R12 are independently selected from the group consisting of optionally substituted C12-C17alkyl and C12-C17alkenyl, optionally wherein R11and R12are independently selected from the group consisting of optionally substituted C12-C17alkyl and C12- C17 alkenyl. In some embodiments, n6 and n7 are independently 5, 6, or 7. In some embodiments, R11or R12include 1, 2, 3, 4, 5, 6, or more sites of unsaturation. In some embodiments, R11 is selected from the group consisting of optionally substitutedC8-C17 alkyl and C8-C17 alkenyl, and R12 is selected from the group consisting of optionally substitutedC8-C17alkyl and C8-C17alkenyl. In some embodiments, n6and n7are 5. In some embodiments, G5 and G6 are independently a bond or -(CO)O-. In some embodiments, R11or R12are independently selected from the group consisting of optionally substituted C8, C12, C15, or C17alkyl and C8, C12, C15, or C17alkenyl, optionally wherein R11 and R12 are independently selected from the group consisting of optionally substitutedC8, C12, C15, or C17alkyl and C8, C12, C15, or C17alkenyl. In some embodiments, R11and R12are independently an alkyl selected from the group consisting of octane, nonane, decane, undecane, and dodecane, each of which is optionally substituted. In some embodiments, R11and R12are independently an alkyl selected from the group consisting of octane, nonane, decane, undecane, dodecane, tridecane, tetradecane, pentadecane, hexadecane, heptadecane, octadecane, nonadecane, and icosane. In some embodiments, R11and R12are independently an alkenyl selected from the group consisting of oct-1-ene, oct-2-ene, oct-3-ene, oct-4-ene, non-1-ene, non-2-ene, non-3-ene, non-4- ene, non-5-ene, dec-1-ene, dec-2-ene, dec-3-ene, dec-4-ene, dec-5-ene, dec-6-ene, undec-1-ene, undec-2-ene, undec-3-ene, undec-4-ene, undec-5-ene, undec-6-ene, undec-7-ene, dodec-1-ene, dodec-2-ene, dodec-3-ene, dodec-4-ene, dodec-5-ene, dodec-6-ene, tridec-1-ene, tridec-2-ene, tridec-3-ene, tridec-4-ene, tridec-5-ene, tridec-6-ene, tridec-7-ene, tetradec-1-ene, tetradec-2-ene, tetradec-3-ene, tetradec-4-ene, tetradec-5-ene, tetradec-6-ene, tetradec-7-ene, pentadec-1-ene, pentadec-2-ene, pentadec-3-ene, pentadec-4-ene, pentadec-5-ene, pentadec-6-ene, pentadec-7- ene, hexadec-1-ene, hexadec-2-ene, hexadec-3-ene, hexadec-4-ene, hexadec-5-ene, hexadec-6- ene, hexadec-7-ene, hexadec-8-ene, heptadec-1-ene, heptadec-2-ene, heptadec-3-ene, heptadec-4- ene, heptadec-5-ene, heptadec-6-ene, heptadec-7-ene, heptadec-8-ene, octadec-1-ene, octadec-2- ene, octadec-3-ene, octadec-4-ene, octadec-5-ene, octadec-6-ene, octadec-7-ene, octadec-8-ene, octadec-9-ene, nonadec-1-ene, nonadec-2-ene, nonadec-3-ene, nonadec-4-ene, nonadec-5-ene, nonadec-6-ene, nonadec-7-ene, nonadec-8-ene, nonadec-9-ene, icos-1-ene, icos-2-ene, icos-3-ene, icos-4-ene, icos-5-ene, icos-6-ene, icos-7-ene, icos-8-ene, and icos-9-ene. In some embodiments, R11and R12independently comprise one or more additional double bonds, optionally wherein R11 and R12 independently comprise one double bond. An aspect of the disclosure provides a chemical compound of Formula VIII: (VIII) or a salt or isomer thereof, where m5 is 4, 5, 6, 7, or 8; G7 is a bond; -(CO)O-; or -O(CO)-; and R13 and R14 are each independently, optionally substituted, C8-C20 alkyl or C8-C20 alkenyl. In some embodiments, R13and R14are the same. In some embodiments, R13 and R14 are different. In some embodiments, R13 or R14 are independently selected from the group consisting of optionally substituted C8-C19alkyl and C8-C19alkenyl, optionally R13and R14are independently selected from the group consisting of optionally substituted C8-C19alkyl and C8-C19alkenyl. In some embodiments, R13 or R14 are independently selected from the group consisting of optionally substituted C8-C18alkyl and C8-C18alkenyl, optionally R13and R14are independently selected from the group consisting of optionally substituted C8-C18alkyl and C8-C18alkenyl. In some embodiments, R13 or R14 are independently selected from the group consisting of optionally substituted C8-C17 alkyl and C8-C17 alkenyl, optionally R13 and R14 are independently selected from the group consisting of optionally substituted C8-C17alkyl and C8-C17alkenyl. In some embodiments, R13 or R14 are independently selected from the group consisting of optionally substituted C8-C16 alkyl and C8-C16 alkenyl, optionally R13 and R14 are independently selected from the group consisting of optionally substituted C8-C16alkyl and C8-C16alkenyl. In some embodiments, R13or R14are independently selected from the group consisting of optionally substituted C8-C15 alkyl and C8-C15 alkenyl, optionally wherein R13 and R14 are independently selected from the group consisting of optionally substituted C8-C15alkyl and C8-C15alkenyl. In some embodiments, R13or R14are independently selected from the group consisting of optionally substituted C9-C12 alkyl and C9-C12 alkenyl, optionally wherein R13 and R14 are independently selected from the group consisting of optionally substituted C9-C12alkyl and C9-C12alkenyl. In some embodiments, m5is 4, 5, 6, 7, or 8. In some embodiments, R13 or R14 include 1, 2, 3, 4, 5, 6, or more sites of unsaturation. In some embodiments, m5 is 5, 6, or 7. In some embodiments, R13or R14include 1, 2, 3, 4, 5, 6, or more sites of unsaturation. In some embodiments, R13 or R14 are independently selected from the group consisting of optionally substituted C10-C17 alkyl and C10-C17 alkenyl, optionally wherein R13 and R14 are independently selected from the group consisting of optionally substituted C10-C17alkyl and C10- C17alkenyl. In some embodiments, m5 is 5, 6, or 7. In some embodiments, R13 or R14 include 1, 2, 3, 4, 5, 6, or more sites of unsaturation. In some embodiments, R13 or R14 are independently selected from the group consisting of optionally substituted C12-C17alkyl and C12-C17alkenyl, optionally wherein R13and R14are independently selected from the group consisting of optionally substituted C12-C17 alkyl and C12- C17 alkenyl. In some embodiments, m5is 5, 6, or 7. In some embodiments, R13or R14include 1, 2, 3, 4, 5, 6, or more sites of unsaturation. In some embodiments, R13 is selected from the group consisting of optionally substituted C8-C17alkyl and C8-C17alkenyl, and R14is selected from the group consisting of optionally substitutedC8-C17alkyl and C8-C17alkenyl. In some embodiments, m5 is 5. In some embodiments, G7 is a bond or -(CO)O-. In some embodiments, R13or R14are independently selected from the group consisting of optionally substituted C8, C12, C15, or C17 alkyl and C8, C12, C15, or C17 alkenyl, optionally wherein R3 and R4 are independently selected from the group consisting of optionally substituted C8, C12, C15, or C17alkyl and C8, C12, C15, or C17alkenyl. In some embodiments, R13and R14are independently an alkyl selected from the group consisting of octane, nonane, decane, undecane, and dodecane, each of which is optionally substituted. In some embodiments, R13and R14are independently an alkyl selected from the group consisting of octane, nonane, decane, undecane, dodecane, tridecane, tetradecane, pentadecane, hexadecane, heptadecane, octadecane, nonadecane, and icosane. In some embodiments, R13and R14are independently an alkenyl selected from the group consisting of oct-1-ene, oct-2-ene, oct-3-ene, oct-4-ene, non-1-ene, non-2-ene, non-3-ene, non-4- ene, non-5-ene, dec-1-ene, dec-2-ene, dec-3-ene, dec-4-ene, dec-5-ene, dec-6-ene, undec-1-ene, undec-2-ene, undec-3-ene, undec-4-ene, undec-5-ene, undec-6-ene, undec-7-ene, dodec-1-ene, dodec-2-ene, dodec-3-ene, dodec-4-ene, dodec-5-ene, dodec-6-ene, tridec-1-ene, tridec-2-ene, tridec-3-ene, tridec-4-ene, tridec-5-ene, tridec-6-ene, tridec-7-ene, tetradec-1-ene, tetradec-2-ene, tetradec-3-ene, tetradec-4-ene, tetradec-5-ene, tetradec-6-ene, tetradec-7-ene, pentadec-1-ene, pentadec-2-ene, pentadec-3-ene, pentadec-4-ene, pentadec-5-ene, pentadec-6-ene, pentadec-7- ene, hexadec-1-ene, hexadec-2-ene, hexadec-3-ene, hexadec-4-ene, hexadec-5-ene, hexadec-6- ene, hexadec-7-ene, hexadec-8-ene, heptadec-1-ene, heptadec-2-ene, heptadec-3-ene, heptadec-4- ene, heptadec-5-ene, heptadec-6-ene, heptadec-7-ene, heptadec-8-ene, octadec-1-ene, octadec-2- ene, octadec-3-ene, octadec-4-ene, octadec-5-ene, octadec-6-ene, octadec-7-ene, octadec-8-ene, octadec-9-ene, nonadec-1-ene, nonadec-2-ene, nonadec-3-ene, nonadec-4-ene, nonadec-5-ene, nonadec-6-ene, nonadec-7-ene, nonadec-8-ene, nonadec-9-ene, icos-1-ene, icos-2-ene, icos-3-ene, icos-4-ene, icos-5-ene, icos-6-ene, icos-7-ene, icos-8-ene, and icos-9-ene. In some embodiments, R13and R14independently comprise one or more additional double bonds, optionally wherein R13 and R14 independently comprise one double bond. In one aspect the disclosure provides a chemical compound selected from the group consisting of: (9,9'-di(heptadecan-9-yl) O'1,O1-((((((piperazine-1,4-diylbis(2-oxoethane-2,1- diyl))bis(piperidine-1,4-diyl))bis(ethane-2,1-diyl))bis(oxy))bis(2-oxoethane-2,1-diyl))bis(4,1- p O ((((((piperazine-1,4-diylbis(2-oxoethane-2,1-diyl))bis(piperidine-1,4-diyl))bis(ethane-2,1- diyl))bis(oxy))bis(2-oxoethane-2,1-diyl))bis(4,1-phenylene) dioleate, SM-074); O O (9,9'-bis(2-butyloctyl) O'1,O1-((((((piperazine-1,4-diylbis(2-oxoethane-2,1-diyl))bis(piperidine- 1,4-diyl))bis(ethane-2,1-diyl))bis(oxy))bis(2-oxoethane-2,1-diyl))bis(4,1-phenylene)) di(nonanedioate), SM-076); (1-(heptadecan-9-yl) 9-(4-(2-(2-(1-(2-(4-(2-(4-(2-(2-(4- (oleoyloxy)phenyl)acetoxy)ethyl)piperidin-1-yl)acetyl)piperazin-1-yl)-2-oxoethyl)piperidin-4- yl)ethoxy)-2-oxoethyl)phenyl) nonanedioate, SM-077);

[0016] O O ((((((piperazine-1,4-diylbis(2-oxoethane-2,1-diyl))bis(piperidine-1,4-diyl))bis(ethane-2,1- diyl))bis(oxy))bis(2-oxoethane-2,1-diyl))bis(4,1-phenylene) bis(9-((2- h O (9,9'-bis(2-ethylhexyl) O'1,O1-((((((piperazine-1,4-diylbis(2-oxoethane-2,1-diyl))bis(piperidine- 1,4-diyl))bis(ethane-2,1-diyl))bis(oxy))bis(2-oxoethane-2,1-diyl))bis(4,1-phenylene)) di(nonanedioate), SM-083);

[0017] O O (di(heptadecan-9-yl) 9,9'-(((((((((piperazine-1,4-diylbis(2-oxoethane-2,1-diyl))bis(piperidine-1,4- diyl))bis(ethane-2,1-diyl))bis(oxy))bis(2-oxoethane-2,1-diyl))bis(4,1- phenylene))bis(oxy))bis(carbonyl))bis(azanediyl))dinonanoate; SM-085); (9,9'-di(heptadecan-9-yl) O'1,O1-(((((((piperazine-1,4-diylbis(2-oxoethane-2,1- diyl))bis(piperidine-1,4-diyl))bis(ethane-2,1-diyl))bis(oxy))bis(2-oxoethane-2,1-diyl))bis(4,1- phenylene))bis(methylene)) di(nonanedioate); SM-088);

[0018] O O (7,7'-dinonyl O'1,O1-((((((piperazine-1,4-diylbis(2-oxoethane-2,1-diyl))bis(piperidine-1,4- diyl))bis(ethane-2,1-diyl))bis(oxy))bis(2-oxoethane-2,1-diyl))bis(4,1-phenylene)) di(heptanedioate); SM-100); (di(heptadecan-9-yl) 9,9'-((2,2'-((((((piperazine-1,4-diylbis(2-oxoethane-2,1-diyl))bis(piperidine- 1,4-diyl))bis(ethane-2,1-diyl))bis(oxy))bis(2-oxoethane-2,1-diyl))bis(4,1- phenylene))bis(acetyl))bis(oxy))dinonanoate; SM-109);

[0019] O O (di(heptadecan-9-yl) O,O'-((((((piperazine-1,4-diylbis(2-oxoethane-2,1-diyl))bis(piperidine-1,4- diyl))bis(ethane-2,1-diyl))bis(oxy))bis(2-oxoethane-2,1-diyl))bis(4,1-phenylene)) diglutarate; S O O (bis(9-(heptadecan-9-yloxy)-9-oxononyl) O,O'-(((piperazine-1,4-diylbis(2-oxoethane-2,1- diyl))bis(piperidine-1,4-diyl))bis(ethane-2,1-diyl)) diterephthalate; SM-125); and salts and isomers thereof. In one aspect, the disclosure provides a lipid particle comprising any of the compounds disclosed herein. In some embodiments, the lipid particle further includes a therapeutic agent. In some embodiments, the therapeutic agent is a nucleic acid. In one aspect, the disclosure provides a pharmaceutical composition including one of the above-referenced lipid particles, optionally including and a pharmaceutically acceptable excipient, carrier, or diluent. In one aspect, the disclosure provides a nucleic acid-lipid particle for delivering a nucleic acid cargo to a subject, the nucleic acid-lipid particle comprising a compound selected from the group consisting of: (9,9'-di(heptadecan-9-yl) O'1,O1-((((((piperazine-1,4-diylbis(2-oxoethane-2,1- diyl))bis(piperidine-1,4-diyl))bis(ethane-2,1-diyl))bis(oxy))bis(2-oxoethane-2,1-diyl))bis(4,1- p O ((((((piperazine-1,4-diylbis(2-oxoethane-2,1-diyl))bis(piperidine-1,4-diyl))bis(ethane-2,1- diyl))bis(oxy))bis(2-oxoethane-2,1-diyl))bis(4,1-phenylene) dioleate, SM-074);

[0020] O O (9,9'-bis(2-butyloctyl) O'1,O1-((((((piperazine-1,4-diylbis(2-oxoethane-2,1-diyl))bis(piperidine- 1,4-diyl))bis(ethane-2,1-diyl))bis(oxy))bis(2-oxoethane-2,1-diyl))bis(4,1-phenylene)) di(nonanedioate), SM-076); (1-(heptadecan-9-yl) 9-(4-(2-(2-(1-(2-(4-(2-(4-(2-(2-(4- (oleoyloxy)phenyl)acetoxy)ethyl)piperidin-1-yl)acetyl)piperazin-1-yl)-2-oxoethyl)piperidin-4- yl)ethoxy)-2-oxoethyl)phenyl) nonanedioate, SM-077);

[0021] O O ((((((piperazine-1,4-diylbis(2-oxoethane-2,1-diyl))bis(piperidine-1,4-diyl))bis(ethane-2,1- diyl))bis(oxy))bis(2-oxoethane-2,1-diyl))bis(4,1-phenylene) bis(9-((2- h O (9,9'-bis(2-ethylhexyl) O'1,O1-((((((piperazine-1,4-diylbis(2-oxoethane-2,1-diyl))bis(piperidine- 1,4-diyl))bis(ethane-2,1-diyl))bis(oxy))bis(2-oxoethane-2,1-diyl))bis(4,1-phenylene)) di(nonanedioate), SM-083);

[0022] O O (di(heptadecan-9-yl) 9,9'-(((((((((piperazine-1,4-diylbis(2-oxoethane-2,1-diyl))bis(piperidine-1,4- diyl))bis(ethane-2,1-diyl))bis(oxy))bis(2-oxoethane-2,1-diyl))bis(4,1- phenylene))bis(oxy))bis(carbonyl))bis(azanediyl))dinonanoate; SM-085); (9,9'-di(heptadecan-9-yl) O'1,O1-(((((((piperazine-1,4-diylbis(2-oxoethane-2,1- diyl))bis(piperidine-1,4-diyl))bis(ethane-2,1-diyl))bis(oxy))bis(2-oxoethane-2,1-diyl))bis(4,1- phenylene))bis(methylene)) di(nonanedioate); SM-088);

[0023] O O (7,7'-dinonyl O'1,O1-((((((piperazine-1,4-diylbis(2-oxoethane-2,1-diyl))bis(piperidine-1,4- diyl))bis(ethane-2,1-diyl))bis(oxy))bis(2-oxoethane-2,1-diyl))bis(4,1-phenylene)) di(heptanedioate); SM-100); (di(heptadecan-9-yl) 9,9'-((2,2'-((((((piperazine-1,4-diylbis(2-oxoethane-2,1-diyl))bis(piperidine- 1,4-diyl))bis(ethane-2,1-diyl))bis(oxy))bis(2-oxoethane-2,1-diyl))bis(4,1- phenylene))bis(acetyl))bis(oxy))dinonanoate; SM-109);

[0024] O O (di(heptadecan-9-yl) O,O'-((((((piperazine-1,4-diylbis(2-oxoethane-2,1-diyl))bis(piperidine-1,4- diyl))bis(ethane-2,1-diyl))bis(oxy))bis(2-oxoethane-2,1-diyl))bis(4,1-phenylene)) diglutarate; S O O (bis(9-(heptadecan-9-yloxy)-9-oxononyl) O,O'-(((piperazine-1,4-diylbis(2-oxoethane-2,1- diyl))bis(piperidine-1,4-diyl))bis(ethane-2,1-diyl)) diterephthalate; SM-125), further comprising about 30-70 mol % or about 40-60 mol % or about 50 mol % of the total lipid present in the nucleic acid-lipid particle, optionally comprising 45 mol %, 46 mol %, 47 mol %, 48 mol %, 49 mol %, 50 mol %, 51 mol %, 52 mol %, 53 mol %, 54 mol %, or 55 mol % of the total lipid present in the nucleic acid-lipid particle. In some embodiments, the nucleic acid-lipid particle includes a conjugated lipid that inhibits aggregation of particles comprising from 0.01 to 2% of the total lipid present, optionally wherein the conjugated lipid comprises a polyethyleneglycol (PEG)-lipid conjugate, optionally wherein the PEG of the PEG-lipid conjugate has an average molecular weight of from 550 Daltons to 5000 Daltons, optionally wherein the PEG-lipid conjugate is a PEG5000-lipid conjugate, optionally wherein the PEG-lipid conjugate is a PEG2000-lipid conjugate, optionally wherein the PEG2000-lipid conjugate comprises one or more of 1,2-dimyristoyl-rac-glycero-3- methoxypolyethylene glycol-2000 (DMG-PEG2k) and 1,2-distearoyl-rac-glycero-3- methoxypolyethylene glycol-2000 (DSG-PEG2k), optionally wherein the PEG2000-lipid conjugate is 1,2-Dimyristoyl-rac–glycero-3-methoxypolyethylene glycol-2000 (DMG-PEG2k), optionally wherein the PEG2000-lipid conjugate is 1,2-Dioleoyl-sn–glycero-3- phosphoethanolamine (DOPE)-polyethylene glycol methoxy (DOPE-mPEG2k), optionally wherein the PEG2000-lipid conjugate is 1,2-Distearoyl-sn-Glycero-3-Phosphoethanolamine with conjugated methoxyl poly(ethylene glycol) (DSPE-mPEG2k), optionally wherein the nucleic acid- lipid particle comprises a PEG-lipid conjugate at a concentration selected from the group consisting of about 0.5 mol % of the total lipid present in the nucleic acid-lipid particle, about 1.0 mol % of the total lipid present in the nucleic acid-lipid particle, and about 0.5-3.0 mol % of the total lipid present in the nucleic acid-lipid particle. In some embodiments, the PEG-lipid conjugate is DMG-PEG2k comprising about 1.5 mol % of the total lipid present in the nucleic acid-lipid particle. In some embodiments, the nucleic acid-lipid particle includes one or more non-cationic lipids comprising from 20 mol % to 80 mol % of the total lipid present in the lipid-nucleic acid particle, optionally wherein the one or more non-cationic lipids comprise cholesterol or a derivative thereof. In some embodiments, the nucleic acid-lipid particle includes cholesterol or a derivative thereof at a concentration range selected from the group consisting of 35 mol % to 45 mol % of the total lipid present in the nucleic acid-lipid particle, 45 mol % to 55 mol % of the total lipid present in the nucleic acid-lipid particle, and 55 mol % to 65 mol % of the total lipid present in the nucleic acid-lipid particle, optionally wherein the cholesterol or a derivative thereof is about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, or about 45% of the total lipid present in the nucleic acid-lipid particle, optionally wherein the cholesterol or a derivative thereof is about 40% of the total lipid present in the nucleic acid-lipid particle. In some embodiments, the nucleic acid-lipid particle includes one or more non-cationic lipid other than cholesterol or a derivative thereof, optionally wherein the one or more non-cationic lipid other than cholesterol or a derivative thereof comprises from 5 mol % to 20 mol % of the total lipid present in the lipid-nucleic acid particle, optionally wherein the one or more non-cationic lipid other than cholesterol or a derivative thereof comprises about 10 mol % of the total lipid present in the nucleic acid-lipid particle. In some embodiments, the one or more non-cationic lipid other than cholesterol or a derivative thereof comprises a non-cationic lipid selected from the group consisting of 1,2- dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2-Distearoyl-sn-glycero-3-phosphocholine (DSPC), 1,2-Dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), 1,2-Distearoyl-sn-glycero-3- phosphoethanolamine (DSPE), and β-sitosterol, optionally wherein the one or more non-cationic lipid other than cholesterol or a derivative thereof is DOPE. In some embodiments, the nucleic acid cargo comprises a synthetic or naturally occurring RNA or DNA, or derivatives thereof, optionally wherein the nucleic acid cargo is a modified RNA, optionally wherein the modified RNA is selected from the group consisting of a modified mRNA, a modified antisense oligonucleotide and a modified siRNA, optionally wherein the modified mRNA encodes a nucleic acid modulating controller. In some embodiments, the nucleic acid cargo comprises one or more modifications selected from the group consisting of 2′-O-methyl modified nucleotides, a nucleotide comprising a 5′- phosphorothioate group, a terminal nucleotide linked to a cholesteryl derivative, a 2′-deoxy-2′- fluoro modified nucleotide, a 5′-methoxy-modified nucleotide (e.g., 5′-methoxyuridine), a 2′- deoxy-modified nucleotide, a locked nucleotide, an abasic nucleotide, a 2′-amino-modified nucleotide, a 2′-alkyl-modified nucleotide, a morpholino nucleotide, a phosphoramidate, a non- natural base comprising nucleotide; internucleoside linkages or backbones including phosphorothioates, chiral phosphorothioates, phosphorodithioates, phosphotriesters, aminoalkylphosphotriesters, methyl and other alkyl phosphonates including 3′-alkylene phosphonates and chiral phosphonates, phosphinates, phosphoramidates including 3′-amino phosphoramidate and aminoalkylphosphoramidates, thionophosphoramidates, thionoalkylphosphonates, thionoalkylphosphotriesters, and boranophosphates having normal 3′-5′ linkages, 2′-5′ linked analogs of these, and those having inverted polarity wherein the adjacent pairs of nucleoside units are linked 3′-5′ to 5′-3′ or 2′-5′ to 5′-2′. In some embodiments, the nucleic acid-lipid particle comprises SM-048, SM-074, SM- 076, SM-077, SM-079, SM-083, SM-085, SM-088, SM-100, SM-109, SM-113, or SM-125 at about 50 mol % of the total lipid present in the nucleic acid-lipid particle, cholesterol at about 38.5 mol % of the total lipid present in the nucleic acid-lipid particle, DOPE at about 10 mol % of the total lipid present in the nucleic acid-lipid particle, and DMG-PEG2k at about 1.5 mol % of the total lipid present in the nucleic acid-lipid particle. In and aspect, the disclosure provide a compound of the following structures: . Additional aspects of the present disclosure are based, at least in part, upon the discovery that other aryl and heteroaryl lipid compounds may be used to form novel ionizable lipids having advantageous properties when used in lipid particles for the in vivo delivery of a therapeutic agent(s). In particular, the techniques herein provide lipid-based nanoparticle compositions and formulations capable of specifically targeting a cargo moiety (e.g., a nucleic acid cargo) to specific tissues of a subject, without requiring a ligand-based targeting strategy. Certain aryl and heteroaryl lipid compounds as disclosed herein may comprise the following general structure: In one aspect, the disclosure provides a compound of Formula IX:

[0025] (IX) or a salt or isomer thereof, where X2, X3, and X4 are independently CH or N; G8, G9, and G10 are independently O, -(CO)O-, -CH2O(CO)-, -(CH2)2(CO)NR15-, - (CH2)O(CO)NR15-, CH2(CO)NR15-, -(CO)NR15-, -NR15(CO)-, or NR15(CO)O-, wherein if X2, X3, and X4 are all CH, then not all of G8, G9, and G10 are -(CO)NR1-; a1, b1, and c1 are independently 0, 1, 2, 3, or 4; m6, m7, and m8are independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; E5, E6, and E7are independently -(CO)O- or -O(CO)-; T5, T6, and T7 are independently branched or unbranched C5-C22 alkyl, C5-C22 alkenyl, or C5-C22alkynyl; and R15 is H, or optionally functionalized C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl. In some embodiments, two or more of m6-m8, E5-E7, and T5-T7 are the same. In some embodiments, one or more of m6-m8, E5-E7, and T5-T7are different. In some embodiments, two of m6-m8, E5-E7, and T5-T7 are the same. In some embodiments, a1, b1, or c1 are 2, 3, or 4. In some embodiments, a1, b1, and c1are 2, 3, and 4. In some embodiments, a1, b1, or c1are 3 or 4. In some embodiments, a1 and b1 are 3 and c1 is 4. In some embodiments, a1, b1, and c1are 3. In some embodiments, m6, m7, and m8are 1-8. In some embodiments, m6, m7, or m8 are 5-8, optionally wherein m6, m7, and m8 are 5-8. In some embodiments, m6, m7, or m8 are 5-6, optionally wherein m6, m7, and m8 are 5-6. In some embodiments, m6, m7, or m8are 6, optionally wherein m6, m7, and m8are 6. In some embodiments, one of X2, X3, or X4 is N, optionally two of X2, X3, or X4are N. In some embodiments, X2, X3, and X4 are CH. In some embodiments, two of G8, G9, or G10are the same, optionally wherein all of G8, G9, and G10are the same. In some embodiments, one or more of G8, G9, or G10 are different. In some embodiments, one of X2, X3, or X4is N, and G8, G9, and G10are -(CO)NR15-. In some embodiments, G8, G9, and G10are -(CO)O-. In some embodiments, two of G8, G9, and G10 are -(CO)NR15-. In some embodiments, one of G8, G9, and G10is -NR15(CO)-. In some embodiments, all of G8, G9, and G10are -NR15(CO)-. In some embodiments, one of G8, G9, and G10 is -(CO)NR15- and two of G8, G9, and G10 are -NR15(CO)-. In some embodiments, one of G8, G9, and G10is -(CO)NR15- and two of G8, G9, and G10are O. In some embodiments, T5, T6, or T7 are independently selected from the group consisting of C5-C18alkyl, C5-C18alkenyl, and C5-C18alkynyl, each of which is optionally substituted, optionally wherein T5, T6, and T7are independently selected from the group consisting of C5-C18alkyl, C5-C18 alkenyl, and C5-C18 alkynyl, each of which is optionally substituted. In some embodiments, T5, T6, or T7 are independently selected from the group consisting of C5-C12 alkyl, C5-C12 alkenyl, and C5-C12 alkynyl, each of which is optionally substituted, optionally wherein T5, T6, and T7are independently selected from the group consisting of C5-C12alkyl, C5-C12 alkenyl, and C5-C12 alkynyl, each of which is optionally substituted. In some embodiments, T5, T6, or T7 are independently selected from the group consisting of C5-C10alkyl, C5-C10alkenyl, and C5-C10alkynyl, each of which is optionally substituted, optionally wherein T5, T6, and T7are independently selected from the group consisting of C5-C10alkyl, C5-C10 alkenyl, and C5-C10 alkynyl, each of which is optionally substituted. In some embodiments, T5, T6, or T7are independently selected from the group consisting of C5-C8alkyl, C5-C8alkenyl, and C5-C8alkynyl, each of which is optionally substituted, optionally wherein T5, T6, and T7 are independently selected from the group consisting of C5-C8 alkyl, C5-C8 alkenyl, and C5-C8 alkynyl, each of which is optionally substituted. In some embodiments, T5, T6, or T7are independently selected from the group consisting of C6-C8 alkyl, C6-C8 alkenyl, and C6-C8 alkynyl, each of which is optionally substituted, optionally wherein T5, T6, and T7 are independently selected from the group consisting of C6-C8 alkyl, C6-C8alkenyl, and C6-C8alkynyl, each of which is optionally substituted. In some embodiments, T5, T6, or T7are independently selected from the group consisting of C7 or C8 alkyl, C7 or C8 alkenyl, and C7 or C8 alkynyl, each of which is optionally substituted, optionally wherein T5, T6, and T7are independently selected from the group consisting of C7or C8alkyl, C7or C8alkenyl, and C7or C8alkynyl, each of which is optionally substituted. In some embodiments, T5, T6, or T7 are independently C8 alkyl, C8 alkenyl, or C8 alkynyl, each of which is optionally substituted, optionally wherein T5, T6, and T7are C8alkyl, C8alkenyl, or C8alkynyl, each of which is optionally substituted. In some embodiments, E5, E6, or E7 are -(CO)O-, optionally wherein E5, E6, and E7 are - (CO)O-. In some embodiments, m6, m7, or m8are 8, optionally wherein m6, m7, and m8are 8. In some embodiments, T5, T6, and T7 are independently an alkyl selected from the group consisting of butane, pentane, hexane, heptane, octane, nonane, decane, undecane, dodecane, and tridecane, each of which is optionally substituted. In some embodiments, T5, T6, and T7are octane or tridecane. In some embodiments, T5, T6, and T7 are independently an alkenyl selected from the group consisting of but-1-ene, but-2-ene, pent-1-ene, pent-2-ene, hex-1-ene, hex-2-ene, hex3-ene, hept- 1-ene, hept-2-ene, hept-3-ene, oct-1-ene, oct-2-ene, oct-3-ene, oct-4-ene, non-1-ene, non-2-ene, non-3-ene, non-4-ene, non-5-ene, dec-1-ene, dec-2-ene, dec-3-ene, dec-4-ene, dec-5-ene, dec-6- ene, undec-1-ene, undec-2-ene, undec-3-ene, undec-4-ene, undec-5-ene, undec-6-ene, undec-7- ene, dodec-1-ene, dodec-2-ene, dodec-3-ene, dodec-4-ene, dodec-5-ene, dodec-6-ene, dodec-8- ene, and an alkenyl group comprising two or more double bonds, each of which is optionally substituted. In some embodiments, T5, T6, and T7are independently an alkynyl selected from the group consisting of but-1-yne, but-2-yne, pent-1-yne, pent-2-yne, hex-1-yne, hex-2-yne, hex3-yne, hept- 1-yne, hept-2-yne, hept-3-yne, oct-1-yne, oct-2-yne, oct-3-yne, oct-4-yne, non-1-yne, non-2-yne, non-3-yne, non-4-yne, non-5-yne, dec-1-yne, dec-2-yne, dec-3-yne, dec-4-yne, dec-5-yne, dec-6- yne, undec-1-yne, undec-2-yne, undec-3-yne, undec-4-yne, undec-5-yne, undec-6-yne, undec-7- yne, dodec-1-yne, dodec-2-yne, dodec-3-yne, dodec-4-yne, dodec-5-yne, dodec-6-yne, dodec-8- yne, and an alkynyl group comprising two or more triple bonds, each of which is optionally substituted. In some embodiments, R15is H. In one aspect, the disclosure provides a compound selected from the group consisting of: (SM-016; 1-ethylhexyl 9-[3-[[3,5-bis[3-[bis[9-(1-ethylhexoxy)-9-oxo- nonyl]amino]propylcarbamoyl]benzoyl]amino]propyl-[9-(1-ethylhexoxy)-9-oxo- nonyl]amino]nonanoate)

[0026] (SM-062; hexa(octan-3-yl) 9,9',9'',9''',9'''',9'''''-((((pyridine-2,4,6- tricarbonyl)tris(azanediyl))tris(propane-3,1-diyl))tris(azanetriyl))hexanonanoate), (SM-065; tris(3-(bis(9-(octan-3-yloxy)-9-oxononyl)amino)propyl) benzene-1,3,5-tricarboxylate),

[0027] (SM-067; tetra(octan-3-yl) 9,9',9'',9'''-((((5-(4-(bis(9-(octan-3-yloxy)-9- oxononyl)amino)butanamido)isophthaloyl)bis(azanediyl))bis(propane-3,1- diyl))bis(azanetriyl))tetranonanoate),

[0028] (SM-068; hexa(octan-3-yl) 9,9',9'',9''',9'''',9'''''-(((benzene-1,3,5-triyltris(azanediyl))tris(4- oxobutane-4,1-diyl))tris(azanetriyl))hexanonanoate),

[0029] (SM-070; tetra(octan-3-yl) 9,9',9'',9'''-((((5-((3-(bis(9-(octan-3-yloxy)-9- oxononyl)amino)propyl)carbamoyl)-1,3-phenylene)bis(azanediyl))bis(4-oxobutane-4,1- diyl))bis(azanetriyl))tetranonanoate), (SM-072; tetra(octan-3-yl) 9,9',9'',9'''-((((5-((3-(bis(9-(octan-3-yloxy)-9- oxononyl)amino)propyl)carbamoyl)-1,3-phenylene)bis(oxy))bis(propane-3,1- diyl))bis(azanetriyl))tetranonanoate),

[0030] ( oxononyl)amino)propyl)amino)-2-oxoethyl)isophthaloyl)bis(azanediyl))bis(propane-3,1- d ( oxononyl)amino)propyl)amino)-3-oxopropyl)isophthaloyl)bis(azanediyl))bis(propane-3,1- oxononyl)amino)pentanoyl)oxy)methyl)isophthaloyl)bis(azanediyl))bis(propane-3,1- d (SM-112; tetra(octan-3-yl) 9,9',9'',9'''-((((5-(19-ethyl-8-(9-(octan-3-yloxy)-9-oxononyl)-3,17- dioxo-2,18-dioxa-4,8-diazatetracosyl)isophthaloyl)bis(azanediyl))bis(propane-3,1- diyl))bis(azanetriyl))tetranonanoate). In one aspect, the disclosure provides a pharmaceutical composition comprising a lipid of Formula IX: (IX) or a salt or isomer thereof, where X2, X3, and X4are independently CH or N; G8, G9, and G10are independently O, -(CO)O-, -CH2O(CO)-, -(CH2)2(CO)NR15-, - (CH2)O(CO)NR15-, CH2(CO)NR15-, -(CO)NR15-, -NR15(CO)-, or NR15(CO)O-, wherein if X2, X3, and X4are all CH, then not all of G8, G9, and G10 are –(CO)NR15-; a1, b1, and c1are independently 0, 1, 2, 3, or 4; m6, m7, and m8 are independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; E5, E6, and E7 are independently –(CO)O- or -O(CO)-; T5, T6, and T7are independently branched or unbranched C5-C22alkyl, C5-C22alkenyl, or C5-C22 alkynyl; and R1 is H, or optionally functionalized C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl. In some embodiments, two or more of m6-m8, E5-E7, and T5-T7are the same. In some embodiments, one or more of m6-m8, E5-E7, and T5-T7are different. In some embodiments, two of m6-m8, E5-E7, and T5-T7 are the same. In some embodiments, a1, b1, or c1are 2, 3, or 4. In some embodiments, a1, b1, and c1are 2, 3, or 4. In some embodiments, a1, b1, or c1 are 3 or 4. In some embodiments, a1 and b1 are 3 and c1 is 4. In some embodiments, a1, b1, and c1are 3. In some embodiments, m6, m7, or m8 are 1-8. In some embodiments, m6, m7, or m8 are 5-8, optionally wherein m6, m7, and m8 are 5-8. In some embodiments, m6, m7, or m8are 5-6, optionally wherein m6, m7, and m8are 5-6. In some embodiments, m6, m7, or m8are 6, optionally wherein m6, m7, and m8are 6. In some embodiments, one of X2, X3, or X4is N, optionally two of X2, X3, or X4are N. In some embodiments, X2, X3, and X4are CH. In some embodiments, two of G8, G9, or G10are the same-, optionally wherein all G8, G9, and G10 are the same. In some embodiments, one or more of G8, G9, or G10are different. In some embodiments, one of X2, X3, or X4is N, and G8, G9, and G10are –(CO)NR15-. In some embodiments, G8, G9, and G10 are –(CO)O-. In some embodiments, two of G8, G9, and G10 are –(CO)NR15-. In some embodiments, one of G8, G9, and G10is -NR15(CO)-. In some embodiments, all of G8, G9, and G10 are -NR15(CO)-. In some embodiments, one of G8, G9, and G10 is –(CO)NR15- and two of G8, G9, and G10 are -NR15(CO)-. In some embodiments, one of G8, G9, and G10is –(CO)NR15- and two of G8, G9, and G10are O. In some embodiments, T5, T6, or T7 are independently selected from the group consisting of C5-C18 alkyl, C5-C18 alkenyl, and C5-C18 alkynyl, each of which is optionally substituted, optionally wherein T5, T6, and T7are independently selected from the group consisting of C5-C18alkyl, C5-C18 alkenyl, and C5-C18 alkynyl, each of which is optionally substituted. In some embodiments, T5, T6, or T7 are independently selected from the group consisting of C5-C12alkyl, C5-C12alkenyl, and C5-C12alkynyl, each of which is optionally substituted, optionally T5, T6, and T7are independently selected from the group consisting of C5-C12alkyl, C5- C12 alkenyl, and C5-C12 alkynyl, each of which is optionally substituted. In some embodiments, T5, T6, or T7are independently selected from the group consisting of C5-C10alkyl, C5-C10alkenyl, and C5-C10alkynyl, each of which is optionally substituted, optionally T5, T6, and T7 are independently selected from the group consisting of C5-C10 alkyl, C5- C10 alkenyl, and C5-C10 alkynyl, each of which is optionally substituted. In some embodiments, T5, T6, or T7are independently selected from the group consisting of C5-C8 alkyl, C5-C8 alkenyl, and C5-C8 alkynyl, each of which is optionally substituted, optionally T5, T6, and T7 are independently selected from the group consisting of C5-C8 alkyl, C5- C8alkenyl, and C5-C8alkynyl, each of which is optionally substituted. In some embodiments, T5, T6, or T7are independently selected from the group consisting of C6-C8 alkyl, C6-C8 alkenyl, and C6-C8 alkynyl, each of which is optionally substituted, optionally T5, T6, and T7are independently selected from the group consisting of C6-C8alkyl, C6- C8alkenyl, and C6-C8alkynyl, each of which is optionally substituted. In some embodiments, T5, T6, or T7 are independently selected from the group consisting of C7or C8alkyl, C7or C8alkenyl, and C7or C8alkynyl, each of which is optionally substituted, optionally T5, T6, and T7are independently selected from the group consisting of C7or C8alkyl, C7 or C8 alkenyl, and C7 or C8 alkynyl, each of which is optionally substituted. In some embodiments, T5, T6, or T7 are independently C8 alkyl, C8 alkenyl, or C8 alkynyl, each of which is optionally substituted, optionally T5, T6, and T7are C8alkyl, C8alkenyl, or C8alkynyl, each of which is optionally substituted. In some embodiments, E5, E6, or E7 are –(CO)O-, optionally wherein E5, E6, and E7 are – (CO)O-. In some embodiments, m6, m7, or m8are 8, optionally wherein m6, m7, and m8are 8. In some embodiments, T5, T6, and T7 are independently an alkyl selected from the group consisting of butane, pentane, hexane, heptane, octane, nonane, decane, undecane, dodecane, and tridecane, each of which is optionally substituted. In some embodiments, T5, T6, and T7 are octane or tridecane. In some embodiments, T5, T6, and T7 are independently an alkenyl selected from the group consisting of but-1-ene, but-2-ene, pent-1-ene, pent-2-ene, hex-1-ene, hex-2-ene, hex3-ene, hept- 1-ene, hept-2-ene, hept-3-ene, oct-1-ene, oct-2-ene, oct-3-ene, oct-4-ene, non-1-ene, non-2-ene, non-3-ene, non-4-ene, non-5-ene, dec-1-ene, dec-2-ene, dec-3-ene, dec-4-ene, dec-5-ene, dec-6- ene, undec-1-ene, undec-2-ene, undec-3-ene, undec-4-ene, undec-5-ene, undec-6-ene, undec-7- ene, dodec-1-ene, dodec-2-ene, dodec-3-ene, dodec-4-ene, dodec-5-ene, dodec-6-ene, dodec-8- ene, and an alkenyl group comprising two or more double bonds, each of which is optionally substituted. In some embodiments, T5, T6, and T7are independently an alkynyl selected from the group consisting of but-1-yne, but-2-yne, pent-1-yne, pent-2-yne, hex-1-yne, hex-2-yne, hex3-yne, hept- 1-yne, hept-2-yne, hept-3-yne, oct-1-yne, oct-2-yne, oct-3-yne, oct-4-yne, non-1-yne, non-2-yne, non-3-yne, non-4-yne, non-5-yne, dec-1-yne, dec-2-yne, dec-3-yne, dec-4-yne, dec-5-yne, dec-6- yne, undec-1-yne, undec-2-yne, undec-3-yne, undec-4-yne, undec-5-yne, undec-6-yne, undec-7- yne, dodec-1-yne, dodec-2-yne, dodec-3-yne, dodec-4-yne, dodec-5-yne, dodec-6-yne, dodec-8- yne, and an alkynyl group comprising two or more triple bonds, each of which is optionally substituted. In some embodiments, R15 is H. In some embodiments, the lipid is selected from the group consisting of:

[0031] (SM-016; 1-ethylhexyl 9-[3-[[3,5-bis[3-[bis[9-(1-ethylhexoxy)-9-oxo- nonyl]amino]propylcarbamoyl]benzoyl]amino]propyl-[9-(1-ethylhexoxy)-9-oxo- nonyl]amino]nonanoate) (SM-062; hexa(octan-3-yl) 9,9',9'',9''',9'''',9'''''-((((pyridine-2,4,6- tricarbonyl)tris(azanediyl))tris(propane-3,1-diyl))tris(azanetriyl))hexanonanoate),

[0032] (SM-065; tris(3-(bis(9-(octan-3-yloxy)-9-oxononyl)amino)propyl) benzene-1,3,5-tricarboxylate), ( oxononyl)amino)butanamido)isophthaloyl)bis(azanediyl))bis(propane-3,1- diyl))bis(azanetriyl))tetranonanoate),

[0033] (SM-068; hexa(octan-3-yl) 9,9',9'',9''',9'''',9'''''-(((benzene-1,3,5-triyltris(azanediyl))tris(4- oxobutane-4,1-diyl))tris(azanetriyl))hexanonanoate),

[0034] (SM-070; tetra(octan-3-yl) 9,9',9'',9'''-((((5-((3-(bis(9-(octan-3-yloxy)-9- oxononyl)amino)propyl)carbamoyl)-1,3-phenylene)bis(azanediyl))bis(4-oxobutane-4,1- diyl))bis(azanetriyl))tetranonanoate), (SM-072; tetra(octan-3-yl) 9,9',9'',9'''-((((5-((3-(bis(9-(octan-3-yloxy)-9- oxononyl)amino)propyl)carbamoyl)-1,3-phenylene)bis(oxy))bis(propane-3,1- diyl))bis(azanetriyl))tetranonanoate),

[0035] ( oxononyl)amino)propyl)amino)-2-oxoethyl)isophthaloyl)bis(azanediyl))bis(propane-3,1- d ( oxononyl)amino)propyl)amino)-3-oxopropyl)isophthaloyl)bis(azanediyl))bis(propane-3,1- oxononyl)amino)pentanoyl)oxy)methyl)isophthaloyl)bis(azanediyl))bis(propane-3,1- d (SM-112; tetra(octan-3-yl) 9,9',9'',9'''-((((5-(19-ethyl-8-(9-(octan-3-yloxy)-9-oxononyl)-3,17- dioxo-2,18-dioxa-4,8-diazatetracosyl)isophthaloyl)bis(azanediyl))bis(propane-3,1- diyl))bis(azanetriyl))tetranonanoate). In an aspect, the disclosure provides a lipid particle comprising any of the above-described compounds. In some embodiments, the lipid particle further comprises a therapeutic agent. In some embodiments, the therapeutic agent is a nucleic acid. In an aspect, the disclosure provides a pharmaceutical composition comprising a lipid particle as described above and a pharmaceutically acceptable excipient, carrier, or diluent. Definitions Unless specifically stated or obvious from context, as used herein, the term "about" is understood as within a range of normal tolerance in the art, for example within 2 standard deviations of the mean. "About" can be understood as within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01% of the stated value. In certain embodiments, the term "approximately" or "about" refers to a range of values that fall within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in either direction (greater than or less than) of the stated reference value unless otherwise stated or otherwise evident from the context (except where such number would exceed 100% of a possible value). Unless otherwise clear from context, all numerical values provided herein are modified by the term "about." As used herein, "fully closed RNA" and "circular RNA" refer to closed-loop oligoribonucleotide molecules in which the free 3' and 5' ends found in linear RNA forms are joined together to form a closed-loop that appears to render them stable and long-lasting. Without wishing to be bound by theory, this is believed to be due to the lack of free ends making such fully closed / circular RNAs resistant to exonuclease digestion. Certain such closed-loop RNAs have recently been designed to include translatable sequences (e.g., mRNAs) in a format commercially referred to as "Endless RNA™" or "eRNA" (refer, e.g., to U.S. Publication Nos.2022 / 0257794 and 2022 / 0143062, and to U.S. Patent No. 10,953,033). Fully closed or circular RNAs can therefore refer to a mRNA that is circular and reads through continuously. Without wishing to be bound by theory, circular RNA has been described as a versatile synthetic RNA platform that instructs cells to express a desired therapeutic protein and, because of its natural stability, the protein expression is persistent for long periods of time (in contrast with the transient existence of linear translatable RNA). In addition, because of its lack of immunogenicity, circular RNA has also been described to allow for repeat redosing; and because of its inherent stability, circular RNA has also been described to allow for multiple routes of administration, including intravenous dosing, subcutaneous dosing, topical dosing, intratracheal administration, etc. The term "lipid" refers to a group of organic compounds that include, but are not limited to, esters of fatty acids and are characterized by being insoluble in water, but soluble in many organic solvents. They are usually divided into at least three classes: (1) "simple lipids" which include fats and oils as well as waxes; (2) "compound lipids" which include phospholipids and glycolipids; (3) "derived lipids' such as steroids. As used herein, the term "cationic lipid" refers to any lipid species that carries a net positive charge at a selected pH such as, for example, physiological pH. A cationic lipid may have a head group that is always positively charged in aqueous solution (an "obligate cationic lipid"). For example, and without limitation, an obligate cationic lipid may have a quaternary amine as a head group. Alternatively, a cationic lipid may have a head group that accepts a proton in solution such that the lipid exists predominantly as a cation below its pKa and predominantly as a neutral moiety above its pKa, e.g., it may have a pH-titratable amino head group or a substituted aryl and heteroaryl compound (e.g., for an "ionizable substituted aryl and heteroaryl compound lipid", as defined infra and / or for a “substituted piperazine ionizable lipid”, as defined infra). For example, and without limitation, an ionizable lipid may have a primary, secondary, or tertiary amine as a head group, (e.g., an alkylamino or dialkylamino head group). In some embodiments, the ionizable lipids comprise: a protonatable tertiary amine (e.g., pH-titratable) head group; C18hydrocarbon chains e.g., alkyl, alkenyl, or alkynyl chains, wherein each hydrocarbon chain independently has 0 to 3 (e.g., 0, 1, 2, or 3) double bonds; and ether, ester, or ketal linkages between the head group and hydrocarbon chains. In some embodiments, an ionizable substituted aryl and heteroaryl compound may have a generic structure according to Formula I as disclosed herein or a substituted aryl or heteroaryl compound may have a generic structure according to Formula IX as disclosed herein. In some embodiments, a substituted piperazine ionizable lipid may include a piperazine such as ((piperazine-1,4-diylbis(2-oxoethane-2,1-diyl))bis(piperidine-1,4-diyl))bis(ethane-2,1- diyl) bis(2-phenylacetate), having the following structure: . Examples of obligate cationic lipids include, but are not limited to, Dimethyldioctadecylammonium, Bromide Salt (DDAB), N-(4-carboxybenzyl)-N,N-dimethyl- 2,3-bis(oleoyloxy) propan-1-aminium (DOBAQ), 1,2-dioleoyl-3-trimethylammonium-propane or 18:1 TAP, a di-chain or gemini, cationic lipid (DOTAP), 1,2-di-O-octadecenyl-3- trimethylammonium propane, chloride salt (DOTMA), ethyl phosphatidylcholine (EPC), and trimethyl sphingosine A range of forms of the obligate cationic lipid EPC, as well as related forms of obligate cationic phosphatidylcholines, are commercially available. Ethyl phosphatidylcholine, 18:1 EPC (Cl Salt), also known as 1,2-dioleoyl-sn-glycero-3-ethylphosphocholine (chloride salt), has the following structure: . 18:0 EPC (Cl Salt), also known as 1,2-distearoyl-sn-glycero-3-ethylphosphocholine (chloride . 14:0 EPC (Cl Salt), also known as 1,2-dimyristoyl-sn-glycero-3-ethylphosphocholine (chloride salt), has the following structure: . 12:0 EPC (Cl Salt), also known as 1,2-dilauroyl-sn-glycero-3-ethylphosphocholine (chloride salt), has the following structure: . 14:1 EPC (Tf Salt), also known as 1,2-dimyristoleoyl-sn-glycero-3-ethylphosphocholine (Tf salt), has the following structure: . 16:0-18:1 EPC (Cl Salt), also known as 1-palmitoyl-2-oleoyl-sn-glycero-3-ethylphosphocholine (chloride salt), has the following structure: . 18:1 EPC (Cl Salt), also known as 1,2-dioleoyl-sn-glycero-3-ethylphosphocholine (chloride salt), has the following structure: . 16:0-18:0 PC, also known as 1-palmitoyl-2-stearoyl-sn-glycero-3-phosphocholine, has the following structure: . 16:0 / 16:1(9Z)-PC, also known as 1-(1-enyl-palmitoyl)-2-palmitoleoyl-sn-glycero-3- phosphocholine, has the following structure: . 16:0-18:2 PC, also known as 1-palmitoyl-2-linoleoyl-sn-glycero-3-phosphocholine, has the following structure: . 18:0-18:1(9Z)-PC, also known as 1-stearoyl-2-oleoyl-sn-glycero-3-phosphocholine, has the following structure: . 18:0-18:2(9Z, 12Z)-PC, also known as 1-Octadecanyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3- phosphocholine, has the following structure: . 18:1-18:2(9Z, 12Z)-PC, also known as 1-(9Z,12Z-octadecadienoyl)-2-(9Z-octadecenoyl)-glycero- 3-phosphocholine, has the following structure:

[0036] . As used herein, the term "ionizable lipid" or "ionizable cationic lipid" refers to a lipid that becomes cationic (protonated) as the pH is lowered below the pKa of the ionizable group of the lipid but is progressively more neutral at higher pH values. When a component of a lipid-nucleic acid particle, at pH values below the pKa, the lipid is then able to associate with negatively charged polynucleic acids. Certain examples of such ionizable lipids include lipids and salts thereof having one, two, three, or more fatty acid or fatty hydrocarbon chains and a pH-titratable amino head group (e.g., an alkylamino or dialkylamino head group). In some embodiments, the substituted piperazine ionizable lipids comprise: a protonatable piperazine (e.g., pH-titratable) head group; one or more hydrocarbon chains e.g., alkyl or alkenyl chains, wherein each of the one or more hydrocarbon chains may or may not include one or more double bonds; and the head group is connected to the hydrocarbon chains via a linker having the following structure: is 2, 3, 4, 5, 6, 7, or 8, and G4is a bond, -(CO)O-, or -O(CO)-. In some embodiments, a substituted piperazine ionizable lipid may include a substituted piperazine having a head group with the following five ring structure:

[0037] , where the wavy bonds indicate connection points for the above-described linker. Exemplary ionizable lipids include, without limitation, 1,2-Dioleoyl-3- dimethylammonium-propane (DODAP), 9-Heptadecanyl 8-{(2-hydroxyethyl)[6-oxo-6- (undecyloxy)hexyl]amino}octanoate (SM-102), disulfanediylbis(ethane-2,1-diyl)bis(piperidine- 1,4-diyl)bis(ethane-2,1-diyl)bis(oxy)bis(2-oxoethane-2,1-diyl)bis(4,1-phenylene) dioleate (SS- OP), Dimethyl Sphingosine, 3-(N—(N′,N′-dimethylaminoethane)-carbamoyl)cholesterol (DC- Cholesterol), C12-200; N4-Cholesteryl-Spermine HCl Salt (GL67); N1-[2-((1S)-1-[(3- aminopropyl)amino]-4-[di(3-amino-propyl)amino]butylcarboxamido)ethyl]-3,4-di[oleyloxy]- benzamide (MVL5); 1,2-distearyloxy-N,N-dimethyl-3-aminopropane (DSDMA); 1,2-dioleyloxy- N,N-dimethyl-3-aminopropane (DODMA); 1,2-dilinoleyloxy-N,N-dimethyl-3-aminopropane (DLinDMA); 1,2-dilinolenyloxy-N,N-dimethyl-3-aminopropane (DLenDMA); 1,2-di-γ- linolenyloxy-N,N-dimethylaminopropane (γ-DLenDMA); 1,2-dilinoleyloxy-keto-N,N-dimethyl- 3-aminopropane (DLinK-DMA); 1,2-dilinoleyl-4-(2-dimethylaminoethyl)-[1,3]-dioxolane (DLinKC2-DMA) (also known as DLin-C2K-DMA, XTC2, and C2K); 2,2-dilinoleyl-4-(3- dimethylaminopropyl)[1,3]-dioxolane (DLin-K-C3-DMA); 2,2-dilinoleyl-4-(4- dimethylaminobutyl)[1,3]-dioxolane (DLin-K-C4-DMA); 1,2-dilinolenyloxy-4-(2- dimethylaminoethyl)- [1,3]-dioxolane (γ-DLen-C2K-DMA); 1,2-di-γ-linolenyloxy-4-(2- dimethylaminoethyl)-[1,3]-dioxolane (γ-DLen-C2K-DMA); dilinoleylmethyl-3- dimethylaminopropionate (DLin-M-C2-DMA) (also known as MC2); (6Z,9Z,28Z,31Z)- heptatriaconta-6,9,28,31-tetraen-19-yl 4-(dimethylamino) butanoate (DLin-M-C3-DMA) (also known as MC3); 3-(dilinoleylmethoxy)-N,N-dimethylpropan-1-amine (DLin-MP-DMA) (also known as 1-B11); 2-({8-[(3β)-cholest-5-en-3-yloxy]octyl}oxy)-N,N-dimethyl-3-[(9Z,12Z)- octadeca-9,12-dien-1-yloxy]propan-1-amine (Octyl-CLinDMA); (2R) 2-({8-[(3β)-cholest-5-en- 3-yloxy]octyl}oxy)-N,N-dimethyl-3-[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]propan-1-amine (R- Octyl-CLinDMA); (2S) 2-({8-[(3β)-cholest-5-en-3-yloxy]octyl}oxy)-N,N-dimethyl-3-[(9Z,12Z)- octadeca-9,12-dien-1-yloxy]propan-1-amine (S-Octyl-CLinDMA); (2S)-1-{7-[(3β)-cholest-5-en- 3-yloxy]heptyloxy}-3-[(4Z)-dec-4-en-1-yloxy]-N, N -dimethylpropan-2-amine; (2R)-1-{4-[(3β)- cholest-5-en-3-yloxy]butoxy}-3-[(4Z)-dec-4-en-1-yloxy]-N,N-dimethylpropan-2-amine; 1-[(2R)- 1-{4-[(3β)-cholest-5-en-3-yloxy]butoxy}-3-(octyloxy)propan-2-yl]guanidine; 1-[(2R)-1-{7- [(3β)-cholest-5-en-3-yloxy]heptyloxy}-N,N-dimethyl-3-[(9Z,12Z)-octadeca-9,12-dien-1- yloxy]propan-2-amine; 1-[(2R)-1-{4-[(3β)-cholest-5-en-3-yloxy]butoxy}-N,N-dimethyl-3- [(9Z,12Z)-octadeca-9,12-dien-1-yloxy]propan-2-amine; (2S)-1-({6-[(3β))-cholest-5-en-3- yloxy]hexyl}oxy)-N,N-dimethyl-3-[(9Z)-octadec-9-en-1-yloxy]propan-2-amine; (3β)-3-[6- {[(2S)-3-[(9Z)-octadec-9-en-1-yloxyl]-2-(pyrrolidin-1-yl)propyl]oxy}hexyl)oxy]cholest-5-ene; (2R)-1-{4-[(3β)-cholest-5-en-3-yloxy]butoxy}-3-(octyloxy)propan-2-amine; (2R)-1-({8-[(3β)- cholest-5-en-3-yloxy]octyl}oxy)-N,N-dimethyl-3-(pentyloxy)propan-2-amine; (2R)-1-({8-[(3β)- cholest-5-en-3-yloxy]octyl}oxy)-3-(heptyloxy)-N,N-dimethylpropan-2-amine; (2R)-1-({8-[(3β)- cholest-5-en-3-yloxy]octyl}oxy)-N,N-dimethyl-3-[(2Z)-pent-2-en-1-yloxy]propan-2-amine; (2S)-1-butoxy-3-({8-[(3β)-cholest-5-en-3-yloxy]octyl}oxy)-N,N-dimethylpropan-2-amine; (2S- 1-({8-[(3β)-cholest-5-en-3-yloxy]octyl}oxy)-3-[2,2,3,3,4,4,5,5,6,6,7,7,8,8,9,9- hexadecafluorononyl)oxy]-N,N-dimethylpropan-2-amine; 2-amino-2-{[(9Z,12Z)-octadeca-9,12- dien-1-yloxy]methyl}propane-1,3-diol; 2-amino-3-({9-[(3β,8ξ,9ξ,14ξ,17ξ,20ξ)-cholest-5-en-3- yloxy]nonyl}oxy)-2-{[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]methyl}propan-1-ol; 2-ammo-3- ({6-[(3β,8ξ,9ξ,14ξ,17ξ,20ξ)-cholest-5-en-3-yloxy]hexyl}oxy)-2-{[(9Z)-octadec-9-en-1- yloxy]methyl}propan-1-ol; (20Z,23Z)-N,N-dimethylnonacosa-20,23-dien-10-amine; (17Z,20Z)- N,N-dimethylhexacosa-17,20-dien-9-amine; (16Z,19Z)-N,N-dimethylpentacosa-16,19-dien-8- amine; (13Z,16Z)-N,N-dimethyldocosa-13,16-dien-5-amine; (12Z,15Z)-N,N-dimethylhenicosa- 12,15-dien-4-amine; (14Z,17Z)-N,N-dimethyltricosa-14,17-dien-6-amine; (15Z,18Z)-N,N- dimethyltetracosa-15,18-dien-7-amine; (18Z,21Z)-N,N-dimethylheptacosa-18,21-dien-10-amine; (15Z,18Z)-N,N-dimethyltetracosa-15,18-dien-5-amine; (14Z,17Z)-N,N-dimethyltricosa-14,17- dien-4-amine; (19Z,22Z)-N,N-dimethyloctacosa-19,22-dien-9-amine; (18Z,21Z)-N,N- dimethylheptacosa-18,21-dien-8-amine; (17Z,20Z)-N,N-dimethylhexacosa-17,20-dien-7-amine; (16Z,19Z)-N,N-dimethylpentacosa-16,19-dien-6-amine; (22Z,25Z)-N,N-dimethylhentriaconta- 22,25-dien-10-amine; (21Z,24Z)-N,N-dimethyltriaconta-21,24-dien-9-amine; (18Z)-N,N- dimethylheptacos-18-en-10-amine; (17Z)-N,N-dimethylhexacos-17-en-9-amine; (19Z,22Z)-N,N- dimethyloctacosa-19,22-dien-7-amine; N,N-dimethylheptacosan-10-amine; (20Z,23Z)-N-ethyl- N-methylnonacosa-20,23-dien-10-amine; 1-[(11Z,14Z)-1-nonylicosa-11,14-dien-1- yl]pyrrolidine; (20Z)-N,N-dimethylheptacos-20-en-10-amine; (15Z)-N,N-dimethylheptacos-15- en-10-amine; (14Z)-N,N-dimethylnonacos-14-en-10-amine; (17Z)-N,N-dimethylnonacos-17-en- 10-amine; (24Z)-N,N-dimethyltritriacont-24-en-10-amine; (20Z)-N,N-dimethylnonacos-20-en- 10-amine; (22Z)-N,N-dimethylhentriacont-22-en-10-amine; (16Z)-N,N-dimethylpentacos-16-en- 8-amine; (12Z,15Z)-N,N-dimethyl-2-nonylhenicosa-12,15-dien-1-amine; (13Z,16Z)-N,N- dimethyl-3-nonyldocosa-13,16-dien-1-amine; N,N-dimethyl-1-[(1S,2R)-2- octylcyclopropyl]heptadecan-8-amine; 1-[(1S,2R)-2-hexylcyclopropyl]-N,N- dimethylnonadecan-10-amine; N,N-dimethyl-1-[(1S,2R)-2-octylcyclopropyl]nonadecan-10- amine; N,N-dimethyl-21-[(1S,2R)-2-octylcyclopropyl]henicosan-10-amine; N,N-dimethyl-1- [(1S,2S)-2-{[(1R,2R)-2-pentylcyclopropyl]methyl}cyclopropyl]nonadecan-10-amine; N,N- dimethyl-1-[(1S,2R)-2-octylcyclopropyl]hexadecan-8-amine; N,N-dimethyl-1-[(1R,2S)-2- undecylcyclopropyl]tetradecan-5-amine; N,N-dimethyl-3-{7-[(1S,2R)-2- octylcyclopropyl]heptyl}dodecan-1-amine; 1-[(1R,2S)-2-heptylcyclopropyl]-N,N- dimethyloctadecan-9-amine; 1-[(1S,2R)-2-decylcyclopropyl]-N,N-dimethylpentadecan-6-amine; N,N-dimethyl-1-[(1S,2R)-2-octylcyclopropyl]pentadecan-8-amine; (11E,20Z,23Z)-N,N- dimethylnonacosa-11,20,23-trien-10-amine; 2,2-dilinoleyl-5-dimethylaminomethyl-[1,3]- dioxane (DLin-K6-DMA), 2,2-dilinoleyl-4-N-methylpepiazino-[1,3]-dioxolane (DLin-K-MPZ), 2,2-dioleoyl-4-dimethylaminomethyl-[1,3]-dioxolane (DO-K-DMA), 2,2-distearoyl-4- dimethylaminomethyl-[1,3]-dioxolane (DS-K-DMA), 2,2-dilinoleyl-4-N-morpholino-[1,3]- dioxolane (DLin-K-MA), 2,2-Dilinoleyl-4-trimethylamino-[1,3]-dioxolane chloride (DLin-K- TMA.Cl), 2,2-dilinoleyl-4,5-bis(dimethylaminomethyl)-[1,3]-dioxolane (DLin-K2-DMA), 2,2- dilinoleyl-4-methylpiperzine-[1,3]-dioxolane (D-Lin-K—N-methylpiperzine), DLen-C2K-DMA, γ-DLen-C2K-DMA, DPan-C2K-DMA, DPan-C3K-DMA, DLen-C2K-DMA, γ-DLen-C2K- DMA, DPan-C2K-DMA, TLinDMA, C2-TLinDMA, C3-TLinDMA, 1,2-di-γ-linolenyloxy-N,N- dimethylaminopropane (γ-DLenDMA), 1,2-dilinoleyloxy-(N,N-dimethyl)-butyl-4-amine (C2- DLinDMA), 1,2-dilinoleoyloxy-(N,N-dimethyl)-butyl-4-amine (C2-DLinDAP), CP-LenMC3, CP-γ-LenMC3, CP-MC3, CP-DLen-C2K-DMA, CP-γDLen-C2K-DMA, CP-C2K-DMA, CP- DODMA, CP-DPetroDMA, CP-DLinDMA, CP-DLenDMA, CP-γDLenDMA, 1,2- dioeylcarbamoyloxy-3-dimethylaminopropane (DO-C-DAP), 1,2-dimyristoleoyl-3- dimethylaminopropane (DMDAP), 1,2-dioleoyl-3-trimethylaminopropane chloride (DOTAP.Cl), 1,2-dilinoleylcarbamoyloxy-3-dimethylaminopropane (DLin-C-DAP), 1,2-dilinoleyoxy-3- (dimethylamino)acetoxypropane (DLin-DAC), 1,2-dilinoleyoxy-3-morpholinopropane (DLin- MA), 1,2-dilinoleoyl-3-dimethylaminopropane (DLinDAP), 1,2-dilinoleylthio-3- dimethylarninopropane (DLin-S-DMA), 1-linoleoyl-2-linoleyloxy-3-dimethylaminopropane (DLin-2-DMAP), 1,2-dilinoleyloxy-3-trimethylaminopropane chloride salt (DLin-TMA.Cl), 1,2- dilinoleoyl-3-trimethylaminopropane chloride salt (DLin-TAP.Cl), 1,2-dilinoleyloxy-3-(N- methylpiperazino)propane (DLin-MPZ), 3-(N,N-dilinoleylamino)-1,2-propanediol (DLinAP), 3- (N,N-dioleylamino)-1,2-propanedio (DOAP), 1,2-dilinoleyloxo-3-(2-N,N- dimethylamino)ethoxypropane (DLin-EG-DMA), 3-dimethylamino-2-(cholest-5-en-3-beta- oxybutan-4-oxy)-1-(cis,cis-9,12-octadecadienoxy)propane (CLinDMA), 2-[5′-(cholest-5-en-3- beta-oxy)-3′-oxapentoxy)-3-dimethy-1-(cis,cis-9′,1-2′-octadecadienoxy)propane (CpLinDMA), N,N-dimethyl-3,4-dioleyloxybenzylamine (DMOBA), 1,2-N,N′-dioleylcarbamyl-3- dimethylaminopropane (DOcarbDAP), and 1,2-N,N′-dilinoleylcarbamyl-3- dimethylaminopropane (DLincarbDAP); as well as pharmaceutically acceptable salts thereof, and stereoisomers of any of the foregoing. As used herein, the term "non-cationic lipid" refers to any uncharged, anionic, or zwitterionic lipid. At physiological pH, such lipids include, for example, diacylphosphatidylcholine, diacylphosphatidylethanolamine, ceramide, sphingomyelin, cephalin, cholesterol, cerebrosides, diacylglycerols, phosphatidylglycerols, cardiolipins, diacylphosphatidylserines, diacylphosphatidic acids, N-dodecanoyl phosphatidylethanolamines, N-succinyl phosphatidylethanolamines, N-glutarylphosphatidylethanolamines, lysylphosphatidylglycerols, palmitoyloleyolphosphatidylglycerol (POPG), and other anionic modifying groups joined to neutral lipids. In some embodiments, the non-cationic lipid used in the instant disclosure is 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2-Distearoyl-sn- glycero-3-phosphocholine (DSPC), and / or 1,2-Dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE). In embodiments, the non-cationic lipid is cholesterol (CHE) and / or β-sitosterol. In some embodiments, the non-cationic lipid present in the lipid particles comprises or consists of a mixture of one or more phospholipids and cholesterol or a derivative thereof. In certain embodiments, a lipid composition of the disclosure can include lipids such as "neutral lipids," "helper lipids," and / or "stealth lipids." "Neutral lipids" suitable for use in a lipid composition of the disclosure include, for example, a variety of neutral, uncharged or zwitterionic lipids. In some embodiments, neutral lipids disclosed herein may include, for example, diacylphosphatidylcholine, diacylphosphatidylethanolamine, ceramide, sphingomyelin, cephalin, cholesterol, cerebrosides and diacylglycerols. Other examples of neutral phospholipids suitable for use in the present disclosure include, but are not limited to, distearoylphosphatidylcholine (DSPC), pohsphocholine (DOPC), dimyristoylphosphatidylcholine (DMPC), phosphatidylethanolamine (PE), egg phosphatidylcholine (EPC), palmitoyloleoyl phosphatidylcholine (POPC), dioleoyl phosphatidylethanolamine (DOPE), dilinoleoylphosphatidylcholine distearoylphosphatidylethanolamine (DSPE), dimyristoyl phosphatidylethanolamine (DMPE), dipalmitoyl phosphatidylethanolamine (DPPE), palmitoyloleoyl phosphatidylethanolamine (POPE), lysophosphatidylethanolamine and combinations thereof. In one embodiment, the neutral phospholipid may be selected from the group consisting of dioleoyl phosphatidylethanolamine (DOPE). In another embodiment, the neutral phospholipid may be distearoylphosphatidylcholine (DSPC). Without wishing to be bound by theory, neutral lipids have been described to function to stabilize and improve processing of the LNPs. "Helper lipids" are lipids that enhance transfection (e.g., transfection of the nanoparticle including the biologically active agent). Without wishing to be bound by theory, the mechanism by which the helper lipid enhances transfection includes enhancing particle stability. In certain embodiments, the helper lipid enhances membrane fusogenicity. Helper lipids include the above- referenced "neutral lipids," including but not limited to include, but are not limited to, distearoylphosphatidylcholine (DSPC), pohsphocholine (DOPC), dimyristoylphosphatidylcholine (DMPC), phosphatidylethanolamine (PE), egg phosphatidylcholine (EPC), palmitoyloleoyl phosphatidylcholine (POPC), dioleoyl phosphatidylethanolamine (DOPE), dilinoleoylphosphatidylcholine distearoylphosphatidylethanolamine (DSPE), dimyristoyl phosphatidylethanolamine (DMPE), dipalmitoyl phosphatidylethanolamine (DPPE), palmitoyloleoyl phosphatidylethanolamine (POPE), lysophosphatidylethanolamine and combinations thereof, as well as steroids, and sterols. Helper lipids suitable for use in the present disclosure include, but are not limited to, neutral lipids, cholesterol, and PEG-cholesterol. In one embodiment, the helper lipid may be cholesterol. In one embodiment, the helper lipid may be PEG- cholesterol. "Stealth lipids" are lipids that alter the length of time the nanoparticles can exist in vivo (e.g., in the blood). Without wishing to be bound by theory, stealth lipids may assist in the formulation process by, for example, reducing particle aggregation and controlling particle size. Stealth lipids used herein may modulate pharmacokinetic properties of the LNP. Stealth lipids suitable for use in a lipid composition of the disclosure include, but are not limited to, stealth lipids having a hydrophilic head group linked to a lipid moiety. Stealth lipids suitable for use in a lipid composition of the present disclosure and information about the biochemistry of such lipids can be found in Romberg et al, Pharmaceutical Research, Vol.25, No.1, 2008, pg.55-71 and Hoekstra et al, Biochimica et Biophysica Acta 1660 (2004) 41-52. In one embodiment, the hydrophilic head group of stealth lipid comprises a polymer moiety selected from polymers based on PEG (sometimes referred to as poly(ethylene oxide)), poly(oxazoline), poly(vinyl alcohol), poly(glycerol), poly(N- vinylpyrrolidone), polyaminoacids and poly N-(2- hydroxypropyl)methacrylamide. Stealth lipids may comprise a lipid moiety. In some embodiments, the lipid moiety of the stealth lipid may be derived from diacylglycerol or diacylglycamide, including those comprising a dialkylglycerol or dialkylglycamide group having alkyl chain length independently comprising from about C4to about C40saturated or unsaturated carbon atoms, wherein the chain may comprise one or more functional groups such as, for example, an amide or ester. The dialkylglycerol or dialkylglycamide group can further comprise one or more substituted alkyl groups. In some embodiments, stealth lipids may comprise α-Methoxy-ω-(3- oxopropoxy), polyoxyethylene (Methoxy PEG, Aldehyde), PEG2k-DMG, PEG2k-DSG, PEG2k- DSPE, PEG2K-DOPE, PEG5k-DOPE, Methoxy PEG aldehyde 20k, PEG2K-Cholesterol, and the like. The term "lipid nanoparticle (LNP)" as used herein refers to different types of compositions of nano-scale particles, wherein the particles comprising lipids function as carriers across cell membranes and biological barriers and deliver compounds to targeted cells and tissues of humans and other organisms. As used herein, "lipid nanoparticles" of the instant disclosure may further comprise additional lipids and other components. Other lipids may be included for a variety of purposes, such as to prevent lipid oxidation or to attach ligands onto the lipid nanoparticle surface. Any of a number of lipids may be present in lipid nanoparticles of the present disclosure, including amphipathic, neutral, cationic, and anionic lipids. Such lipids can be used alone or in combination and can also include bilayer stabilizing components such as polyamide oligomers (see, e.g., U.S. Pat. No. 6,320,017), peptides, proteins, detergents, lipid-derivatives, such as PEG coupled to phosphatidylethanolamine and PEG conjugated to ceramides (see, e.g., U.S. Pat. No.5,885,613). As used herein, a "PEG" conjugated lipid that inhibits aggregation of particles refers to one or more of a polyethyleneglycol (PEG)-lipid conjugate, a polyamide (ATTA)-lipid conjugate, and a mixture thereof. In one aspect, the PEG-lipid conjugate is one or more of a PEG- dialkyloxypropyl (DAA), a PEG-diacylglycerol (DAG), a PEG-phospholipid, a PEG-ceramide, and a mixture thereof. In one aspect, the PEG-DAG conjugate is one or more of a PEG- dilauroylglycerol (C12), a PEG-dimyristoylglycerol (C14), a PEG-dipalmitoylglycerol (C16), and a PEG-distearoylglycerol (C18). In one aspect, the PEG-DAA conjugate is one or more of a PEG- dilauryloxypropyl (C12), a PEG-dimyristyloxypropyl (C14), a PEG-dipalmityloxypropyl (C16), and a PEG-di stearyloxypropyl (C18). In some embodiments, PEG is 2-dimyristoyl-rac-glycero-3- methoxypolyethylene glycol-2000 (PEG-DMG or PEG2k-DMG) and / or 1,2-distearoyl-rac- glycero-3-methoxypolyethylene glycol-2000 (PEG-DSG). The term "N / P ratio" as used herein refers to the (N)itrogen-to-(P)hosphate molar ratio between the cationic amino lipid and negatively charged phosphate groups of the nucleic acid. The "polydispersity index" or "PDI" as used herein is a measure of the heterogeneity of a sample based on size. Polydispersity can occur due to size distribution in a sample or agglomeration or aggregation of the sample during isolation or analysis. The "zeta potential" or "surface charge" as used herein refers to the degree of electrostatic repulsion between adjacent, similarly charged particles in a dispersion. For molecules and particles that are small enough, a high zeta potential will confer stability, i.e., the solution or dispersion will resist aggregation. As used herein, the term nucleic acid "cargo" refers to the intended nucleic acid for delivery to the cell or tissue (in embodiments, a therapeutic nucleic acid for delivery to the cell or tissue). As used herein, the term "nucleic acid-lipid nanoparticle" refers to lipid nanoparticles as described above that associate with or encapsulate one or more nucleic acids to deliver one or more nucleic acid cargoes to a tissue. As used herein, "encapsulated" can refer to a nucleic acid-lipid nanoparticle formulation that provides a nucleic acid with full encapsulation, partial encapsulation, association by ionic or van der Waals forces, or all of the aforementioned. In one embodiment, the nucleic acid is fully encapsulated in the nucleic acid-lipid nanoparticle. As used herein, "nucleic acid" refers to a synthetic or naturally occurring RNA or DNA, or derivatives thereof. In one embodiment, a cargo and / or agent of the instant disclosure is a nucleic acid, such as a double-stranded RNA (dsRNA). In one embodiment, the nucleic acid or nucleic acid cargo is a single-stranded DNA or RNA, or double-stranded DNA or RNA, or DNA-RNA hybrid. For example, a double-stranded DNA can be a structural gene, a gene including control and termination regions, or a self-replicating system such as a viral or plasmid DNA. A double- stranded RNA can be, e.g., a dsRNA or another RNA interference reagent. A single-stranded nucleic acid can be, e.g., an mRNA, an antisense oligonucleotide, ribozyme, a microRNA, or triplex-forming oligonucleotide. In certain embodiments, the nucleic acid or nucleic acid cargo may comprise a modified RNA, wherein the modified RNA is one or more of a modified mRNA, a modified antisense oligonucleotide and a modified siRNA. In some embodiments, a nucleic acid cargo of the instant disclosure includes or is a modified mRNA that encodes a nucleic acid modulating controller. As used herein, the term "modified nucleic acid" refers to any non-natural nucleic acid, including but not limited to those selected from the group comprising 2′-O-methyl modified nucleotides, a nucleotide comprising a 5′-phosphorothioate group, a terminal nucleotide linked to a cholesteryl derivative, a 2′-deoxy-2′-fluoro modified nucleotide, a 5′-methoxy-modified nucleotide (e.g., 5′-methoxyuridine), a 2′-deoxy-modified nucleotide, a locked nucleotide, an abasic nucleotide, a 2′-amino-modified nucleotide, a 2′-alkyl-modified nucleotide, a morpholino nucleotide, a phosphoramidate, a non-natural base comprising nucleotide; internucleoside linkages or backbones including phosphorothioates, chiral phosphorothioates, phosphorodithioates, phosphotriesters, aminoalkylphosphotriesters, methyl and other alkyl phosphonates including 3′- alkylene phosphonates and chiral phosphonates, phosphinates, phosphoramidates including 3′- amino phosphoramidate and aminoalkylphosphoramidates, thionophosphoramidates, thionoalkylphosphonates, thionoalkylphosphotriesters, and boranophosphates having normal 3′-5′ linkages, 2′-5′ linked analogs of these, and those having inverted polarity wherein the adjacent pairs of nucleoside units are linked 3′-5′ to 5′-3′ or 2′-5′ to 5′-2′. As used herein, the term "nucleic acid modulating controller" refers to a mRNA that encodes for protein controller components, though reference to "nucleic acid modulating controller" can also refer to the mRNA-expressed protein controller components themselves. In certain embodiments, the mRNA-encoded protein controller components include Zinc-Finger proteins (ZFPs) or other forms of DNA or RNA binding domains (DBDs or RBDs) that are associated with (and optionally tethered to) one or more epigenetic regulators or nucleases (the epigenetic regulators or nucleases are generally referred to as effectors, effector domains, or effector moieties). Without wishing to be bound by theory, an advantage of a nucleic acid modulating controller as described herein is that it provides durable gene programming only at the confluence of (1) where the nucleic acid modulating controller-encoding mRNA is expressed, (2) where nucleic acid binding of the ZFP or other nucleic acid binding domain occurs and (3) where the associated effector domain is able to exert activity (i.e. where the effector domain is capable of changing the epigenomic state (e.g., in the instance of an epigenomic controller)). As used herein, the term "effector moiety" or "effector domain" refers to a domain that is capable of altering the expression of a target gene when localized to an appropriate site in a cell, e.g., in the nucleus of a cell. In some embodiments, an effector moiety recruits components of the transcription machinery. In some embodiments, an effector moiety inhibits recruitment of components of transcription factors or expression repressing factors. In some embodiments, an effector moiety comprises an epigenetic modifying moiety (e.g., epigenetically modifies a target DNA sequence). Specific examples of effector moieties include, without limitation, effectors capable of binding Krueppel-associated box (KRAB) domains (KRAB is a domain of around 75 amino acids that is found in the N-terminal part of about one third of eukaryotic Krueppel-type C2H2 zinc finger proteins (ZFPs)) and the engineered prokaryotic DNA methyltransferase MQ1, among others. As used herein, "epigenetic modifying moiety" refers to a domain that alters: i) the structure, e.g., two-dimensional structure, of chromatin; and / or ii) an epigenetic marker (e.g., one or more of DNA methylation, histone methylation, histone acetylation, histone sumoylation, histone phosphorylation, and RNA-associated silencing), when the epigenetic modifying moiety is appropriately localized to a nucleic acid (e.g., by a targeting moiety). In some embodiments, an epigenetic modifying moiety comprises an enzyme, or a functional fragment or variant thereof, that affects (e.g., increases or decreases the level of) one or more epigenetic markers. In some embodiments, an epigenetic modifying moiety comprises a DNA methyltransferase, a histone methyltransferase, CREB-binding protein (CBP), or a functional fragment of any thereof. As used herein, the term "expression control sequence" refers to a nucleic acid sequence that increases or decreases transcription of a gene and includes (but is not limited to) a promoter and an enhancer. An "enhancing sequence" refers to a subtype of expression control sequence and increases the likelihood of gene transcription. A "silencing or repressor sequence" refers to a subtype of expression control sequence and decreases the likelihood of gene transcription. As used herein, the term "expression repressor" refers to an agent or entity with one or more functionalities that decreases expression of a target gene in a cell and that specifically binds to a DNA sequence (e.g., a DNA sequence associated with a target gene or a transcription control element operably linked to a target gene). In certain embodiments, an expression repressor comprises at least one targeting moiety and optionally one effector moiety. As used herein, the term "targeting moiety" means an agent or entity that specifically targets, e.g., binds, a genomic sequence element (e.g., an expression control sequence or anchor sequence; promoter, enhancer or CTCF site). In some embodiments, the genomic sequence element is proximal to and / or operably linked to a target gene (e.g., MYC). As used herein, "localization" refers to the position of a lipid, peptide, or other component of a lipid particle of the instant disclosure, within an organism and / or tissue. In some embodiments, localization can be detectible in individual cells. In some embodiments a label can be used for detecting localization, e.g., a fluorescent label, optionally a fluorescently labeled lipid, optionally Cy7. In some embodiments, the label of the lipid nanoparticle may be a quantum dot, or the lipid detectible by stimulated Raman scattering. In other embodiments, the label is any fluorophore known in the art, i.e. with excitation and emission in the ultraviolet, visible, or infrared spectra. In some embodiments the localization is detected or further corroborated by immunohistochemistry or immunofluorescence. As used herein, the term "activity" refers to any detectable effect that is mediated by a component or composition of the instant disclosure. In embodiments, "activity" as used herein, can refer to a measurable (whether directly or by proxy) effect, e.g., of a cargo of the instant lipid particles of the disclosure. Examples of activity include, without limitation, the intracellular expression and resulting effect(s) of a nucleic acid cargo (e.g., a mRNA, a CRISPR / Cas system, a RNAi agent, a nucleic acid modulating controller, etc.), which can optionally be measured at a cellular, tissue, organ and / or organismal level. As used herein, "multidosing" refers to two or more doses of a lipid nanoparticle formulation given as part of a therapeutic regimen to a subject. As used herein, the term "subject" includes humans and mammals (e.g., mice, rats, pigs, cats, dogs, and horses). In many embodiments, subjects are mammals, particularly primates, especially humans. In some embodiments, subjects are livestock such as cattle, sheep, goats, cows, swine, and the like; poultry such as chickens, ducks, geese, turkeys, and the like; and domesticated animals particularly pets such as dogs and cats. In some embodiments (e.g., particularly in research contexts) subject mammals will be, for example, rodents (e.g., mice, rats, hamsters), rabbits, primates, or swine such as inbred pigs and the like. As used herein, "administration" to a subject may include parenteral administration, optionally for intravenous injection, inhalation, intravenous, intra-arterial, intratracheal, topical, or involve direct injection into a tissue. The term "treating" includes the administration of compositions to prevent or delay the onset of the symptoms, complications, or biochemical indicia of a disease (e.g., cancer, including, e.g., tumor formation, growth and / or metastasis), alleviating the symptoms or arresting or inhibiting further development of the disease, condition, or disorder. Treatment may be prophylactic (to prevent or delay the onset of the disease, or to prevent the manifestation of clinical or subclinical symptoms thereof) or therapeutic suppression or alleviation of symptoms after the manifestation of the disease. As used herein, a "pharmaceutical composition" comprises a pharmacologically effective amount of a lipid particle, optionally a nucleic-acid lipid nanoparticle (NLNP) and a pharmaceutically acceptable carrier. As used herein, "pharmacologically effective amount," "therapeutically effective amount" or simply "effective amount" refers to that amount of nucleic acid effective to produce the intended pharmacological, therapeutic or preventive result. For example, if a given clinical treatment is considered effective when there is at least a 25% reduction in a measurable parameter associated with a disease or disorder, a therapeutically effective amount of a drug for the treatment of that disease or disorder is the amount necessary to induce at least a 25% reduction in that parameter. The term "pharmaceutically acceptable carrier" refers to a carrier for administration of a therapeutic agent. Such carriers include, but are not limited to, saline, buffered saline, dextrose, water, glycerol, ethanol, and combinations thereof. As used herein, "lung tissue" may refer to any cell within the organ of the lung including but not limited to the group comprising the epithelium, endothelium, interstitial connective tissue, blood vessel, hematopoietic tissue, lymphoid tissue, and pleura. In preferred embodiments, the nucleic acid-lipid nanoparticle targets lung tissue. In some other embodiments, the nucleic acid- lipid nanoparticle may target other cells or tissues including but not limited to brain, nerve, skin, eye, pharynx, larynx, heart, vascular, hematopoietic (e.g., white blood cell or red blood cell), breast, liver, pancreas, spleen, esophagus, gall bladder, stomach, intestine, colon, kidney, urinary bladder, ovary, uterus, cervix, prostate, muscle, bone, thyroid, parathyroid, adrenal, and pituitary cells or tissues. As used herein, "localization" refers to the position of a lipid, peptide, or other component of a lipid particle of the instant disclosure, within an organism and / or tissue. In some embodiments, localization can be detectible in individual cells. In some embodiments a label can be used for detecting localization, e.g., a fluorescent label, optionally a fluorescently labeled lipid, optionally Cy7. In some embodiments, the label of the lipid nanoparticle may be a quantum dot, or the lipid detectible by stimulated Raman scattering. In other embodiments, the label is any fluorophore known in the art, i.e. with excitation and emission in the ultraviolet, visible, or infrared spectra. In some embodiments the localization is detected or further corroborated by immunohistochemistry or immunofluorescence. As used herein, the term "lung disease or disorder" may include, without limitation, a disease or disorder selected from the following: lung cancer, pneumonia, pulmonary fibrosis, COPD, asthma, bronchiectasis, sarcoidosis, pulmonary hypertension, emphysema, alpha-1 antitrypsin deficiency, aspergillosis, bronchiolitis, bronchitis, pneumoconiosis, Coronaviruses, Middle Eastern Respiratory Syndrome, Severe Acute Respiratory Syndrome, cystic fibrosis, Legionnaire's disease, influenza, pertussis, pulmonary embolism, and tuberculosis. As used herein, a "joint diseases or disorder," may include, without limitation, a disease or disorder selected from the following: rheumatoid arthritis, psoriatic arthritis, gout, tendinitis, bursitis, Carpal Tunnel Syndrome, and osteoarthritis. As used herein, an "inflammatory disease or disorder," may include, without limitation, a disease or disorder selected from the following: inflammatory bowel disease, peritonitis, osteomyelitis, cachexia, pancreatitis, trauma induced shock, bronchial asthma, allergic rhinitis, cystic fibrosis, acute bronchitis, acute intense bronchitis, osteoarthritis, rheumatoid arthritis, infectious arthritis, post-infectious arthritis, gonocoele arthritis, tuberculous arthritis, arthritis, osteoarthritis, gout, spondyloarthropathies, ankylosing spondylitis, arthritis associated with vasculitis syndrome, nodular polyarteritis nervosa, irritable vasculitis, rugenic granulomatosis, rheumatoid polyposis myalgia, arthritis cell arteritis, calcium polycystic arthropathy, caustic gout, non-arthritic rheumatism, bursitis, hay fever, suppurative inflammation (e.g., tennis elbow), neuropathic joint disease, hemarthrosic, Henoch-Schlein purpura, hypertrophic osteoarthritis, multisized hemorrhoids, scoliosis, hemochromatosis, hyperlipoproteinemia, hypogammaglobulinemia, COPD, acute respiratory distress syndrome, acute lung injury, broncho-pulmonary dysplasia and systemic lupus erythematosus (SLE). As used herein, an "epidermal disease or disorder," may include, without limitation, a disease or disorder selected from the following: psoriasis, atopic dermatitis, scleroderma, eczema, rosacea, seborrheic dermatitis, melanoma, solar keratosis, ichthyosis, Grover's disease, common warts, keratoacanthoma, and seborrhoeic keratosis. Unless specifically stated or obvious from context, as used herein, the term "or" is understood to be inclusive. Unless specifically stated or obvious from context, as used herein, the terms "a," "an," and "the" are understood to be singular or plural. Ranges can be expressed herein as from "about" one particular value, and / or to "about" another particular value. When such a range is expressed, another aspect includes from the one particular value and / or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent "about," it is understood that the particular value forms another aspect. It is further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. It is also understood that there are a number of values disclosed herein, and that each value is also herein disclosed as “about” that particular value in addition to the value itself. It is also understood that throughout the application, data are provided in a number of different formats and that this data represent endpoints and starting points and ranges for any combination of the data points. For example, if a particular data point "10" and a particular data point "15" are disclosed, it is understood that greater than, greater than or equal to, less than, less than or equal to, and equal to 10 and 15 are considered disclosed as well as between 10 and 15. It is also understood that each unit between two particular units are also disclosed. For example, if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also disclosed. Ranges provided herein are understood to be shorthand for all of the values within the range. For example, a range of 1 to 50 is understood to include any number, combination of numbers, or sub-range from the group consisting 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 as well as all intervening decimal values between the aforementioned integers such as, for example, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, and 1.9. With respect to sub-ranges, "nested sub-ranges" that extend from either end point of the range are specifically contemplated. For example, a nested sub-range of an exemplary range of 1 to 50 may comprise 1 to 10, 1 to 20, 1 to 30, and 1 to 40 in one direction, or 50 to 40, 50 to 30, 50 to 20, and 50 to 10 in the other direction. The transitional term "comprising," which is synonymous with "including," "containing," or "characterized by," is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. By contrast, the transitional phrase "consisting of" excludes any element, step, or ingredient not specified in the claim. The transitional phrase "consisting essentially of" limits the scope of a claim to the specified materials or steps "and those that do not materially affect the basic and novel characteristic(s)" of the disclosure. As used herein, the term "alkyl" refers to a straight-chain or branched saturated hydrocarbon group having from 1 to 22 carbon atoms ("C1–22alkyl"). In some embodiments, an alkyl group may have 3 to 22 carbon atoms ("C3–22alkyl") and / or 7 to 22 carbon atoms ("C7–22alkyl"). In some embodiments, an alkyl group may have 7 to 18 carbon atoms ("C7–18alkyl") and / or 7 to 12 carbon atoms ("C7–12alkyl"). In some embodiments, an alkyl group has 7 to 8 carbon atoms ("C7–8alkyl"). In some embodiments, an alkyl group has 7 to 9 carbon atoms ("C7–9alkyl"). In some embodiments, an alkyl group may have 7 to 10 carbon atoms (“C7–10 alkyl”). In some embodiments, an alkyl group has 7 to 11 carbon atoms ("C7–11 alkyl"). In some embodiments, an alkyl group may have 8 to 12 carbon atoms ("C8–12 alkyl"). In some embodiments, an alkyl group has 9 to 12 carbon atoms ("C9–12 alkyl"). In some embodiments, an alkyl group has 10 to 12 carbon atoms ("C10–12 alkyl"). In some embodiments, an alkyl group has 11 to 12 carbon atoms ("C11–12 alkyl"). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (C8), n-nonyl (C9), n- decyl (C10), n-undecyl (C11), n-dodecyl (C12), and the like. An "alkyl" group as used herein may be unsubstituted or optionally substituted. Unless otherwise specified, each instance of an alkyl group is independently optionally substituted, i.e., unsubstituted (an "unsubstituted alkyl") or substituted (a "substituted alkyl") with one or more substituents. Suitable substituent groups may include, but are not limited to, hydroxyl, nitro, amino (e.g., —NH2or dialkyl amino), imino, cyano, halo (e.g., F, Cl, Br, I, and the like), haloalkyl (e.g., —CCl3, —CF3, and the like), thio, sulfonyl, thioamido, amidino, imidino, oxo, oxamidino, methoxamidino, imidino, guanidino, sulfonamido, carboxyl, formyl, alkyl, alkoxy, alkoxy-alkyl, alkylcarbonyl, alkylcarbonyloxy (e.g., —OCOR), aminocarbonyl, arylcarbonyl, aralkylcarbonyl, carbonylamino, heteroarylcarbonyl, heteroaralkyl-carbonyl, alkylthio, aminoalkyl, cyanoalkyl, carbamoyl (e.g., —NHCOOR— or —OCONHR—), urea (e.g., —NHCONHR—), cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, (═O), thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, C-carboxy, O-carboxy, nitro, amino, heterocycle, —CN, and the like. An "alkyl" as used herein may be combined with other groups, for example, those provided above, to form one or more substituted alkyl groups and / or a functionalized alkyl. An "alkyl" group, as defined above, may further comprise 1 or more (e.g., 1, 2, 3, 4, etc.) heteroatoms (e.g., a "heteroalkyl" such as, e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus, and the like) within the parent chain, wherein the one or more heteroatoms are inserted between adjacent carbon atoms within the parent carbon chain and / or one or more heteroatoms are inserted between a carbon atom and the parent molecule, i.e., between the point of attachment. In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 22 carbon atoms and 1, 2, 3, 4, etc. heteroatoms ("heteroC1-22 alkyl"). In some embodiments, a heteroalkyl group refers to a saturated group having from 3 to 22 carbon atoms and / or 7 to 22 carbon atoms and 1, 2, 3, 4, etc. heteroatoms ("heteroC3-22alkyl" and / or "hetero C7–22alkyl”). In some embodiments, a heteroalkyl group may have 7 to 18 carbon atoms and / or 7 to 12 carbon atoms and 1, 2, 3, 4, etc. heteroatoms ("heteroC7-18alkyl" and / or "hetero C7–12alkyl”). In some embodiments, a heteroalkyl group may have 7 to 8 carbon atoms and 1, 2, 3, 4, etc. heteroatoms ("heteroC7-8 alkyl"). In some embodiments, a heteroalkyl group may have 7 to 9 carbon atoms and 1, 2, 3, 4, etc. heteroatoms ("heteroC7-9alkyl"). In some embodiments, a heteroalkyl group has 7 to 10 carbon atoms and 1, 2, 3, 4, etc. heteroatoms ("heteroC7-10 alkyl"). In some embodiments, a heteroalkyl group has 7 to 11 carbon atoms and 1, 2, 3, 4, etc. heteroatoms ("heteroC7-11 alkyl"). In some embodiments, a heteroalkyl group has 8 to 12 carbon atoms and 1, 2, 3, 4, etc. heteroatoms ("heteroC8-12 alkyl"). In some embodiments, a heteroalkyl group has 9 to 12 carbon atoms and 1, 2, 3, 4, etc. heteroatoms ("heteroC9-12 alkyl"). In some embodiments, a heteroalkyl group has 10 to 12 carbon atoms and 1, 2, 3, 4, etc. heteroatoms ("heteroC10-12alkyl"). In some embodiments, a heteroalkyl group has 11 to 12 carbon atoms and 1, 2, 3, 4, etc. heteroatoms ("heteroC11-12alkyl"). As used herein, the term "alkenyl" includes a chain of carbon atoms, which is optionally branched, having from 2 to 22 carbon atoms and including at least one double bond (e.g., 1, 2, 3, 4, etc. carbon-carbon double bonds) ("C2–22 alkenyl"). In some embodiments, an alkenyl group may have 3 to 22 carbon atoms ("C3–22 alkenyl") and / or 7 to 22 carbon atoms ("C7–22 alkenyl"). In some embodiments, an alkenyl group may have 7 to 18 carbon atoms ("C7–18alkenyl") and / or 7 to 12 carbon atoms ("C7–12alkenyl"). In some embodiments, an alkenyl group has 7 to 8 carbon atoms ("C7–8alkenyl"). In some embodiments, an alkenyl group has 7 to 9 carbon atoms ("C7–9alkenyl"). In some embodiments, an alkenyl group may have 7 to 10 carbon atoms ("C7–10alkenyl"). In some embodiments, an alkenyl group has 7 to 11 carbon atoms ("C7–11alkenyl"). In some embodiments, an alkenyl group may have 8 to 12 carbon atoms ("C8–12alkenyl"). In some embodiments, an alkenyl group has 9 to 12 carbon atoms ("C9–12alkenyl"). In some embodiments, an alkenyl group has 10 to 12 carbon atoms ("C10–12alkenyl"). In some embodiments, an alkenyl group has 11 to 12 carbon atoms ("C11–12alkenyl"). Additional examples of alkenyl groups include n-heptyl (C7), n- octyl (C8), n-nonyl (C9), n-decyl (C10), n-undecyl (C11), n-dodecyl (C12), and the like. The one or more carbon-carbon double bonds may be internal (e.g., 2-butenyl) or terminal (e.g., 1- butenyl). Examples of C2-4alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples of C2-6 alkenyl groups include the aforementioned C2-4 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Unless otherwise specified, each instance of an alkenyl group is independently optionally substituted, i.e., unsubstituted (an "unsubstituted alkenyl") or substituted (a "substituted alkenyl") with one or more substituents e.g., from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, the alkenyl group is unsubstituted C3-22 alkenyl. In certain embodiments, the alkenyl group is substituted C3-22 alkenyl. Exemplary substituents are listed above with respect to "alkyl" and may be used here with respect to "alkenyl" as well. The term "heteroalkenyl," as used herein, refers to an alkenyl group, as defined above, which further comprises one or more (e.g., 1, 2, 3, 4, etc.) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus, and the like), wherein the one or more heteroatoms is inserted between adjacent carbon atoms within the parent carbon chain and / or one or more heteroatoms are inserted between a carbon atom and the parent molecule, i.e., between the point of attachment. In some embodiments, a heteroalkenyl group refers to an unsaturated group having 2 to 22 carbon atoms and 1, 2, 3, 4, etc. heteroatoms ("heteroC2-22alkenyl"). In some embodiments, a heteroalkenyl group refers to an unsaturated group having from 7 to 18 carbon atoms and / or 7 to 12 carbon atoms and 1, 2, 3, 4, etc. heteroatoms ("heteroC7-18 alkenyl" or "hetero C7–12 alkenyl”). In some embodiments, a heteroalkenyl group may have 7 to 8 carbon atoms and 1, 2, 3, 4, etc. heteroatoms ("heteroC7-8alkenyl"). In some embodiments, a heteroalkenyl group may have 7 to 9 carbon atoms and 1, 2, 3, 4, etc. heteroatoms ("heteroC7-9 alkenyl"). In some embodiments, a heteroalkenyl group has 7 to 10 carbon atoms and 1, 2, 3, 4, etc. heteroatoms ("heteroC7-10 alkenyl"). In some embodiments, a heteroalkenyl group has 7 to 11 carbon atoms and 1, 2, 3, 4, etc. heteroatoms ("heteroC7-11 alkenyl"). In some embodiments, a heteroalkenyl group has 8 to 12 carbon atoms and 1, 2, 3, 4, etc. heteroatoms ("heteroC8-12 alkenyl"). In some embodiments, a heteroalkenyl group has 9 to 12 carbon atoms and 1, 2, 3, 4, etc. heteroatoms ("heteroC9-12alkenyl"). In some embodiments, a heteroalkenyl group has 10 to 12 carbon atoms and 1, 2, 3, 4, etc. heteroatoms ("heteroC10-12 alkenyl"). In some embodiments, a heteroalkenyl group has 11 to 12 carbon atoms and 1, 2, 3, 4, etc. heteroatoms ("heteroC11-12 alkenyl"). Additional examples of alkenyl groups include n-heptyl (C7), n-octyl (C8), n-nonyl (C9), n-decyl (C10), n-undecyl (C11), n- dodecyl (C12), and the like. The one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. As used herein, the term "alkynyl" includes a chain of carbon atoms, which is optionally branched, and contains from 2 to 22 carbon atoms ("C2–22 alkynyl"), including at least one carbon- carbon triple bond (i.e., C≡C). In some embodiments, an alkynyl group may have 3 to 22 carbon atoms ("C3–22 alkynyl") and / or 7 to 22 carbon atoms ("C7–22 alkynyl"). In some embodiments, an alkynyl group may have 7 to 18 carbon atoms ("C7–18alkynyl") and / or 7 to 12 carbon atoms ("C7–12 alkynyl"). In some embodiments, an alkynyl group has 7 to 8 carbon atoms ("C7–8 alkynyl"). In some embodiments, an alkynyl group has 7 to 9 carbon atoms (“C7–9 alkynyl”). In some embodiments, an alkynyl group may have 7 to 10 carbon atoms ("C7–10 alkynyl"). In some embodiments, an alkynyl group has 7 to 11 carbon atoms ("C7–11 alkynyl"). In some embodiments, an alkynyl group may have 8 to 12 carbon atoms (“C8–12 alkynyl”). In some embodiments, an alkynyl group has 9 to 12 carbon atoms ("C9–12 alkynyl"). In some embodiments, an alkynyl group has 10 to 12 carbon atoms ("C10–12 alkynyl"). In some embodiments, an alkynyl group has 11 to 12 carbon atoms ("C11–12 alkynyl"). Alkynyl may be unsubstituted or substituted as described above for "alkyl" or as described in the various embodiments provided herein. Illustrative alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl, and the like. The term "heteroalkynyl," as used herein, refers to an alkynyl group, as defined above, which further comprises one or more (e.g., 1, 2, 3, 4, etc.) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus, and the like), wherein the one or more heteroatoms are inserted between adjacent carbon atoms within the parent carbon chain and / or one or more heteroatoms are inserted between a carbon atom and the parent molecule, i.e., between the point of attachment. In some embodiments, a heteroalkynyl group refers to an unsaturated group having 2 to 22 carbon atoms and 1, 2, 3, 4, etc. heteroatoms ("heteroC2-22 alkynyl"). In some embodiments, a heteroalkynyl group refers to an unsaturated group having from 7 to 18 carbon atoms and / or 7 to 12 carbon atoms and 1, 2, 3, 4, etc. heteroatoms ("heteroC7-18alkynyl" or "hetero C7–12alkynyl”). In some embodiments, a heteroalkynyl group may have 7 to 8 carbon atoms and 1, 2, 3, 4, etc. heteroatoms ("heteroC7-8 alkynyl"). In some embodiments, a heteroalkynyl group may have 7 to 9 carbon atoms and 1, 2, 3, 4, etc. heteroatoms ("heteroC7-9alkynyl"). In some embodiments, a heteroalkynyl group has 7 to 10 carbon atoms and 1, 2, 3, 4, etc. heteroatoms ("heteroC7-10alkynyl"). In some embodiments, a heteroalkynyl group has 7 to 11 carbon atoms and 1, 2, 3, 4, etc. heteroatoms ("heteroC7-11alkynyl"). In some embodiments, a heteroalkynyl group has 8 to 12 carbon atoms and 1, 2, 3, 4, etc. heteroatoms ("heteroC8-12alkynyl"). In some embodiments, a heteroalkynyl group has 9 to 12 carbon atoms and 1, 2, 3, 4, etc. heteroatoms ("heteroC9-12 alkynyl"). In some embodiments, a heteroalkynyl group has 10 to 12 carbon atoms and 1, 2, 3, 4, etc. heteroatoms ("heteroC10-12 alkynyl"). In some embodiments, a heteroalkynyl group has 11 to 12 carbon atoms and 1, 2, 3, 4, etc. heteroatoms ("heteroC11-12 alkynyl"). As used herein, "carbocyclyl" or "carbocyclic" refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 8 ring carbon atoms ("C3-8 carbocyclyl") and zero heteroatoms in the non-aromatic ring system. In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms ("C3-7carbocyclyl"). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C3-6carbocyclyl"). In some embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms ("C4-6 carbocyclyl"). In some embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms ("C5-6carbocyclyl"). In some embodiments, a carbocyclyl group has 5 to 8 ring carbon atoms ("C5-8carbocyclyl"). Exemplary C3-6carbocyclyl groups include, without limitation, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. Exemplary C3-8carbocyclyl groups include, without limitation, the aforementioned C3-6carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like. As the foregoing examples illustrate, in certain embodiments, the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or polycyclic (e.g., containing a fused, bridged or spiro ring system such as a bicyclic system ("bicyclic carbocyclyl") or tricyclic system ("tricyclic carbocyclyl")) and can be saturated or can contain one or more carbon-carbon double or triple bonds. "Carbocyclyl" also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system. Unless otherwise specified, each instance of a carbocyclyl group is independently unsubstituted (an "unsubstituted carbocyclyl") or substituted (a "substituted carbocyclyl") with one or more substituents. In certain embodiments, the carbocyclyl group is an unsubstituted C3-10carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted C3-10 carbocyclyl. In some embodiments, "carbocyclyl" or "carbocyclic" is referred to as a "cycloalkyl," i.e., a monocyclic, saturated carbocyclyl group having from 3 to 8 ring carbon atoms ("C3-8cycloalkyl"). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("C3-6, cycloalkyl"). In some embodiments, a cycloalkyl group has 4 to 6 ring carbon atoms ("C4-6 cycloalkyl"). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms ("C5-6 cycloalkyl"). In some embodiments, a cycloalkyl group has 5 to 8 ring carbon atoms ("C5-8 cycloalkyl"). Examples of C5-6cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). Examples of C3-6 cycloalkyl groups include the aforementioned C5-6 cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C4). Examples of C3-8 cycloalkyl groups include the aforementioned C3-6cycloalkyl groups as well as cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted (an "unsubstituted cycloalkyl") or substituted (a "substituted cycloalkyl") with one or more substituents. In certain embodiments, the cycloalkyl group is an unsubstituted C3-8cycloalkyl. In certain embodiments, the cycloalkyl group is a substituted C3-8cycloalkyl. The term "heterocycle" or "heterocyclyl" refers to a saturated or an unsaturated aromatic or non-aromatic group having from 1 to 8 annular carbon atoms and from 1 to 4 annular heteroatoms, such as nitrogen, oxygen, sulfur, boron, phosphorus, silicon, and the like, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized. A heterocycle group may have a single ring or multiple condensed rings. A heterocycle comprising more than one ring may be fused, spiro or bridged, or any combination thereof. In fused ring systems, one or more of the fused rings can be aryl or heteroaryl. Examples of heterocycle groups include, but are not limited to, dihydropyranyl, thiazolinyl, thiazolidinyl, tetrahydrothiophenyl, 2,3-dihydrobenzo[b]thiophen-2-yl, 4-amino-2-oxopyrimidin-1(2H)-yl, benzoimidazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, oxetanyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, tetrahydropyranyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, azetidinyl, 1,4-dioxanyl, hexahydroazepinyl, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, dihydrobenzoimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, methylenedioxybenzoyl, tetrahydrofuranyl, and tetrahydrothienyl, N-oxides thereof, and the like. A "heterocycle" as disclosed herein may be optionally substituted with one or more substituents, including e.g., but not limited to, hydroxyl, nitro, amino (e.g., —NH2 or dialkyl amino), imino, cyano, halo (e.g., F, Cl, Br, I, and the like), haloalkyl (e.g., —CCl3, —CF3, and the like), thio, sulfonyl, thioamido, amidino, imidino, oxo, oxamidino, methoxamidino, imidino, guanidino, sulfonamido, carboxyl, formyl, alkyl, alkoxy, alkoxy-alkyl, alkylcarbonyl, alkylcarbonyloxy (e.g., —OCOR), aminocarbonyl, arylcarbonyl, aralkylcarbonyl, carbonylamino, heteroarylcarbonyl, heteroaralkyl-carbonyl, alkylthio, aminoalkyl, cyanoalkyl, carbamoyl (e.g., —NHCOOR— or —OCONHR—), urea (e.g., — NHCONHR—), cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, (═O), thiocarbonyl, O-carbamyl, N-carbamyl, O- thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, C-carboxy, O-carboxy, nitro, amino, heterocycle, —CN, and the like. For example and without limitation, additional optional substituents include fluorine, chlorine, bromine, and iodine atoms and CF3, CN, OH, =O, SH, =S, NH2, =NH, N3 and NO2 groups. Optional substituents also include C1-C10 alkyl, C1-C10 heteroalkyl, C2-C10alkenyl, C2-C10heteroalkenyl, C2-C10alkynyl, C2-C10hetero alkynyl, and the like. Exemplary substituents are F, Cl, Br, OH, SH, =O, NH2, amino, C1-4alkyl (e.g., methyl, ethyl, t-butyl), C1-4 heteroalkyl cyclopropyl, SF5, NO, NO2, NMe2, CONH2, CH2NMe2, NHSO2Me, C(CH3)2CN, COMe, OMe, SMe, COOMe, COOEt, CH2COOH, OCH2COOH, COOH, SOMe, SO2Me, cyclopropyl, SO2NH2, SO2NHMe, SO2CH2CH2OH, NHCH2CH2OH, CH2CH2OCH3, SF5, SO2NMe2, NO, NO2, OCF3, SO2CF3, CN or CF3. In heterocycle groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocycle group can either be monocyclic ("monocyclic heterocycle") or a fused, bridged or spiro ring system such as a bicyclic system ("bicyclic heterocycle"), and can be saturated or can be partially unsaturated. Heterocycle bicyclic ring systems can include one or more heteroatoms in one or both rings. "Heterocycle" also includes ring systems wherein the heterocycle ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each instance of heterocyclyl is independently optionally substituted, i.e., unsubstituted (an "unsubstituted heterocyclyl") or substituted (a "substituted heterocycle") with one or more substituents. In certain embodiments, the heterocycle group is unsubstituted 3-8 membered heterocycle. In certain embodiments, the heterocycle group is substituted 3-8 membered heterocycle. In some embodiments, a heterocycle group is a 3-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("5-10 membered heterocycle"). In some embodiments, a heterocycle group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heterocycle"). In some embodiments, a heterocycle group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heterocycle"). In some embodiments, the 5-6 membered heterocycle has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocycle has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocycle has one ring heteroatom selected from nitrogen, oxygen, and sulfur. The term "non-aromatic heterocycle" refers to a mono- or poly-cyclic compound, which is not aromatic, and which comprises one or more heteroatom in the ring structure. Such heteroatoms are preferably selected from the group consisting of S, N and O. Examples of non-aromatic heterocycle includes but are not limited to pyrrolidine, piperidine, piperazine, morpholine, and thiomorpholine. As used herein, the expression "optionally substituted" means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Heteroatoms, such as nitrogen, may have substituents, such as any suitable substituent described herein which satisfies the valencies of the heteroatoms and results in the formation of a stable moiety. The embodiments set forth below and recited in the claims can be understood in view of the above definitions. Other features and advantages of the disclosure will be apparent from the following description of the preferred embodiments thereof, and from the claims. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. All published foreign patents and patent applications cited herein are incorporated herein by reference. All other published references, documents, manuscripts and scientific literature cited herein are incorporated herein by reference. In the case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting. DETAILED DESCRIPTION The present disclosure provides, in certain aspects, novel ionizable substituted aryl and heteroaryl lipid-like compounds (e.g., as represented by Formula I) that were designed and synthesized according to techniques disclosed herein. These novel ionizable substituted aryl and heteroaryl lipid-like compounds were formulated into lipid nanoparticles (LNPs) and shown to provide a stable and efficient LNP formulations, which was comparable to, or better than, benchmark lipids of the prior art. The present disclosure also provides novel ionizable lipid-like chemicals (e.g., substituted piperazine ionizable lipids as represented by Formula VII) that were designed and synthesized according to the techniques disclosed herein. These novel ionizable lipid-like chemicals were also formulated into lipid nanoparticles (LNPs), and shown to provide a stable and efficient LNP formulation, which was comparable to, or better than, benchmark lipids of the prior art. The present disclosure further provides other novel aryl and heteroaryl lipid compounds (e.g., as represented by formula IX) that were designed and synthesized according to techniques disclosed herein. These other aryl and heteroaryl lipid compounds were also formulated into lipid nanoparticles (LNPs) and shown to provide stable and efficient LNP formulations, which were comparable to, or better than, benchmark lipids of the prior art. The present disclosure is based, at least in part, upon the discovery that ionizable substituted aryl and heteroaryl lipid-like compounds may be used to form novel ionizable lipids having advantageous properties when used in lipid particles for the delivery of a therapeutic agent(s). In particular, the techniques herein provide lipid-based nanoparticle compositions and formulations capable of specifically targeting a cargo moiety (e.g., a nucleic acid cargo) to specific tissues of a subject, without requiring a ligand-based targeting strategy. Lipid-like substituted aryl and heteroaryl compounds as disclosed herein may comprise the following general structure:

[0038] ( or a salt or isomer thereof, where X is CH or N; a and b are independently 2-5; m1, m2, m3, and m4are independently 4-10; E1, E2, E3, and E4 are independently -O(CO)O-, -(CO)O- or -O(CO)-; T1, T2, T3, and T4 are independently branched or unbranched C5-C22 alkyl, C5-C22 alkenyl, or C5-C22alkynyl; R1 and R2 are independently H or C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; R3 is independently H or C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl or G is O, -(CO)NR3-, -NR3(CO)-, -(CO)O-, or -CH2(CO)NR3-; L is a bond or optionally substituted C1-C4alkyl; Z is CH or N, and R4 and R5 are independently H, C1-C3 alkyl, C2-C3 alkenyl, or C2-C3 alkynyl, or optionally substituted 3-7 membered ring comprising 0-2 heteroatoms, or R4 and R5 together with L form a substituted 3-7 membered ring. Lipid-like substituted aryl and heteroaryl compounds as disclosed herein may also comprise the following general structures:

[0039] (II), or a salt or isomer thereof, where X is CH or N; L1, L2, and L3are independently -O-, -(CO)NRx-, -NRx(CO)-, -(CO)O-, -CH2(CO)NRx-, provided that when A is CH not all of L1, L2, and L3 are -(CO)NRx-; Rx is H, C1-C6 alkyl, or C3-C6 cycloalkyl; G1 and G2 are Formula III: or salt or isomer thereof, where n1 is 3, 45, 6, 7, 8, 9, or 10; L4 is -(CO)O- or -O(CO)-; R6is branched C5-C20alkyl; G3 is Formula (III), Formula (IV), Formula (V), or Formula (VI): R7 and R8 are independently, optionally functionalized, C1-C5 alkyl; n2, n3, and n4are independently 0, 1, 2, or 3; X1 is C, N, or O; and R9 and R10 are independently H or optionally functionalized C1-C5 alkyl. The present disclosure is also based, at least in part, upon the discovery that substituted piperazines may be used to form novel ionizable lipids having advantageous properties when used in lipid particles for the delivery of a therapeutic agent(s). In particular, the techniques herein provide lipid-based nanoparticle compositions and formulations capable of specifically targeting a cargo moiety (e.g., a nucleic acid cargo) to specific tissues of a subject, without requiring a ligand-based targeting strategy. Substituted piperazines ionizable lipids as disclosed herein comprise a head group having the following structure:

[0040] , where the protonatable piperazine (e.g., pH-titratable) head group is connected to C5-C20 hydrocarbon chains e.g., alkyl or alkenyl chains, where each hydrocarbon chain independently has 0 to 5 (e.g., 0, 1, 2, 3, 4, or 5) double bonds, via a linker having the following structure: , where L5 is -O(CO)-, -CH2-O(CO)-, -CH2(CO)O-, or -O(CO)-NH-, n5is 2, 3, 4, 5, 6, 7, or 8, and G4is a bond, -(CO)O-, or -O(CO)-. The C5-C20hydrocarbon chains may be attached to the G atom of the linker. The present disclosure is further based, at least in part, upon the discovery that other aryl and heteroaryl lipid compounds may be used to form novel ionizable lipids having advantageous properties when used in lipid particles for the delivery of a therapeutic agent(s). In particular, the techniques herein provide lipid-based nanoparticle compositions and formulations capable of specifically targeting a cargo moiety (e.g., a nucleic acid cargo) to specific tissues of a subject, without requiring a ligand-based targeting strategy. The other aryl and heteroaryl compounds as disclosed herein may comprise the following general structure represented by Formula IX:

[0041] (IX) or a salt or isomer thereof, where X2, X3, and X4are independently CH or N; G8, G9, and G10 are independently O, -(CO)O-, -CH2O(CO)-, -(CH2)2(CO)NR15-, - (CH2)O(CO)NR15-, CH2(CO)NR15-, -(CO)NR15-, -NR15(CO)-, or NR15(CO)O-, wherein if X2, X3, and X4are all CH, then not all of G8, G9, and G10 are -(CO)NR15-; a1, b1, and c1 are independently 0,1, 2, 3, or 4; m6, m7, and m8are independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; E5, E6, and E7are independently -(CO)O- or -O(CO)-; T5, T6, and T7 are independently branched or unbranched C5-C22 alkyl, C5-C22 alkenyl, or C5-C22alkynyl; and R15 is H, or optionally functionalized C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl. Substituted aryl and heteroaryl lipid-like compounds, substituted piperazine ionizable lipids, and / or other ionizable aryl and / or heteroaryl lipid compound(s) disclosed herein provide stable and efficient lipid nanoparticle (LNP) formulations for delivery of therapeutic oligonucleotides to specific target tissues of interest. Traditional LNPs are composed of four main components. An ionizable or cationic lipid for mRNA encapsulation, amphipathic helper phospholipids for increased efficacy, cholesterol for structural stability and polyethylene glycol (PEG)-lipids for steric stability. This first generation of LNPs can be considered as "one ionizable lipid-only LNPs," or "single LNPs." Conventionally, effective intracellular delivery materials have relied on an optimal balance of ionizable amines to bind and release RNAs (pKa between 6.0 and 6.5) and nanoparticle-stabilizing hydrophobicity. Thus, there has been an exhaustive focus on developing ionizable lipids, which have been proven to be highly effective delivery platforms for liver and hepatocytes. However, changing the chemical structure of the ionizable / cationic lipid to achieve different pKa values and generating libraries, although validated, is a time consuming, investment heavy and labor-intensive exercise.Certain aspects of the present disclosure provide ionizable substituted aryl and heteroaryl lipid-like compounds having the surprising ability to provide stable and efficient LNP formulations for delivery of therapeutic oligonucleotides to specific target tissues of interest. Without wishing to be bound by theory, certain ionizable substituted aryl and heteroaryl lipid-like compounds (e.g., SM-066, SM-078, SM-081, SM-082, SM-084, SM-089, SM-090, SM-091, SM-092, SM-093, SM- 094, SM-095, SM-096, SM-098, SM-101, SM-103, SM-106, SM-114, SM-115, SM-117, SM-120, SM-129, SM-131, SM-138, SM-141, SM-152, SM-155, SM-158, SM-163, SM-170, and SM-173) disclosed herein appear to be able to shift the tropism of LNP vectors disclosed herein to specific tissues of interest without requiring a further active-targeting component in the LNPs of the instant disclosure. Table 1: Ionizable substituted aryl and heteroaryl lipid-like compounds

[0042] have the general structure set forth in Formula I or Formula II herein and include the (R) and / or (S) enantiomers thereof. The present disclosure also provides substituted piperazines ionizable lipids having the surprising ability to provide stable and efficient LNP formulations for delivery of therapeutic oligonucleotides to specific target tissues of interest. Without wishing to be bound by theory, certain substituted piperazines ionizable lipids (e.g., SM-048, SM-074, SM-076, SM-077, SM- 079, SM-083, SM-085, SM-088, SM-100, SM-109, SM-113, and SM-125) disclosed herein appear to be able to shift the tropism of LNP vectors disclosed herein to specific tissues of interest without requiring a further active-targeting component in the LNPs of the instant disclosure. Table 2: Substituted piperazines ionizable lipid compounds

[0043] The novel substituted piperazine ionizable lipids disclosed herein have the general structure set forth in Formula VII or Formula VIII herein and include the (R) and / or (S) enantiomers thereof. The present disclosure further provides substituted piperazines ionizable lipids having the surprising ability to provide stable and efficient LNP formulations for delivery of therapeutic oligonucleotides to specific target tissues of interest. Without wishing to be bound by theory, certain substituted piperazines ionizable lipids (e.g., SM-048, SM-074, SM-076, SM-077, SM- 079, SM-083, SM-085, SM-088, SM-100, SM-109, SM-113, and SM-125) disclosed herein appear to be able to shift the tropism of LNP vectors disclosed herein to specific tissues of interest without requiring a further active-targeting component in the LNPs of the instant disclosure. The present disclosure additionally provides other aryl and heteroaryl lipid compounds having the surprising ability to provide stable and efficient LNP formulations for delivery of therapeutic oligonucleotides to specific target tissues of interest. Without wishing to be bound by theory, certain aryl and heteroaryl lipid compounds (e.g., SM-016, SM-062, SM-065, SM-067, SM-068, SM-070, SM-072, SM-073, SM-107, SM-111, and SM-112) disclosed herein appear to be able to shift the tropism of LNP vectors disclosed herein to specific tissues of interest without requiring a further active-targeting component in the LNPs of the instant disclosure. Certain of the additional aryl and heteroaryl lipid compounds disclosed herein have the general structure set forth in Formula IX herein and include the (R) and / or (S) enantiomers thereof. In embodiments, the techniques herein provide improved lipid-based compositions for the delivery of therapeutic agents, in particular, nucleic acid therapeutic agents. As disclosed herein, these lipid-based compositions are effective in increasing the efficiency of cargo release from lipid-based composition such as LNPs. Furthermore, the present disclosure demonstrates that the activity of these improved lipid-based compositions is dependent on the presence of certain novel ionizable substituted aryl and heteroaryl lipid-like compounds, certain novel substituted piperazine ionizable lipids, and / or other ionizable aryl and / or heteroaryl lipid compound(s) disclosed herein. It is contemplated within the scope of the disclosure that the lipid-based compositions including the ionizable substituted aryl and heteroaryl lipid-like compounds, the substituted piperazine ionizable lipids, and / or the other ionizable aryl and / or heteroaryl lipid compound(s) disclosed herein may be used for a variety of purposes such as, for example, the delivery of encapsulated therapeutic agents to cells, in vitro and / or in vivo. In this regard, the present disclosure provides methods of treating diseases or disorders in a subject in need thereof by contacting the subject with the lipid-based compositions disclosed herein when combined with the suitable therapeutic agent such as, for example, nucleic acids (e.g., siRNA, ASO, tRNA, miRNA, mRNA, DNA, and the like), proteins, peptides, and other macromolecules. Nucleic acid therapy has well-known, tremendous potential to treat diseases at the gene level. However, safe and effective delivery systems are essential for nucleic acid therapeutics. Non-specific delivery to organs and tissues often results in off-site effects and toxicity. Delivery of therapeutics to a specific organ of interest is a well-recognized need in the development of lipid- nanoparticles, as well as in drug development generally. The concept of only targeting the cause of a disease without harming other parts of the body was described by Ehrlich 120 years ago. However, extant methods do not provide defined or well-known methodologies for developing nanoparticles targeting specific tissues without introducing additional ligand-based targeting strategies. Organ-specific targeting of lipid nanoparticles based on the structural affinity of the lipid to the tissue, as now disclosed herein, therefore meets a well-established need in terms of reducing off-site effects and toxicity. The ability to specifically deliver nucleic acid therapeutics to specific tissues or organs while avoiding activity in the other tissues or organs is vital to treat many tissue- or organ-specific diseases effectively. The instant disclosure demonstrates that incorporation of substituted aryl and heteroaryl lipid-like compounds such as, for example, SM-066, SM-078, SM-081, SM-082, SM- 084, SM-089, SM-090, SM-091, SM-092, SM-093, SM-094, SM-095, SM-096, SM-098, SM-101, SM-103, SM-106, SM-114, SM-115, SM-117, SM-120, SM-129, SM-131, SM-138, SM-141, SM- 152, SM-155, SM-158, SM-163, SM-170, and / or SM-173; substituted piperazine ionizable lipids such as, for example, SM-048, SM-074, SM-076, SM-077, SM-079, SM-083, SM-085, SM-088, SM-100, SM-109, SM-113, and / or SM-125; and / or SM-016, SM-062, SM-065, SM-067, SM-068, SM-070, SM-072, SM-073, SM-107, SM-111, and / or SM-112 into LNPs shifts the tropism of vectors to specific tissues of interest without requiring an active-targeting component in the LNPs. In embodiments, the lipid-based compositions disclosed herein are particularly useful for the delivery of nucleic acid therapeutics (e.g., siRNA, ASO, tRNA, miRNA, mRNA, DNA, and the like). The lipid-based compositions disclosed herein may be used to modulate the expression of target genes and proteins both in vitro and in vivo by contacting tissues / cells with a lipid-based composition including a lipid as disclosed herein carrying a cargo such as a therapeutic nucleic acid (e.g., an siRNA) that may reduce expression of a desired target gene. The techniques herein provide ionizable substituted aryl and heteroaryl lipid-like compounds that enable the formulation of pharmaceutical compositions for the in vitro or in vivo delivery of therapeutic agents such as, for example, nucleic acids (e.g., siRNA, ASO, tRNA, miRNA, mRNA, DNA, and the like), proteins, peptides, and other macromolecules. Exemplary embodiments of the ionizable substituted aryl and heteroaryl lipid-like compounds of the present disclosure and lipid-based compositions comprising the same, as well as their synthesis and LNP formulation is described in further detail below. Lipids In certain aspects, the present disclosure provides novel ionizable substituted aryl and heteroaryl lipid-like compounds of the general structure of Formula I.

[0044] (I) The ionizable substituted aryl and heteroaryl lipid-like compounds have design features including a central six-member heterocycle ring backbone having three side groups at positions 2, 4, and 6 of the heterocycle ring. The present disclosure also provides novel substituted piperazine ionizable lipids of the general structure of Formula VII. The substituted piperazine ionizable lipids disclosed herein have design features including a piperazine head group having the following structure: , where the protonatable piperazine (e.g., pH-titratable) head group is connected to C5-C20 hydrocarbon chains e.g., alkyl or alkenyl chains, where each hydrocarbon chain independently has 0 to 5 (e.g., 0, 1, 2, 3, 4, or 5) double bonds, via a linker having the following structure: NH-, n5is 2, 3, 4, 5, 6, 7, or 8, and G4is a bond, -(CO)O-, or -O(CO)-. The C5-C20hydrocarbon chains may be attached to the G atom of the linker. Substituted piperazine ionizable lipids disclosed herein provide stable and efficient lipid nanoparticle (LNP) formulations for delivery of therapeutic oligonucleotides to specific target tissues of interest. The present disclosure additionally provides other ionizable substituted aryl and heteroaryl lipid-like compounds of the general structure of Formula IX. Certain ionizable aryl and heteroaryl lipid compounds have design features including a central six-member heterocycle ring backbone having three side groups at positions 2, 4, and 6 of the heterocycle ring, where each of the atoms at positions 1, 3, and 5 may be either CH or N. Exemplary ionizable aryl and heteroaryl lipid compounds are disclosed herein. Table 3: Ionizable aryl and heteroaryl lipid compounds

[0045]

[0046] Certain aspects of the present disclosure provide novel ionizable lipids that may be advantageously used in lipid-based compositions of the present disclosure for the in vivo delivery of therapeutic agents to tissues / cells. It is contemplated within the scope of the disclosure that the ionizable lipid (e.g., an ionizable substituted aryl and / or heteroaryl lipid-like compound, a substituted piperazine ionizable lipid, and / or other ionizable aryl and / or heteroaryl lipid compound(s)) comprises a racemic mixture or a mixture of one or more diastereomers. In some embodiments, the ionizable lipid is enriched in one enantiomer, such that the ionizable lipid comprises at least about 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% enantiomeric excess. In some embodiments, the ionizable lipid is enriched in one diastereomer, such that the cationic lipid comprises at least about 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% diastereomeric excess. In some embodiments, the ionizable lipid is chirally pure (e.g., comprises a single optical isomer). In some embodiments, the ionizable lipid is enriched in one optical isomer (e.g., an optically active isomer), such that the ionizable lipid comprises at least about 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% isomeric excess. The disclosure provides the synthesis of ionizable lipids of Formula I, Formula VII, and / or Formula IX as a racemic mixture or in optically pure form. As used herein, the term "salts" includes any anionic and cationic complex, such as the complex formed between an ionizable substituted aryl or heteroaryl lipid-like compounds, a substituted piperazine ionizable lipid, and / or other ionizable aryl and / or heteroaryl lipid compound(s) disclosed herein and one or more anions. Examples of anions include, but are not limited to, inorganic and organic anions such as, e.g., hydride, fluoride, chloride, bromide, iodide, oxalate (e.g., hemioxalate), phosphate, phosphonate, hydrogen phosphate, dihydrogen phosphate, oxide, carbonate, bicarbonate, nitrate, nitrite, nitride, bisulfite, sulfide, sulfite, bisulfate, sulfate, thiosulfate, hydrogen sulfate, borate, formate, acetate, benzoate, citrate, tartrate, lactate, acrylate, polyacrylate, fumarate, maleate, itaconate, glycolate, gluconate, malate, mandelate, tiglate, ascorbate, salicylate, polymethacrylate, perchlorate, chlorate, chlorite, hypochlorite, bromate, hypobromite, iodate, an alkylsulfonate, an arylsulfonate, arsenate, arsenite, chromate, dichromate, cyanide, cyanate, thiocyanate, hydroxide, peroxide, permanganate, and mixtures thereof. In particular embodiments, the salts of the substituted aryl and heteroaryl lipid-like compounds disclosed herein are crystalline salts. As used herein, the term "alkyl" includes a straight chain or branched, noncyclic or cyclic, saturated aliphatic hydrocarbon containing from 1 to 24 carbon atoms. Representative saturated straight chain alkyls include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n- hexyl, and the like, while saturated branched alkyls include, without limitation, isopropyl, sec- butyl, isobutyl, tert-butyl, isopentyl, and the like. Representative saturated cyclic alkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like, while unsaturated cyclic alkyls include, without limitation, cyclopentenyl, cyclohexenyl, and the like. As used herein, the term "alkenyl" includes an alkyl, as defined above, containing at least one double bond between adjacent carbon atoms. Alkenyls include both cis and trans isomers. Representative straight chain and branched alkenyls include, but are not limited to, ethylenyl, propylenyl, 1-butenyl, 2-butenyl, isobutylenyl, 1-pentenyl, 2-pentenyl, 3-methyl-1-butenyl, 2- methyl-2-butenyl, 2,3-dimethyl-2-butenyl, and the like. Cyclic alkenyls are also contemplated for the lipids of the instant disclosure. As used herein, the term "alkynyl" includes any alkyl or alkenyl, as defined above, which additionally contains at least one triple bond between adjacent carbons. Representative straight chain and branched alkynyls include, without limitation, acetylenyl, propynyl, 1-butynyl, 2- butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-1 butynyl, and the like. As used herein, the term "acyl" includes any alkyl, alkenyl, or alkynyl wherein the carbon at the point of attachment is substituted with an oxo group, as defined below. The following are non-limiting examples of acyl groups: —C(═O)alkyl, —C(═O)alkenyl, and —C(═O)alkynyl. As used herein, the term "heterocycle" includes a monocyclic (e.g., 5-, 6-, 7-membered, and the like), bicyclic (e.g., 7-, 8-, 9-, 10-membered, and the like), or heterocyclic ring which is either saturated, unsaturated, or aromatic, and which contains from 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and wherein the nitrogen and sulfur heteroatoms may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized, including bicyclic rings in which any of the above heterocycles are fused to a benzene ring. The heterocycle may be attached via any heteroatom or carbon atom. Heterocycles include, but are not limited to, heteroaryls as defined below, as well as morpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperizynyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydroprimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like. As used herein, the terms "optionally substituted alkyl," "optionally substituted alkenyl," "optionally substituted alkynyl," "optionally substituted acyl," and "optionally substituted heterocycle" mean that, when substituted, at least one hydrogen atom is replaced with a substituent. In the case of an oxo substituent (═O), two hydrogen atoms are replaced. In this regard, substituents include, but are not limited to, oxo, halogen, heterocycle, —CN, —NRxRy, — NRxC(═O)Ry, —NRxSO2Ry, —C(═O)Rx, —C(═O)ORx, —C(═O)NRxRy, —SOnRx, and — SOnNRxRy, wherein n is 0, 1, or 2, Rx and Ry are the same or different and are independently hydrogen, alkyl, or heterocycle, and each of the alkyl and heterocycle substituents may be further substituted with one or more of oxo, halogen, —OH, —CN, alkyl, —ORx, heterocycle, —NRxRy, —NRxC(═O)Ry, —NRxSO2Ry, —C(═O)ORx, —C(═O)ORx, —C(═O)NRxRy, —C(O-R1)(O- R2), —SOnRx, and —SOnNRxRy. The term “optionally substituted,” when used before a list of substituents, means that each of the substituents in the list may be optionally substituted as described herein. As used herein, the term "halogen" includes fluoro, chloro, bromo, and iodo. In embodiments, the present disclosure provides a substituted aryl and heteroaryl lipid-like compounds of Formula I having the following structure: (I) or a salt or isomer thereof, where X is CH or N; a and b are independently 2-5; m1, m2, m3, and m4 are independently 4-10; E1, E2, E3, and E4are independently -O(CO)O-, -(CO)O- or -O(CO)-; T1, T2, T3, and T4 are independently branched or unbranched C5-C22 alkyl, C5-C22 alkenyl, or C5-C22 alkynyl; R1and R2are independently H or C1-C6alkyl, C2-C6alkenyl, or C2-C6alkynyl; R3is independently H or C1-C6alkyl, C2-C6alkenyl, or C2-C6alkynyl or ; G is O, -(CO)NR3-, -NR3(CO)-, -(CO)O-, or -CH2(CO)NR3-; L is a bond or optionally substituted C1-C4 alkyl; Z is CH or N, and R4and R5are independently H, C1-C3alkyl, C2-C3alkenyl, or C2-C3alkynyl, or form an optionally substituted 3-7 membered ring comprising 0-2 heteroatoms, or R4and R5together with L form a substituted 3-7 membered ring. In embodiments, the present disclosure provides a substituted aryl and heteroaryl lipid-like compounds having the following structures:

[0047] (II), or a salt or isomer thereof, where X is CH or N; L1, L2, and L3are independently -O-, -(CO)NRx-, -NRx(CO)-, -(CO)O-, -CH2(CO)NRx-, provided that when A is CH not all of L1, L2, and L3are -(CO)NRx-; Rx is H, C1-C6 alkyl, or C3-C6 cycloalkyl; G1 and G2 are Formula III: or salt or isomer thereof, where n1 is 3, 45, 6, 7, 8, 9, or 10; L4 is -(CO)O- or -O(CO)-; R6is branched C5-C20alkyl; G3 is Formula (III), Formula (IV), Formula (V), or Formula (VI): R7 and R8 are independently, optionally functionalized, C1-C5 alkyl; n2, n3, and n4are independently 0, 1, 2, or 3; X1 is C, N, or O; and R9 and R10 are independently H or optionally functionalized C1-C5 alkyl. In certain embodiments, the present disclosure provides a substituted piperazine ionizable lipid of Formula VII having the following structure:

[0048] (VII), or a salt or isomer thereof, where L6 is -O(CO)-, -CH2-O(CO)-, or -O(CO)-NH-, n6 and n7 are independently 1, 2, 3, 4, 5, 6, 7, or 8, G5and G6are independently a bond; -(CO)O-; or -O(CO)- , and R11 and R12 are each independently, optionally substituted, C5-C20 alkyl or C5-C20 alkenyl. In some embodiments, n6 and n7 are independently 4, 5, 6, 7, or 8. In some embodiments, R11and R12are each independently C8-C9alkyl, C8-C10alkyl, C8- C11alkyl, C8-C12alkyl, C8-C13alkyl, C8-C14alkyl, C8-C15alkyl, C8-C16alkyl, C8-C17alkyl, C8-C18alkyl, C8-C19 alkyl, C8-C20 alkyl, C8-C9 alkenyl, C8-C10 alkenyl, C8-C11 alkenyl, C8-C12 alkenyl, C8-C13 alkenyl, C8-C14 alkenyl, C8-C15 alkenyl, C8-C16 alkenyl, C8-C17 alkenyl, C8-C18 alkenyl, C8- C19alkenyl, and C8-C20. In some embodiments, R11and R12are the same. In some embodiments, R11 and R12 are different. In some embodiments, R11 and R12 are both C8-20 alkyl. In some embodiments, R11 and / or R12 include 1, 2, 3, 4, 5, 6, or more sites of unsaturation that correspond to, for example, cis double bonds, trans double bonds, or combinations thereof, and may be located at specific positions in one or both of the unsaturated R11 and R12 side-chains. For those unsaturated side-chains where a double bond is located between hydrogen atoms and alkyl or alkylene chains, the chemical notation “E” refers to the trans double bond configuration and the chemical notation “Z” refers to the cis double bond configuration. As non-limiting examples, one or both R11 and R12 are C8 alkyl groups containing any combination of double bonds in the cis and / or trans configuration at one or more positions, and / or are of any structure shown in the below Examples. Similarly, as non-limiting examples, one or both R11 and R12 are C12 alkyl groups containing any combination of double bonds which can be characterized by either the “E” chemical notation and / or the “Z” chemical notation at one or more positions in the side-chain. Similarly, as non-limiting examples, one or both R11 and R12 are C15 alkyl groups containing any combination of double bonds which can be characterized by either the “E” chemical notation and / or the “Z” chemical notation at one or more positions in the side-chain. Similarly, as non- limiting examples, one or both R11and R12are C17alkyl groups containing any combination of double bonds which can be characterized by either the “E” chemical notation and / or the “Z” chemical notation at one or more positions in the side-chain. In some embodiments, the positions of saturation in R11and R12are the same. In some embodiments, R11 and R12 are independently an alkenyl selected from the group consisting of hept-1-ene, hept-2-ene, hept-3-ene, oct-1-ene, oct-2-ene, oct-3-ene, oct-4-ene, non- 1-ene, non-2-ene, non-3-ene, non-4-ene, non-5-ene, dec-1-ene, dec-2-ene, dec-3-ene, dec-4-ene, dec-5-ene, dec-6-ene, undec-1-ene, undec-2-ene, undec-3-ene, undec-4-ene, undec-5-ene, undec- 6-ene, undec-7-ene, dodec-1-ene, dodec-2-ene, dodec-3-ene, dodec-4-ene, dodec-5-ene, dodec-6- ene, and dodec-8-ene. In some embodiments, the linker connecting the phosphate group and the amine group may include 1, 2, 3, 4, 5, 6, or more sites of unsaturation that correspond to, for example, cis double bonds, trans double bonds, or combinations thereof, and / or one or more triple bonds and may be located at specific positions within the linker. In embodiments, the present disclosure provides a substitute piperazine ionizable lipid of Formula VIII having the following structure:

[0049] (VIII). or a salt or isomer thereof, where m5 is 4, 5, 6, 7, or 8; G7is a bond; -(CO)O-; or -O(CO)-; and R13and R14are each independently, optionally substituted, C8-C20alkyl or C8-C20alkenyl. In some embodiments, R13 and R14 are the same. In some embodiments, R13and R14are different. In some embodiments, R13or R14are independently selected from the group consisting of optionally substituted C8-C19 alkyl and C8-C19 alkenyl, optionally R13 and R14 are independently selected from the group consisting of optionally substituted C8-C19 alkyl and C8-C19 alkenyl. In some embodiments, R13or R14are independently selected from the group consisting of optionally substituted C8-C18 alkyl and C8-C18 alkenyl, optionally R13 and R14 are independently selected from the group consisting of optionally substituted C8-C18 alkyl and C8-C18 alkenyl. In some embodiments, R13or R14are independently selected from the group consisting of optionally substituted C8-C17alkyl and C8-C17alkenyl, optionally R13and R14are independently selected from the group consisting of optionally substituted C8-C17 alkyl and C8-C17 alkenyl. In some embodiments, R13or R14are independently selected from the group consisting of optionally substituted C8-C16alkyl and C8-C16alkenyl, optionally R13and R14are independently selected from the group consisting of optionally substituted C8-C16 alkyl and C8-C16 alkenyl. In some embodiments, R13 or R14 are independently selected from the group consisting of optionally substituted C8-C15alkyl and C8-C15alkenyl, optionally wherein R13and R14are independently selected from the group consisting of optionally substituted C8-C15 alkyl and C8-C15 alkenyl. In some embodiments, R13 or R14 are independently selected from the group consisting of optionally substituted C9-C12alkyl and C9-C12alkenyl, optionally wherein R13and R14are independently selected from the group consisting of optionally substituted C9-C12alkyl and C9-C12alkenyl. In some embodiments, m5 is 4, 5, 6, 7, or 8. In some embodiments, R13or R14include 1, 2, 3, 4, 5, 6, or more sites of unsaturation. In some embodiments, m5is 5, 6, or 7. In some embodiments, R13 or R14 include 1, 2, 3, 4, 5, 6, or more sites of unsaturation. In some embodiments, R13 or R14 are independently selected from the group consisting of optionally substituted C10-C17alkyl and C10-C17alkenyl, optionally wherein R13and R14are independently selected from the group consisting of optionally substituted C10-C17 alkyl and C10- C17 alkenyl. In some embodiments, m5is 5, 6, or 7. In some embodiments, R13or R14include 1, 2, 3, 4, 5, 6, or more sites of unsaturation. In some embodiments, R13 or R14 are independently selected from the group consisting of optionally substituted C12-C17alkyl and C12-C17alkenyl, optionally wherein R13and R14are independently selected from the group consisting of optionally substituted C12-C17alkyl and C12- C17 alkenyl. In some embodiments, m5is 5, 6, or 7. In some embodiments, R13or R14include 1, 2, 3, 4, 5, 6, or more sites of unsaturation. In some embodiments, R13 is selected from the group consisting of optionally substituted C8-C17 alkyl and C8-C17 alkenyl, and R14 is selected from the group consisting of optionally substitutedC8-C17alkyl and C8-C17alkenyl. In some embodiments, m5 is 5. In some embodiments, G7 is a bond or -(CO)O-. In some embodiments, R13or R14are independently selected from the group consisting of optionally substituted C8, C12, C15, or C17alkyl and C8, C12, C15, or C17alkenyl, optionally wherein R3 and R4 are independently selected from the group consisting of optionally substituted C8, C12, C15, or C17 alkyl and C8, C12, C15, or C17 alkenyl. In some embodiments, R13and R14are independently an alkyl selected from the group consisting of octane, nonane, decane, undecane, and dodecane, each of which is optionally substituted. In some embodiments, R13and R14are independently an alkyl selected from the group consisting of octane, nonane, decane, undecane, dodecane, tridecane, tetradecane, pentadecane, hexadecane, heptadecane, octadecane, nonadecane, and icosane. In some embodiments, R13and R14are independently an alkenyl selected from the group consisting of oct-1-ene, oct-2-ene, oct-3-ene, oct-4-ene, non-1-ene, non-2-ene, non-3-ene, non-4- ene, non-5-ene, dec-1-ene, dec-2-ene, dec-3-ene, dec-4-ene, dec-5-ene, dec-6-ene, undec-1-ene, undec-2-ene, undec-3-ene, undec-4-ene, undec-5-ene, undec-6-ene, undec-7-ene, dodec-1-ene, dodec-2-ene, dodec-3-ene, dodec-4-ene, dodec-5-ene, dodec-6-ene, tridec-1-ene, tridec-2-ene, tridec-3-ene, tridec-4-ene, tridec-5-ene, tridec-6-ene, tridec-7-ene, tetradec-1-ene, tetradec-2-ene, tetradec-3-ene, tetradec-4-ene, tetradec-5-ene, tetradec-6-ene, tetradec-7-ene, pentadec-1-ene, pentadec-2-ene, pentadec-3-ene, pentadec-4-ene, pentadec-5-ene, pentadec-6-ene, pentadec-7- ene, hexadec-1-ene, hexadec-2-ene, hexadec-3-ene, hexadec-4-ene, hexadec-5-ene, hexadec-6- ene, hexadec-7-ene, hexadec-8-ene, heptadec-1-ene, heptadec-2-ene, heptadec-3-ene, heptadec-4- ene, heptadec-5-ene, heptadec-6-ene, heptadec-7-ene, heptadec-8-ene, octadec-1-ene, octadec-2- ene, octadec-3-ene, octadec-4-ene, octadec-5-ene, octadec-6-ene, octadec-7-ene, octadec-8-ene, octadec-9-ene, nonadec-1-ene, nonadec-2-ene, nonadec-3-ene, nonadec-4-ene, nonadec-5-ene, nonadec-6-ene, nonadec-7-ene, nonadec-8-ene, nonadec-9-ene, icos-1-ene, icos-2-ene, icos-3-ene, icos-4-ene, icos-5-ene, icos-6-ene, icos-7-ene, icos-8-ene, and icos-9-ene. In some embodiments, R13 and R14 independently comprise one or more additional double bonds, optionally wherein R13 and R14 independently comprise one double bond. In further embodiments, the present disclosure provides aryl and heteroaryl lipid compounds of Formula IX having the following structure:

[0050] (IX) or a salt or isomer thereof, where X2, X3, and X4are independently CH or N; G8, G9, and G10 are independently O, -(CO)O-, -CH2O(CO)-, -(CH2)2(CO)NR15-, - (CH2)O(CO)NR15-, CH2(CO)NR15-, -(CO)NR15-, -NR15(CO)-, or NR15(CO)O-, wherein if X2, X3, and X4are all CH, then not all of G8, G9, and G10 are -(CO)NR15-; a1, b1, and c1 are independently 0, 1, 2, 3,or 4; m6, m7, and m8are independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; E5, E6, and E7are independently -(CO)O- or -O(CO)-; T5, T6, and T7 are independently branched or unbranched C5-C22 alkyl, C5-C22 alkenyl, or C5-C22alkynyl; and R15 is H, or optionally functionalized C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl. The compounds described herein may be prepared by known organic synthesis techniques, including the methods described in the below Examples. Lipid-based Compositions The techniques herein provide lipid-based compositions (e.g., LNPs and the like) comprising one or more of the ionizable lipids or salts thereof described herein. In some embodiments, the lipid-based compositions of the disclosure further comprise one or more substituted aryl and / or heteroaryl lipid-like compounds, one or more substituted piperazine ionizable lipids, and / or other ionizable aryl and / or heteroaryl lipid compound(s). In some embodiments, the lipid-based compositions further comprise one or more conjugated lipids capable of reducing or inhibiting particle aggregation. In some embodiments, the lipid-based compositions further comprise one or more active agents or therapeutic agents such as, for example, nucleic acids (e.g., siRNA, ASO, tRNA, miRNA, mRNA, DNA, and the like), proteins, peptides, and other macromolecules. As disclosed herein, lipid-based compositions include, but are not limited to, lipid nanoparticles, lipid vesicles (e.g., liposomes), and the like. As used herein, a lipid vesicle may include a structure having lipid-containing membranes enclosing an aqueous interior. In some embodiments, lipid-based compositions comprising one or more of the ionizable lipids described herein may be used to encapsulate therapeutic agents such as, for example, nucleic acids, within the lipid vesicles. In some embodiments, lipid vesicles comprising one or more of the ionizable lipids described herein may be complexed with nucleic acids. The lipid-based compositions of the disclosure typically comprise a therapeutic agent, an ionizable lipid, a non-cationic lipid, and a conjugated lipid (e.g., a polyethylene glycol (PEG)- lipid) that inhibits aggregation of particles. In some embodiments, the therapeutic agent is fully encapsulated within the lipid portion of the lipid-based compositions such that the therapeutic agent is resistant to enzymatic degradation, e.g., by a nuclease or protease. In some embodiments, the lipid-based compositions described herein are substantially non-toxic to mammals such as humans. It is contemplated within the scope of the disclosure that the lipid-based compositions described herein typically have a mean diameter of from about 30 nm to about 250 nm, from about 40 nm to about 200 nm, from about 50 nm to about 150 nm, from about 60 nm to about 130 nm, from about 70 nm to about 110 nm, or from about 70 to about 90 nm. in some embodiments, the lipid-based compositions disclosed herein have a lipid:therapeutic agent (e.g., lipid:nucleic acid) ratio (mass / mass ratio) of from about 1:1 to about 1000:1, from about 1:1 to about 500:1, from about 2:1 to about 250:1, from about 3:1 to about 200:1, from about 5:1 to about 150:1, from about 5:1 to about 100:1, from about 5:1 to about 50:1, from about 5:1 to about 25:1, from about 5:1 to about 20:1, from about 5:1 to about 10:1, or from about 6:1 to about 9:1. Alternatively, the lipid- based compositions disclosed herein have a lipid:therapeutic agent (e.g., lipid:nucleic acid) ratio (mole / mole ratio) of from about 1:1 to about 30:1, from about 2:1 to about 20:1, from about 2:1 to about 15:1, from about 3:1 to about 10:1, from about 4:1 to about 9:1, from about 5:1 to about 8:1, or from about 6:1 to about 8:1. In some embodiments, the lipid-based compositions of the disclosure are nucleic acid-lipid particles that include an interfering RNA (e.g., dsRNA such as siRNA, Dicer-substrate dsRNA, shRNA, aiRNA, and / or miRNA), an ionizable lipid (e.g., one or more lipids of Formulas I-XIX or salts thereof as set forth herein), a non-cationic lipid (e.g., mixtures of one or more phospholipids and cholesterol), and a conjugated lipid that inhibits aggregation of the particles (e.g., one or more PEG-lipid conjugates). The nucleic acid-lipid particle may comprise at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more unmodified and / or modified interfering RNA molecules (e.g., siRNA). Nucleic acid-lipid particles and their method of preparation are described in, e.g., U.S. Pat. Nos.5,753,613; 5,785,992; 5,705,385; 5,976,567; 5,981,501; 6,110,745; and 6,320,017; and PCT Publication No. WO 96 / 40964, the disclosures of which are each herein incorporated by reference in their entirety for all purposes. In the nucleic acid-lipid particles disclosed herein, the nucleic acid may be fully encapsulated within the lipid portion of the particle, thereby protecting the nucleic acid from nuclease degradation. In preferred embodiments, a nucleic acid-lipid particle comprising a nucleic acid such as an interfering RNA may be fully encapsulated within the lipid portion of the particle, thereby protecting the nucleic acid from nuclease degradation. In some embodiments, the nucleic acid may be complexed with the lipid portion of the particle. It is contemplated within the scope of the disclosure that the lipid-based compositions disclosed herein are substantially non-toxic to mammals such as humans. As used herein, the term "fully encapsulated" indicates that the nucleic acid in the nucleic acid-lipid particle is not significantly degraded after exposure to serum or a nuclease assay that would significantly degrade free DNA or RNA. In a fully encapsulated system, preferably less than about 25% of the nucleic acid in the particle is degraded in a treatment that would normally degrade 100% of free nucleic acid, more preferably less than about 10%, and most preferably less than about 5% of the nucleic acid in the particle is degraded. In some embodiments, the present disclosure provides a nucleic acid-lipid particle composition comprising a plurality of nucleic acid-lipid particles. In some instances, the nucleic acid-lipid particle composition comprises nucleic acid that is fully encapsulated within the lipid portion of the particles, such that from about 30% to about 100%, from about 40% to about 100%, from about 50% to about 100%, from about 60% to about 100%, from about 70% to about 100%, from about 80% to about 100%, from about 90% to about 100%, from about 30% to about 95%, from about 40% to about 95%, from about 50% to about 95%, from about 60% to about 95%, from about 70% to about 95%, from about 80% to about 95%, from about 85% to about 95%, from about 90% to about 95%, from about 30% to about 90%, from about 40% to about 90%, from about 50% to about 90%, from about 60% to about 90%, from about 70% to about 90%, from about 80% to about 90%, or at least about 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% (or any fraction thereof or range therein) of the particles have the nucleic acid encapsulated therein. The techniques herein provide that the proportions of the components within the lipid- based compositions may be varied and the delivery efficiency of a particular formulation can be measured using, e.g., an endosomal release parameter (ERP) assay. It is contemplated within the scope of the disclosure that the lipid-based compositions disclosed herein have increased delivery efficiency due to enhanced endosomal release caused, at least in part, by the novel ionizable substituted aryl and / or heteroaryl lipid-like compounds, the novel substituted piperazine ionizable lipids, and / or the other novel ionizable aryl and / or heteroaryl lipid compound(s) disclosed herein. According to certain of the techniques herein, any one or more of the novel ionizable substituted aryl and / or heteroaryl lipid-like compounds of Formula I, any one or more of the novel substituted piperazine ionizable lipids of Formula VII, and / or any one or more of the other ionizable aryl and / or heteroaryl lipid compound(s) of Formula IX, may be used in the lipid-based compositions disclosed herein, either alone or in combination with one or more other cationic lipid species or non-cationic lipid species. Obligate cationic lipids or salts thereof and / or other ionizable lipids or salts thereof may also be included in the lipid-based compositions of the present disclosure. In some embodiments, the ionizable substituted aryl and heteroaryl lipid-like compounds, the substituted piperazine ionizable lipids of Formula VII, and / or the other ionizable aryl and / or heteroaryl lipid compound(s) of Formula IX disclosed herein comprise from about 40 mol % to about 90 mol %, from about 40 mol % to about 85 mol %, from about 40 mol % to about 80 mol %, from about 40 mol % to about 75 mol %, from about 40 mol % to about 70 mol %, from about 40 mol % to about 65 mol %, from about 40 mol % to about 60 mol %, from about 40 mol % to about 55 mol %, from about 50 mol % to about 90 mol %, from about 50 mol % to about 85 mol %, from about 50 mol % to about 80 mol %, from about 50 mol % to about 75 mol %, from about 50 mol % to about 70 mol %, from about 50 mol % to about 65 mol %, from about 50 mol % to about 60 mol % of the total lipid present in the particle. In some embodiments, the ionizable substituted aryl and heteroaryl lipid-like compounds, the substituted piperazine ionizable lipids of Formula VII, and / or the other ionizable aryl and / or heteroaryl lipid compound(s) disclosed herein comprise from about 50 mol % to about 58 mol %, from about 51 mol % to about 59 mol %, from about 51 mol % to about 58 mol %, from about 51 mol % to about 57 mol %, from about 52 mol % to about 58 mol %, from about 52 mol % to about 57 mol %, from about 52 mol % to about 56 mol %, or from about 53 mol % to about 55 mol % of the total lipid present in the particle. In some embodiments, the ionizable substituted aryl and / or heteroaryl lipid-like compounds, the substituted piperazine ionizable lipids of Formula VII, and / or the other ionizable aryl and / or heteroaryl lipid compound(s) comprise about 50 mol %, 51 mol %, 52 mol %, 53 mol %, 54 mol %, 55 mol %, 56 mol %, 57 mol %, 58 mol %, 59 mol %, 60 mol %, 61 mol %, 62 mol %, 63 mol %, 64 mol %, or 65 mol % (or any fraction thereof or range therein) of the total lipid present in the particle. In some embodiments, the ionizable substituted aryl and / or heteroaryl lipid-like compounds, the substituted piperazine ionizable lipids of Formula VII, and / or the other ionizable aryl and / or heteroaryl lipid compound(s) comprise at least about 66 mol %, 67 mol %, 68 mol %, 69 mol %, 70 mol %, 71 mol %, 72 mol %, 73 mol %, 74 mol %, 75 mol %, 76 mol %, 77 mol %, 78 mol %, 79 mol %, 80 mol %, 81 mol %, 82 mol %, 83 mol %, 84 mol %, 85 mol %, 86 mol %, 87 mol %, 88 mol %, 89 mol %, or 90 mol % of the total lipid present in the particle. In some embodiments, the ionizable substituted aryl and / or heteroaryl lipid-like compounds, the substituted piperazine ionizable lipids of Formula VII, and / or the other ionizable aryl and / or heteroaryl lipid compounds disclosed herein comprise about 45 mol %, 46 mol %, 47 mol %, 48 mol %, 49 mol %, 50 mol %, 51 mol %, 52 mol %, 53 mol %, 54 mol %, or 55 mol % of the total lipid present in the nucleic acid-lipid particle. In some embodiments, the ionizable substituted aryl and / or heteroaryl lipid-like compounds, the substituted piperazine ionizable lipids of Formula VII, and / or the other ionizable aryl and / or heteroaryl lipid compounds disclosed herein comprise from about 2 mol % to about 60 mol %, from about 5 mol % to about 50 mol %, from about 10 mol % to about 50 mol %, from about 20 mol % to about 50 mol %, from about 20 mol % to about 40 mol %, from about 30 mol % to about 40 mol %, or about 40 mol % of the total lipid present in the particle. One of skill in the art will appreciate that the percentage of ionizable substituted aryl and / or heteroaryl lipid-like compounds, the percentage of substituted piperazine ionizable lipids of Formula VII, and / or the percentage of other ionizable aryl and / or heteroaryl lipid compounds present in the lipid-based compositions of the disclosure is a target amount, and that the actual amount of cationic lipid present in the formulation may vary, for example, by about ±5 mol %. The lipid-based compositions disclosed herein may also include a variety of non-cationic lipids including, but not limited to, phospholipids such as lecithin, phosphatidylethanolamine, lysolecithin, lysophosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, sphingomyelin, egg sphingomyelin (ESM), cephalin, cardiolipin, phosphatidic acid, cerebrosides, dicetylphosphate, distearoylphosphatidylcholine (DSPC), dioleoylphosphatidylcholine (DOPC), dipalmitoylphosphatidylcholine (DPPC), dioleoylphosphatidylglycerol (DOPG), dipalmitoylphosphatidylglycerol (DPPG), dioleoylphosphatidylethanolamine (DOPE), palmitoyloleoyl-phosphatidylcholine (POPC), palmitoyloleoyl-phosphatidylethanolamine (POPE), palmitoyloleyol-phosphatidylglycerol (POPG), dioleoylphosphatidylethanolamine 4-(N- maleimidomethyl)-cyclohexane-1-carboxylate (DOPE-mal), dipalmitoyl- phosphatidylethanolamine (DPPE), dimyristoyl-phosphatidylethanolamine (DMPE), distearoyl- phosphatidylethanolamine (DSPE), monomethyl-phosphatidylethanolamine, dimethyl- phosphatidylethanolamine, dielaidoyl-phosphatidylethanolamine (DEPE), stearoyloleoyl- phosphatidylethanolamine (SOPE), lysophosphatidylcholine, dilinoleoylphosphatidylcholine, and mixtures thereof. Other diacylphosphatidylcholine and diacylphosphatidylethanolamine phospholipids can also be used. The acyl groups in these lipids are preferably acyl groups derived from fatty acids having C10-C24 carbon chains, e.g., lauroyl, myristoyl, palmitoyl, stearoyl, or oleoyl. Other examples of non-cationic lipids may include, but are not limited to, sterols such as cholesterol and derivatives thereof. Non-limiting examples of cholesterol derivatives include polar analogues such as 5α-cholestanol, 5β-coprostanol, cholesteryl-(2′-hydroxy)-ethyl ether, cholesteryl-(4′-hydroxy)-butyl ether, and 6-ketocholestanol; non-polar analogues such as 5α- cholestane, cholestenone, 5α-cholestanone, 5β-cholestanone, and cholesteryl decanoate; and mixtures thereof. In preferred embodiments, the cholesterol derivative is a polar analogue such as cholesteryl-(4′-hydroxy)-butyl ether. In some embodiments, the non-cationic lipid comprises from about 10 mol % to about 60 mol %, from about 20 mol % to about 55 mol %, from about 20 mol % to about 45 mol %, from about 20 mol % to about 40 mol %, from about 25 mol % to about 50 mol %, from about 25 mol % to about 45 mol %, from about 30 mol % to about 50 mol %, from about 30 mol % to about 45 mol %, from about 30 mol % to about 40 mol %, from about 35 mol % to about 45 mol %, from about 37 mol % to about 42 mol %, or about 35 mol %, 36 mol %, 37 mol %, 38 mol %, 39 mol %, 40 mol %, 41 mol %, 42 mol %, 43 mol %, 44 mol %, or 45 mol % (or any fraction thereof or range therein) of the total lipid present in the particle. As discussed above with respect to cationic lipids, one of skill in the art will also appreciate that the percentage of non-cationic lipid present in the lipid particles of the disclosure is a target amount, and that the actual amount of non-cationic lipid present in the formulation may vary, for example, by ±5 mol %. Lipid nanoparticles of any size may be used according to the instant disclosure. In certain embodiments of the instant disclosure, lipid nanoparticles have a size ranging from about 0.02 microns to about 0.4 microns, between about 0.05 and about 0.2 microns, or between 0.07 and 0.12 microns in diameter. In some embodiments, the LNPs may also comprise other cationic lipids including but not limited to, those comprising a protonatable tertiary amine (e.g., pH-titratable) head group; C18 alkyl chains, wherein each alkyl chain independently has 0 to 3 (e.g., 0, 1, 2, or 3) double bonds; and ether, ester, or ketal linkages between the head group and alkyl chains. Such cationic lipids include, but are not limited to, 1,2-distearyloxy-N,N-dimethyl-3-aminopropane (DSDMA), N,N- dioleyl-N,N-dimethylammonium chloride ("DODAC"); 3 -(N-(N',N'-dimethylaminoethane)- carbamoyl)cholesterol ("DC-Chol"), N-(1,2-dimyristyloxyprop-3-yl)-N,N-dimethyl-N- hydroxyethyl ammonium bromide ("DMRIE"), 1,2-dioleyloxy-N,N-dimethyl-3-aminopropane (DODMA), 1,2-dilinoleyloxy-N,N-dimethyl-3-aminopropane (DLinDMA), 1,2-dilinolenyloxy- N,N-dimethyl-3-aminopropane (DLenDMA), 1,2-di-γ-linolenyloxy-N,N-dimethylaminopropane (γ-DLenDMA, 1,2-dilinoleyloxy-keto-N,N-dimethyl-3-aminopropane (DLinK-DMA), 1,2- dilinoleyl-4-(2-dimethylaminoethyl)-[1,3]-dioxolane (DLinKC2-DMA) (also known as DLin- C2K-DMA, XTC2, and C2K), 2,2-dilinoleyl-4-(3-dimethylaminopropyl)[1,3]-dioxolane (DLin- K-C3-DMA), 2,2-dilinoleyl-4-(4-dimethylaminobutyl)[1,3]-dioxolane (DLin-K-C4-DMA), 1,2- dilinolenyloxy-4-(2-dimethylaminoethyl)- [1,3]-dioxolane (γ-DLen-C2K-DMA), 1,2-di-γ- linolenyloxy-4-(2-dimethylaminoethyl)-[1,3]-dioxolane (γ-DLen-C2K-DMA), dilinoleylmethyl- 3-dimethylaminopropionate (DLin-M-C2-DMA) (also known as MC2), (6Z,9Z,28Z,31Z)- heptatriaconta-6,9,28,31-tetraen-19-yl 4-(dimethylamino) butanoate (DLin-M-C3-DMA) (also known as MC3) and 3-(dilinoleylmethoxy)-N,N-dimethylpropan-1-amine (DLin-MP-DMA) (also known as 1-B11). In some embodiments, the particles of the instant disclosure may include neutral lipids, for example, diacylphosphatidylcholine, diacylphosphatidylethanolamine, ceramide, sphingomyelin, cephalin, cholesterol, cerebrosides and diacylglycerols. In other embodiments, LNPs may include anionic lipids, including but not limited to, phosphatidylglycerols, cardiolipins, diacylphosphatidylserines, diacylphosphatidic acids, N-dodecanoyl phosphatidylethanolamines, N-succinyl phosphatidylethanolamines, N-glutarylphosphatidylethanolamines, lysylphosphatidylglycerols, palmitoyloleyolphosphatidylglycerol (POPG), and other anionic modifying groups joined to neutral lipids. In some aspects, the non-cationic lipid used in the instant disclosure is 1,2-Dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), 1,2-dioleoyl-sn-glycero- 3-phosphocholine (DOPC), and / or 1,2-Distearoyl-sn-glycero-3-phosphocholine (DSPC). In some aspects, one or more non-cationic lipid of the instant particles is cholesterol (CHE), β-sitosterol, and / or derivatives thereof. Cationic lipids disclosed herein may include, but are not limited to, the following exemplary cationic lipids: 1,2-DiLinoleyloxy-N,N-dimethylaminopropane. ("DLinDMA"), 1,2- Dilinolenyloxy-N,N-dimethylaminopropane ("DLenDMA"), dioctadecyldimethylammonium ("DODMA"), Distearyldimethylammonium ("DSDMA"), N,N-dioleyl-N,N-dimethylammonium chloride ("DODAC"); N-(2,3-dioleyloxy)propyl)-N,N,N-trimethylammonium chloride ("DOTMA"); N,N-distearyl-N,N-dimethylammonium bromide ("DDAB"); N-(2,3- dioleoyloxy)propyl)-N,N,N-trimethylammonium chloride ("DOTAP"); 3 -(N-(N',N'- dimethylaminoethane)-carbamoyl)cholesterol ("DC-Chol") and N-(1,2-dimyristyloxyprop-3-yl)- N,N-dimethyl-N-hydroxyethyl ammonium bromide ("DMRIE"). For example, cationic lipids that have a positive charge at below physiological pH include, but are not limited to: DODAP, DODMA, DMDMA, and SM-005. In some cases, the cationic lipids comprise a protonatable tertiary amine head group, C18alkyl chains, ether linkages between the head group and alkyl chains, and 0 to 3 double bonds. Such lipids include, e.g., DSDMA, DLinDMA, DLenDMA, and DODMA. In an exemplary embodiment, such lipids may include SM-005, and salts and isomer thereof. The chemical structure of SM-005 is shown below: (SM-005). In some embodiments that employ PEG-conjugated lipids, the PEG-conjugated lipid is one or more of a polyethyleneglycol (PEG)-lipid conjugate, a polyamide (ATTA)-lipid conjugate, and a mixture thereof. In one aspect, the PEG-lipid conjugate is one or more of a PEG- dialkyloxypropyl (DAA), a PEG-diacylglycerol (DAG), a PEG-phospholipid, a PEG-ceramide, and a mixture thereof. In one aspect, the PEG-DAG conjugate is one or more of a PEG- dilauroylglycerol (C12), a PEG-dimyristoylglycerol (C14), a PEG-dipalmitoylglycerol (C16), and a PEG-distearoylglycerol (C18). In one aspect, the PEG-DAA conjugate is one or more of a PEG- dilauryloxypropyl (C12), a PEG-dimyristyloxypropyl (C14), a PEG-dipalmityloxypropyl (C16), and a PEG-di stearyloxypropyl (C18). In some embodiments, PEG is 2-dimyristoyl-rac-glycero-3- methoxypolyethylene glycol-2000 (PEG-DMG) and / or 1,2-distearoyl-rac-glycero-3- methoxypolyethylene glycol-2000 (PEG-DSG). In some embodiments, amphipathic lipids are included in particles of the instant disclosure. Amphipathic lipids may refer to any suitable material, wherein the hydrophobic portion of the lipid material orients into a hydrophobic phase, while the hydrophilic portion orients toward the aqueous phase. Such compounds include, but are not limited to, phospholipids, aminolipids, and sphingolipids. Representative phospholipids include sphingomyelin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, phosphatidic acid, palmitoyloleoyl phosphatdylcholine, lysophosphatidylcholine, lysophosphatidylethanolamine, dipalmitoylphosphatidylcholine, dioleoylphosphatidylcholine, distearoylphosphatidylcholine, or dilinoleoylphosphatidylcholine. Other phosphorus-lacking compounds, such as sphingolipids, glycosphingolipid families, diacylglycerols, and β-acyloxyacids, can also be used. Additionally, such amphipathic lipids can be readily mixed with other lipids, such as triglycerides and sterols. Also suitable for inclusion in the lipid particles of the instant disclosure are programmable fusion lipid formulations. Such formulations have little tendency to fuse with cell membranes and deliver their cargo until a given signal event occurs. This allows the lipid formulation to distribute more evenly after injection into an organism or disease site before it starts fusing with cells. The signal event can be, for example, a change in pH, temperature, ionic environment, or time. In the latter case, a fusion delaying or "cloaking" component, such as an ATTA-lipid conjugate or a PEG- lipid conjugate, can simply exchange out of the lipid nanoparticle membrane over time. By the time the formulation is suitably distributed in the body, it has lost sufficient cloaking agent so as to be fusogenic. With other signal events, it is desirable to choose a signal that is associated with the disease site or target cell, such as increased temperature at a site of inflammation. In some embodiments, lipid nanoparticles disclosed herein may be formulated using a microfluidic mixer, a cross, or a T-junction by mixing two or three fluid streams containing nucleic acid cargo and lipid components, respectively. In certain embodiments, it can be desirable to target the lipid nanoparticles of this disclosure further, using targeting moieties that are specific to a cell type or tissue. Targeting of lipid nanoparticles using a variety of targeting moieties, such as ligands, cell surface receptors, glycoproteins, vitamins (e.g., riboflavin) and monoclonal antibodies, has been previously described (see, e.g., U.S. Pat. Nos.4,957,773 and 4,603,044). The targeting moieties can comprise the entire protein or fragments thereof. Targeting mechanisms generally require that the targeting agents be positioned on the surface of the lipid nanoparticle in such a manner that the target moiety is available for interaction with the target, for example, a cell surface receptor. A variety of different targeting agents and methods are known and available in the art, including those described, e.g., in Sapra, P. and Allen, T M, Prog. Lipid Res.42(5):439-62 (2003); and Abra, R M et al., J. Lipid nanoparticle Res.12:1- 3, (2002). Standard methods for coupling target agents can be used. For example, phosphatidylethanolamine, which can be activated for attachment of target agents, or derivatized lipophilic compounds, such as lipid-derivatized bleomycin, can be used. Antibody-targeted lipid nanoparticles can be constructed using, for instance, lipid nanoparticles that incorporate protein A (see, Renneisen, et al., J. Bio. Chem., 265:16337-16342 (1990) and Leonetti, et al., Proc. Natl. Acad. Sci. (USA), 87:2448-2451 (1990). Other examples of antibody conjugation are disclosed in U.S. Pat. No.6,027,726, the teachings of which are incorporated herein by reference. Examples of targeting moieties can also include other proteins, specific to cellular components, including antigens associated with neoplasms or tumors. Proteins used as targeting moieties can be attached to the lipid nanoparticles via covalent bonds (see, Heath, Covalent Attachment of Proteins to Lipid nanoparticles, 149 Methods in Enzymology 111-119 (Academic Press, Inc.1987)). Other targeting methods include the biotin-avidin system. A variety of methods for preparing lipid nanoparticles are known in the art, including e.g., those described in Szoka, et al., Ann. Rev. Biophys. Bioeng., 9:467 (1980); U.S. Pat. Nos. 4,186,183, 4,217,344, 4,235,871, 4,261,975, 4,485,054, 4,501,728, 4,774,085, 4,837,028, 4,946,787; PCT Publication No. WO 91 / 17424; Deamer and Bangham, Biochim. Biophys. Acta, 443:629-634 (1976); Fraley, et al., Proc. Natl. Acad. Sci. USA, 76:3348-3352 (1979); Hope, et al., Biochim. Biophys. Acta, 812:55-65 (1985); Mayer, et al., Biochim. Biophys. Acta, 858:161-168 (1986); Williams, et al., Proc. Natl. Acad. Sci., 85:242-246 (1988); Lipid nanoparticles, Marc J. Ostro, ed., Marcel Dekker, Inc., New York, 1983, Chapter 1; Hope, et al., Chem. Phys. Lip., 40:89 (1986); and Lipid nanoparticles: A Practical Approach, Torchilin, V. P. et al., ed., Oxford University Press (2003), and references cited therein. Suitable methods include, but are not limited to, sonication, extrusion, high pressure / homogenization, microfluidization, detergent dialysis, calcium-induced fusion of small lipid nanoparticle vesicles, and ether-infusion methods, all of which are well known in the art. In some embodiments of the disclosure, LNPs including SM-066, SM-078, SM-081, SM- 082, SM-084, SM-089, SM-090, SM-091, SM-092, SM-093, SM-094, SM-095, SM-096, SM-098, SM-101, SM-103, SM-106, SM-114, SM-115, SM-117, SM-120, SM-129, SM-131, SM-138, SM- 141, SM-152, SM-155, SM-158, SM-163, SM-170, and / or SM-173 were prepared using a microfluidic mixing process or a T-junction mixing process involving two fluid streams, one of which contained an aqueous solution of nucleic acid entities and the other had the organic solution of lipid components and / or ic molecules. Lipid / components were prepared by combining a lipid according to the formula of 30-50 mol% of ionizable substituted aryl and heteroaryl lipid-like compounds (e.g., SM-066, SM-078, SM-081, SM-082, SM-084, SM-089, SM-090, SM-091, SM-092, SM-093, SM-094, SM-095, SM- 096, SM-098, SM-101, SM-103, SM-106, SM-114, SM-115, SM-117, SM-120, SM-129, SM-131, SM-138, SM-141, SM-152, SM-155, SM-158, SM-163, SM-170, and / or SM-173), 20 to 40 mol% of a helper such as described herein, 25 to 35 mol% of a structural lipid such as cholesterol (Chol or CHE), and 0.3 to 5 mol% of a PEG-lipid (e.g., PEG-5K) at a combined concentrations of about 10 to 30 mM in ethanol. Lipid components are combined to yield desired molar ratios (see e.g., Table 4 and Table 6) and diluted with aqueous solution of the nucleic acids to a final lipid concentration of between 3 to 15 mM. In other embodiments of the disclosure, LNPs including SM-048, SM-074, SM-076, SM- 077, SM-079, SM-083, SM-085, SM-088, SM-100, SM-109, SM-113, and SM-125 were prepared using a microfluidic mixing process or a T-junction mixing process involving two fluid streams, one of which contained an aqueous solution of nucleic acid entities and the other had the organic solution of lipid components and / or ic molecules. Lipid / components were prepared by combining a lipid according to the formula of 35-55 mol% of substituted piperazine ionizable lipids (e.g., SM-048, SM-074, SM-076, SM-077, SM- 079, SM-083, SM-085, SM-088, SM-100, SM-109, SM-113, and SM-125), 15 to 35 mol% of a helper lipid such as described herein, 25 to 40 mol% of a structural lipid such as cholesterol (Chol or CHE), and 0.3 to 2.5 mol% of a PEG-lipid (e.g., PEG-DMG) at a combined concentrations of about 10 to 30 mM in ethanol. Lipid components are combined to yield desired molar ratios (see e.g., Table 9 and Table 11) and diluted with aqueous solution of the nucleic acids to a final lipid concentration of between 3 to 15 mM. In further embodiments of the disclosure, LNPs including SM-016, SM-062, SM-065, SM- 067, SM-068, SM-070, SM-072, SM-073, SM-107, SM-111, and / or SM-112 were prepared using a microfluidic mixing process or a T-junction mixing process involving two fluid streams, one of which contained an aqueous solution of nucleic acid entities and the other had the organic solution of lipid components and / or ic molecules. Lipid / components were prepared by combining a lipid according to the formula of 30-50 mol% of ionizable substituted aryl and heteroaryl lipid-like compounds (e.g., SM-016, SM-062, SM-065, SM-067, SM-068, SM-070, SM-072, SM-073, SM-107, SM-111, and / or SM-112), 20 to 40 mol% of a helper such as described herein, 25 to 35 mol% of a structural lipid such as cholesterol (Chol or CHE), and 0.3 to 5 mol% of a PEG-lipid (e.g., PEG-5K) at a combined concentrations of about 10 to 30 mM in ethanol. Lipid components are combined to yield desired molar ratios (see e.g., Table 12 and Table 13 below) and diluted with aqueous solution of the nucleic acids to a final lipid concentration of between 3 to 15 mM. Nanoparticle compositions including the nucleic acids and lipid components are prepared by combining the organic solution containing the lipid / components with the aqueous solution of nucleic acids with a total lipid to nucleic acid w / w ratio between about 10:1 and about 100:1. The lipid solution is rapidly injected using a NanoAssemblr microfluidic based system at flow rates between about 8 and about 12 mL / min into the nucleic acid aqueous solution with an aqueous to organic volume ratio between about 1:1 and about 4:1. The mixture is then immediately diluted with nuclease free water at 1:1 volume ratio. The diluted mixture is then processed using a buffer exchange column or a tangential flow filtration (TFF) system to exchange the solution with the final desired buffer, such as Tris-HCl or a Tris / Acetate buffer, at neutral pH between 7.0 and 7.5 containing up to 15% of sucrose. The solution is then subsequently concentrated using a TFF or a centrifugation column with a filter. The concentrated solution is then sterile filtered and diluted to a desired concentration between about 0.1 mg / mL and about 1.0 mg / mL nucleic acid prior to freezing for storage. Lipid particles prepared according to methods as disclosed herein and as known in the art can in certain embodiments be stored for substantial periods of time prior to drug loading and administration to a patient. For example, lipid nanoparticles can be dehydrated, stored, and subsequently rehydrated and loaded with one or more active agents, prior to administration. Lipid nanoparticles may also be dehydrated after being loaded with one or more active agents. Dehydration can be accomplished by a variety of methods available in the art, including the dehydration and lyophilization procedures described, e.g., in U.S. Pat. Nos.4,880,635, 5,578,320, 5,837,279, 5,922,350, 4,857,319, 5,376,380, 5,817,334, 6,355,267, and 6,475,517. In one embodiment, lipid nanoparticles are dehydrated using standard freeze-drying apparatus, i.e., they are dehydrated under low pressure conditions. Also, the lipid nanoparticles can be frozen, e.g., in liquid nitrogen, prior to dehydration. Sugars can be added to the LNP environment, e.g., to the buffer containing the lipid nanoparticles, prior to dehydration, thereby promoting the integrity of the lipid nanoparticle during dehydration. See, e.g., U.S. Pat. No.5,077,056 or 5,736,155. Lipid nanoparticles may be sterilized by conventional methods at any point during their preparation, including, e.g., after sizing or after generating a pH gradient. Cargo-Loaded Lipid Particle Compositions In various embodiments, lipid particles of the instant disclosure may be used for many different applications, including the delivery of an active agent to a cell, tissue, organ or subject. For example, lipid nanoparticles of the instant disclosure may be used to deliver a therapeutic agent systemically via the bloodstream or to deliver a cosmetic agent to the skin. Accordingly, lipid nanoparticles of the instant disclosure and one or more active agents as cargo(es) are included in the instant disclosure. Lipid Particle Cargoes The instant disclosure describes lipid nanoparticles in combination with an active agent as a cargo. Active agents, as used herein, include any molecule or compound capable of exerting a desired effect on a cell, tissue, organ, or subject. Such effects may be biological, physiological, or cosmetic, for example. Active agents may be any type of molecule or compound, including e.g., nucleic acids, such as single- or double-stranded polynucleotides, plasmids, antisense RNA, RNA interference agents, including, e.g., DNA-DNA hybrids, DNA-RNA hybrids, RNA-DNA hybrids, RNA-RNA hybrids, short interfering RNAs (siRNA), micro RNAs (mRNA) and short hairpin RNAs (shRNAs); peptides and polypeptides, including, e.g., antibodies, such as, e.g., polyclonal antibodies, monoclonal antibodies, antibody fragments; humanized antibodies, recombinant antibodies, recombinant human antibodies, and Primatized™ antibodies, cytokines, growth factors, apoptotic factors, differentiation-inducing factors, cell surface receptors and their ligands; hormones; and small molecules, including small organic molecules or compounds. Therapeutic Agents As disclosed herein, therapeutic agents may include any molecule or compound capable of exerting a desired effect on a cell, tissue, tumor, organ, or subject. Therapeutic agents may be any type of molecule or compound including, but not limited to, nucleic acids, peptides, polypeptides, small molecules, and mixtures thereof. In some embodiments, the therapeutic agent may be a salt or derivative thereof. Therapeutic agents may be therapeutically active themselves, or they may be prodrugs, which become active upon further modification / alteration. In some embodiments, the lipid-based compositions described herein may be associated with a nucleic acid such as, for example, an siRNA, Dicer-substrate dsRNA, shRNA, aiRNA, miRNA, antisense oligonucleotides, ribozymes, and immunostimulatory oligonucleotides. Nucleic acid therapy has well-known, tremendous potential to treat diseases at the gene level. However, safe and effective delivery systems are essential for nucleic acid therapeutics. Non-specific delivery to organs and tissues often results in off-site effects and toxicity. Delivery of therapeutics to a specific organ of interest is a well-recognized need in the development of lipid- nanoparticles, as well as in drug development generally. The concept of only targeting the cause of a disease without harming other parts of the body was described by Ehrlich 120 years ago. However, extant methods do not provide defined or well-known methodologies for developing nanoparticles targeting specific tissues without introducing additional ligand-based targeting strategies. Organ-specific targeting of lipid nanoparticles based on the structural affinity of the lipid to the tissue, as now disclosed herein, therefore meets a well-established need in terms of reducing off-site effects and toxicity. Nucleic acids associated with or encapsulated by LNPs may contain modifications including but not limited to those selected from the following group: 2′-O-methyl modified nucleotides, a nucleotide comprising a 5′-phosphorothioate group, a terminal nucleotide linked to a cholesteryl derivative, a 2′-deoxy-2′-fluoro modified nucleotide, a 5′-methoxy-modified nucleotide (e.g., 5′-methoxyuridine), a 2′-deoxy-modified nucleotide, a locked nucleotide, an abasic nucleotide, a 2′-amino-modified nucleotide, a 2′-alkyl-modified nucleotide, a morpholino nucleotide, a phosphoramidate, a non-natural base comprising nucleotide; internucleoside linkages or backbones including phosphorothioates, chiral phosphorothioates, phosphorodithioates, phosphotriesters, aminoalkylphosphotriesters, methyl and other alkyl phosphonates including 3′- alkylene phosphonates and chiral phosphonates, phosphinates, phosphoramidates including 3′- amino phosphoramidate and aminoalkylphosphoramidates, thionophosphoramidates, thionoalkylphosphonates, thionoalkylphosphotriesters, and boranophosphates having normal 3′-5′ linkages, 2′-5′ linked analogs of these, and those having inverted polarity wherein the adjacent pairs of nucleoside units are linked 3′-5′ to 5′-3′ or 2′-5′ to 5′-2.′ In certain embodiments, the active agent is a mRNA or a vector capable expressing a mRNA in a cell. In embodiments, the active agent is a CRISPR / Cas system. Optionally, a LNP of the instant disclosure can be formulated to include, e.g., both a guide strand (gRNA) and a Cas enzyme as cargoes, thereby providing a self-contained delivery vehicle capable of effecting and controlling CRISPR-mediated targeting of a gene in a target cell. In certain featured embodiments, the active agent is a nucleic acid modulating controller (e.g., a mRNA that encodes protein controller components, as described above). In some embodiments, the active agent is a therapeutic agent, or a salt or derivative thereof. Therapeutic agent derivatives may be therapeutically active themselves or they may be prodrugs, which become active upon further modification. Thus, in one embodiment, a therapeutic agent derivative retains some or all of the therapeutic activity as compared to the unmodified agent, while in another embodiment, a therapeutic agent derivative lacks therapeutic activity. In various embodiments, therapeutic agents include agents and drugs, such as anti- inflammatory compounds, narcotics, depressants, anti-depressants, stimulants, hallucinogens, analgesics, antibiotics, birth control medication, antipyretics, vasodilators, anti-angiogenics, cytovascular agents, signal transduction inhibitors, vasoconstrictors, hormones, and steroids. In certain embodiments, the active agent is an oncology drug, which may also be referred to as an anti-tumor drug, an anti-cancer drug, a tumor drug, an antineoplastic agent, or the like. Examples of oncology drugs that may be used according to the instant disclosure include, but are not limited to, adriamycin, alkeran, allopurinol, altretamine, amifostine, anastrozole, araC, arsenic trioxide, azathioprine, bexarotene, biCNU, bleomycin, busulfan intravenous, busulfan oral, capecitabine (Xeloda), carboplatin, carmustine, CCNU, celecoxib, chlorambucil, cisplatin, cladribine, cyclosporin A, cytarabine, cytosine arabinoside, daunorubicin, cytoxan, daunorubicin, dexamethasone, dexrazoxane, dodetaxel, doxorubicin, doxorubicin, DTIC, epirubicin, estramustine, etoposide phosphate, etoposide and VP-16, exemestane, FK506, fludarabine, fluorouracil, 5-FU, gemcitabine (Gemzar), gemtuzumab-ozogamicin, goserelin acetate, hydrea, hydroxyurea, idarubicin, ifosfamide, imatinib mesylate, interferon, irinotecan (Camptostar, CPT- 111), letrozole, leucovorin, leustatin, leuprolide, levamisole, litretinoin, megastrol, melphalan, L- PAM, mesna, methotrexate, methoxsalen, mithramycin, mitomycin, mitoxantrone, nitrogen mustard, paclitaxel, pamidronate, Pegademase, pentostatin, porfimer sodium, prednisone, rituxan, streptozocin, STI-571, tamoxifen, taxotere, temozolamide, teniposide, VM-26, topotecan (Hycamtin), toremifene, tretinoin, ATRA, valrubicin, velban, vinblastine, vincristine, VP16, and vinorelbine. Other examples of oncology drugs that may be used according to the instant disclosure are ellipticin and ellipticin analogs or derivatives, epothilones, intracellular kinase inhibitors and camptothecins. While LNP compositions of the instant disclosure generally comprise a single active agent, in certain embodiments, they may comprise more than one active agent. In other embodiments of the instant disclosure, the lipid nanoparticles of the instant disclosure have a plasma circulation half-life of at least 0.5, 0.8, 1.2, 1.5, 2.0, 4.0, 6.0, 8.0, or 12 hours. In some embodiments, lipid nanoparticles have a plasma drug half-life of at least 0.5, 0.8, 1.2, 1.5, 2.0, 4.0, 6.0, 8.0, or 12 hours. Circulation and blood or plasma clearance half-lives may be determined as described, for example, in U.S. Patent Publication No.2004-0071768-A1. The techniques herein further comprise lipid particles and / or pharmaceutical compositions in which a therapeutic agent such as, for example, nucleic acids (e.g., siRNA, ASO, tRNA, miRNA, mRNA, DNA, and the like), proteins, peptides, and other macromolecules, is enclosed within the lipid portion of the particle or composition so that it is protected from degradation. Such lipid particles and / or pharmaceutical compositions may be formed by any method known in the art including, but not limited to, a continuous mixing method, a direct dilution process, and an in- line dilution process. In some embodiments, lipid particles and / or pharmaceutical compositions may include any of the ionizable lipids disclosed herein, or salts thereof, alone or in combination with other cationic lipids and / or non-cationic lipids. In other embodiments, the non-cationic lipids may be egg sphingomyelin (ESM), distearoylphosphatidylcholine (DSPC), dioleoylphosphatidylcholine (DOPC), 1-palmitoyl-2-oleoyl-phosphatidylcholine (POPC), dipalmitoyl-phosphatidylcholine (DPPC), monomethyl-phosphatidylethanolamine, dimethyl-phosphatidylethanolamine, 14:0 PE (1,2-dimyristoyl-phosphatidylethanolamine (DMPE)), 16:0 PE (1,2-dipalmitoyl- phosphatidylethanolamine (DPPE)), 18:0 PE (1,2-distearoyl-phosphatidylethanolamine (DSPE)), 18:1 PE (1,2-dioleoylphosphatidylethanolamine (DOPE)), 18:1 trans PE (1,2-dielaidoyl- phosphatidylethanolamine (DEPE)), 18:0-18:1 PE (1-stearoyl-2-oleoyl-phosphatidylethanolamine (SOPE)), 16:0-18:1 PE (1-palmitoyl-2-oleoyl-phosphatidylethanolamine (POPE)), polyethylene glycol-based polymers (e.g., PEG 2000, PEG 5000, PEG-modified diacylglycerols, or PEG- modified dialkyloxypropyls), cholesterol, derivatives thereof, or combinations thereof. The lipid particles and / or pharmaceutical compositions disclosed herein may be formed using techniques know in the art such as, for example, continuous mixing in which the process of continuously introducing lipid and buffer solutions into a mixing area causes a continuous dilution of the lipid solution with the buffer solution, which has the effect of producing a lipid vesicle almost immediately upon mixing. By mixing an aqueous solution comprising a therapeutic agent with an organic lipid solution, the organic lipid solution may undergo a continuous stepwise dilution in the presence of the buffer solution to produce a therapeutic agent-lipid particle. Such particles may have a size of from about 30 nm to about 250 nm, from about 40 nm to about 200 nm, from about 50 nm to about 150 nm, from about 60 nm to about 130 nm, from about 70 nm to about 110 nm, from about 70 nm to about 100 nm, from about 80 nm to about 100 nm, from about 90 nm to about 100 nm, from about 70 to about 90 nm, from about 80 nm to about 90 nm, from about 70 nm to about 80 nm, less than about 120 nm, 110 nm, 100 nm, 90 nm, or 80 nm, or about 30 nm, 35 nm, 40 nm, 45 nm, 50 nm, 55 nm, 60 nm, 65 nm, 70 nm, 75 nm, 80 nm, 85 nm, 90 nm, 95 nm, 100 nm, 105 nm, 110 nm, 115 nm, 120 nm, 125 nm, 130 nm, 135 nm, 140 nm, 145 nm, 150 nm, 155 nm, 160 nm, 165 nm, 170 nm, 175 nm, 180 nm, 185 nm, 190 nm, 195 nm, 200 nm, 205 nm, 210 nm, 215 nm, 220 nm, 225 nm, 230 nm, 235 nm, 240 nm, 245 nm, or 250 nm, or any intermediate value or sub-range therein. Once formed, the particles do not aggregate. According to the techniques herein, the particles may be sized to achieve a uniform particle size. It is also contemplated within the scope of the disclosure that such particles may be prepared by a direct dilution process (e.g., forming a lipid vesicle solution and directly introducing it into a container having a controlled amount of dilution buffer) such as is described in U.S. Patent Publication No.20070042031, the disclosure of which is herein incorporated by reference in its entirety for all purposes. The particles formed using the direct dilution processes typically have a size of from about 30 nm to about 250 nm, from about 40 nm to about 200 nm, from about 50 nm to about 150 nm, from about 60 nm to about 130 nm, from about 70 nm to about 110 nm, from about 70 nm to about 100 nm, from about 80 nm to about 100 nm, from about 90 nm to about 100 nm, from about 70 to about 90 nm, from about 80 nm to about 90 nm, from about 70 nm to about 80 nm, less than about 120 nm, 110 nm, 100 nm, 90 nm, or 80 nm, or about 30 nm, 35 nm, 40 nm, 45 nm, 50 nm, 55 nm, 60 nm, 65 nm, 70 nm, 75 nm, 80 nm, 85 nm, 90 nm, 95 nm, 100 nm, 105 nm, 110 nm, 115 nm, 120 nm, 125 nm, 130 nm, 135 nm, 140 nm, 145 nm, 150 nm, 155 nm, 160 nm, 165 nm, 170 nm, 175 nm, 180 nm, 185 nm, 190 nm, 195 nm, 200 nm, 205 nm, 210 nm, 215 nm, 220 nm, 225 nm, 230 nm, 235 nm, 240 nm, 245 nm, or 250 nm, or any intermediate value or sub-range therein. Once formed, the particles do not aggregate. According to the techniques herein, the particles may be sized to achieve a uniform particle size. In some embodiments, non-lipid polycations which are useful to effect the lipofection of cells may be added to the present compositions. Examples of suitable non-lipid polycations include, hexadimethrine bromide (sold under the brand name POLYBRENE®, from Aldrich Chemical Co., Milwaukee, Wis., USA) or other salts of hexadimethrine. Other suitable polycations include, for example, salts of poly-L-ornithine, poly-L-arginine, poly-L-lysine, poly-D-lysine, polyallylamine, and polyethyleneimine. Addition of these salts is preferably after the particles have been formed. Kits The instant disclosure also provides lipid nanoparticles and variations thereof in kit form. The kit may comprise a ready-made formulation or a formulation that requires mixing before administration. The kit will typically comprise a container that is compartmentalized for holding the various elements of the kit. The kit will contain the lipid nanoparticle compositions of the instant disclosure or the components thereof, in hydrated or dehydrated form, with instructions for their rehydration and administration. In particular embodiments, a kit comprises at least one compartment containing a lipid nanoparticle of the instant disclosure that is loaded with an active agent. In another embodiment, a kit comprises at least two compartments, one containing a lipid nanoparticle of the instant disclosure and the other containing an active agent. Of course, it is understood that any of these kits may comprise additional compartments, e.g., a compartment comprising a buffer, such as those described in U.S. Patent Publication No. 2004-0228909-A1. Kits of the instant disclosure, which comprise lipid nanoparticles comprising ionizable lipids (e.g., SM-066, SM-078, SM-80, SM-081, SM-082, SM-084, SM-089, SM-090, SM-091, SM-092, SM- 093, SM-094, SM-095, SM-096, SM-098, SM-101, SM-103, SM-106, SM-114, SM-115, SM-117, SM-120, SM-129, SM-131, SM-138, SM-141, SM-152, SM-155, SM-158, SM-163, SM-170, SM- 173, SM-048, SM-074, SM-076, SM-077, SM-079, SM-083, SM-085, SM-088, SM-100, SM-109, SM-113, SM-125, SM-016, SM-062, SM-065, SM-067, SM-068, SM-070, SM-072, SM-073, SM- 107, SM-111, and / or SM-112), may also contain other features of the kits described in U.S. Patent Publication No.2004-0228909 A1. Further the kit may contain drug-loaded lipid nanoparticles in one compartment and empty lipid nanoparticles in a second compartment. Alternatively, the kit may contain a lipid nanoparticle of the instant disclosure, an active agent to be loaded into the lipid nanoparticle of the instant disclosure in a second compartment, and an empty lipid nanoparticle in a third compartment. In a particular embodiment, a kit of the instant disclosure comprises a therapeutic compound encapsulated in a lipid nanoparticle comprising SM-066, SM-078, SM-081, SM-082, SM-084, SM-089, SM-090, SM-091, SM-092, SM-093, SM-094, SM-095, SM-096, SM-098, SM- 101, SM-103, SM-106, SM-114, SM-115, SM-117, SM-120, SM-129, SM-131, SM-138, SM-141, SM-152, SM-155, SM-158, SM-163, SM-170, SM-173, SM-048, SM-074, SM-076, SM-077, SM- 079, SM-083, SM-085, SM-088, SM-100, SM-109, SM-113, SM-125, SM-016, SM-062, SM-065, SM-067, SM-068, SM-070, SM-072, SM-073, SM-107, SM-111, and / or SM-112, where SM-066, SM-078, SM-081, SM-082, SM-084, SM-089, SM-090, SM-091, SM-092, SM-093, SM-094, SM- 095, SM-096, SM-098, SM-101, SM-103, SM-106, SM-114, SM-115, SM-117, SM-120, SM-129, SM-131, SM-138, SM-141, SM-152, SM-155, SM-158, SM-163, SM-170, SM-173, SM-048, SM- 074, SM-076, SM-077, SM-079, SM-083, SM-085, SM-088, SM-100, SM-109, SM-113, SM-125, SM-016, SM-062, SM-065, SM-067, SM-068, SM-070, SM-072, SM-073, SM-107, SM-111, and / or SM-112 constitutes at least 20%, at least 50%, or at least 70% (molar basis) of total phospholipids present in the lipid nanoparticle, as well as an empty lipid nanoparticle. In some embodiments, SM-066, SM-078, SM-081, SM-082, SM-084, SM-089, SM-090, SM-091, SM- 092, SM-093, SM-094, SM-095, SM-096, SM-098, SM-101, SM-103, SM-106, SM-114, SM-115, SM-117, SM-120, SM-129, SM-131, SM-138, SM-141, SM-152, SM-155, SM-158, SM-163, SM- 170, SM-173, SM-048, SM-074, SM-076, SM-077, SM-079, SM-083, SM-085, SM-088, SM-100, SM-109, SM-113, SM-125, SM-016, SM-062, SM-065, SM-067, SM-068, SM-070, SM-072, SM- 073, SM-107, SM-111, and / or SM-112 constitutes at least 45-55% (molar basis) of total phospholipids present in the lipid nanoparticle, as well as an empty lipid nanoparticle. In some embodiments, SM-066, SM-078, SM-081, SM-082, SM-084, SM-089, SM-090, SM-091, SM- 092, SM-093, SM-094, SM-095, SM-096, SM-098, SM-101, SM-103, SM-106, SM-114, SM-115, SM-117, SM-120, SM-129, SM-131, SM-138, SM-141, SM-152, SM-155, SM-158, SM-163, SM- 170, SM-173, SM-048, SM-074, SM-076, SM-077, SM-079, SM-083, SM-085, SM-088, SM-100, SM-109, SM-113, SM-125, SM-016, SM-062, SM-065, SM-067, SM-068, SM-070, SM-072, SM- 073, SM-107, SM-111, and / or SM-112 constitutes at least 48-52% (molar basis) of total phospholipids present in the lipid nanoparticle, as well as an empty lipid nanoparticle. In some embodiments, SM-066, SM-078, SM-081, SM-082, SM-084, SM-089, SM-090, SM-091, SM- 092, SM-093, SM-094, SM-095, SM-096, SM-098, SM-101, SM-103, SM-106, SM-114, SM-115, SM-117, SM-120, SM-129, SM-131, SM-138, SM-141, SM-152, SM-155, SM-158, SM-163, SM- 170, SM-173, SM-048, SM-074, SM-076, SM-077, SM-079, SM-083, SM-085, SM-088, SM-100, SM-109, SM-113, SM-125, SM-016, SM-062, SM-065, SM-067, SM-068, SM-070, SM-072, SM- 073, SM-107, SM-111, and / or SM-112 constitutes at least 48%, at least 49%, at least 50%, at least 51%, or at least 52% (molar basis) of total phospholipids present in the lipid nanoparticle, as well as an empty lipid nanoparticle. In one embodiment, the lipid nanoparticle containing therapeutic compound and the empty lipid nanoparticle are present in different compartments of the kit. Methods of Treatment The LNP compositions of the instant disclosure may be used to treat any of a wide variety of diseases or disorders, including, but not limited to, inflammatory diseases, cardiovascular diseases, nervous system diseases, tumors, demyelinating diseases, digestive system diseases, endocrine system diseases, reproductive system diseases, hemic and lymphatic diseases, immunological diseases, mental disorders, musculoskeletal diseases, neurological diseases, neuromuscular diseases, metabolic diseases, sexually transmitted diseases, skin and connective tissue diseases, urological diseases, and infections. In certain embodiments, the LNP compositions can be employed to treat or prevent a lung disease or disorder, including but not limited to a disease or disorder selected from the following: lung cancer, pneumonia, pulmonary fibrosis, COPD, asthma, bronchiectasis, sarcoidosis, pulmonary hypertension, emphysema, alpha-1 antitrypsin deficiency, aspergillosis, bronchiolitis, bronchitis, pneumoconiosis, Coronaviruses, Middle Eastern Respiratory Syndrome, Severe Acute Respiratory Syndrome, cystic fibrosis, Legionnaire's disease, influenza, pertussis, pulmonary embolism, and tuberculosis. In other embodiments, the LNP compositions of the instant disclosure can be used to treat or prevent a joint disease or disorder, including but not limited to a disease or disorder selected from the following: rheumatoid arthritis, psoriatic arthritis, gout, tendinitis, bursitis, Carpal Tunnel Syndrome, and osteoarthritis. In other embodiments, the LNP compositions of the instant disclosure can be used to treat or prevent an inflammatory disease or disorder, including but not limited to a disease or disorder selected from the following: inflammatory bowel disease, peritonitis, osteomyelitis, cachexia, pancreatitis, trauma induced shock, bronchial asthma, allergic rhinitis, cystic fibrosis, acute bronchitis, acute intense bronchitis, osteoarthritis, rheumatoid arthritis, infectious arthritis, post- infectious arthritis, gonocoele arthritis, tuberculous arthritis, arthritis, osteoarthritis, gout, spondyloarthropathies, ankylosing spondylitis, arthritis associated with vasculitis syndrome, nodular polyarteritis nervosa, irritable vasculitis, rugenic granulomatosis, rheumatoid polyposis myalgia, arthritis cell arteritis, calcium polycystic arthropathy, caustic gout, non-arthritic rheumatism, bursitis, hay fever, suppurative inflammation (e.g., tennis elbow), neuropathic joint disease, hemarthrosic, Henoch-Schlein purpura, hypertrophic osteoarthritis, multisized hemorrhoids, scoliosis, hemochromatosis, hyperlipoproteinemia, hypogammaglobulinemia, COPD, acute respiratory distress syndrome, acute lung injury, broncho-pulmonary dysplasia and systemic lupus erythematosus (SLE). In other embodiments, the LNP compositions of the instant disclosure can be used to treat or prevent an epidermal disease or disorder, including but not limited to psoriasis, atopic dermatitis, scleroderma, eczema, rosacea, seborrheic dermatitis, melanoma, solar keratosis, ichthyosis, Grover's disease, common warts, keratoacanthoma, and seborrhoeic keratosis. In one embodiment, the LNP compositions of the instant disclosure can be used to treat or prevent a type of cancer. In particular, these methods can be applied to cancers of the blood and lymphatic systems, including lymphomas, leukemia, and myelomas. Examples of specific cancers that may be treated according to the instant disclosure include, but are not limited to, Hodgkin's and non-Hodgkin's Lymphoma (NHL), including any type of NHL as defined according to any of the various classification systems such as the Working formulation, the Rappaport classification and, preferably, the REAL classification. Such lymphomas include, but are not limited to, low- grade, intermediate-grade, and high-grade lymphomas, as well as both B-cell and T-cell lymphomas. Included in these categories are the various types of small cell, large cell, cleaved cell, lymphocytic, follicular, diffuse, Burkitt's, Mantle cell, NK cell, CNS, AIDS-related, lymphoblastic, adult lymphoblastic, indolent, aggressive, transformed and other types of lymphomas. The methods of the instant disclosure can be used for adult or childhood forms of lymphoma, as well as lymphomas at any stage, e.g., stage I, II, III, or IV. The various types of lymphomas are well known to those of skill, and are described, e.g., by the American Cancer Society (see, e.g., www3.cancer.org). The compositions and methods described herein may also be applied to any form of leukemia, including adult and childhood forms of the disease. For example, any acute, chronic, myelogenous, and lymphocytic form of the disease can be treated using the methods of the instant disclosure. In preferred embodiments, the methods are used to treat Acute Lymphocytic Leukemia (ALL). More information about the various types of leukemia can be found, inter alia, from the Leukemia Society of America (see, e.g., www.leukemia.org)Additional types of tumors can also be treated using the methods described herein, such as neuroblastomas, myelomas, prostate cancers, small cell lung cancer, colon cancer, ovarian cancer, non-small cell lung cancer, brain tumors, breast cancer, and others. The LNP compositions of the instant disclosure may be administered as first line treatments or as secondary treatments. In addition, they may be administered as a primary chemotherapeutic treatment or as adjuvant or neoadjuvant chemotherapy. For example, treatments of relapsed, indolent, transformed, and aggressive forms of non-Hodgkin's Lymphoma may be administered following at least one course of a primary anti- cancer treatment, such as chemotherapy and / or radiation therapy. Administration of LNP Compositions LNP compositions of the instant disclosure are administered in any of a number of ways, including parenteral, intravenous, systemic, local, oral, intratumoral, intramuscular, subcutaneous, intraperitoneal, inhalation, or any such method of delivery. In one embodiment, the compositions are administered parenterally, i.e., intraarticularly, intravenously, intraperitoneally, subcutaneously, or intramuscularly. In a specific embodiment, the LNP compositions are administered by intravenous infusion or intraperitoneally by a bolus injection. For example, in one embodiment, a patient is given an intravenous infusion of the lipid nanoparticle-encapsulated active agent through a running intravenous line over, e.g., 5-10 minutes, 15-20 minutes, 30 minutes, 60 minutes, 90 minutes, or longer. In one embodiment, a 60-minute infusion is used. In other embodiments, an infusion ranging from 6-10 or 15-20 minutes is used. Such infusions can be given periodically, e.g., once every 1, 3, 5, 7, 10, 14, 21, or 28 days or longer, preferably once every 7-21 days, and preferably once every 7 or 14 days. LNP compositions of the instant disclosure may be formulated as pharmaceutical compositions suitable for delivery to a subject. The pharmaceutical compositions of the instant disclosure will often further comprise one or more buffers (e.g., neutral buffered saline or phosphate buffered saline), carbohydrates (e.g., glucose, mannose, sucrose, dextrose or dextrans), mannitol, proteins, polypeptides or amino acids such as glycine, antioxidants, bacteriostats, chelating agents such as EDTA or glutathione, adjuvants (e.g., aluminum hydroxide), solutes that render the formulation isotonic, hypotonic or weakly hypertonic with the blood of a recipient, suspending agents, thickening agents and / or preservatives. Alternatively, compositions of the instant disclosure may be formulated as a lyophilizate. The concentration of drug and lipid nanoparticles in the pharmaceutical formulations can vary widely, i.e., from less than about 0.05%, usually at or at least about 2-5% to as much as 10 to 30% by weight and will be selected depend upon the particular drug used, the disease state being treated and the judgment of the clinician taking. Further, the concentration of drug and lipid nanoparticles will also take into consideration the fluid volume administered, the osmolality of the administered solution, and the tolerability of the drug and lipid nanoparticles. In some instances, it may be preferable to use a lower drug or lipid nanoparticle concentration to reduce the incidence or severity of infusion-related side effects. Suitable formulations for use in the instant disclosure can be found, e.g., in Remington's Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, Pa., 17thEd. (1985). Often, intravenous compositions will comprise a solution of the lipid nanoparticles suspended in an acceptable carrier, such as an aqueous carrier. Any of a variety of aqueous carriers can be used, e.g., water, buffered water, 0.4% saline, 0.9% isotonic saline, 0.3% glycine, 5% dextrose, and the like, and may include glycoproteins for enhanced stability, such as albumin, lipoprotein, globulin, etc. Often, normal buffered saline (135-150 mM NaCl) or 5% dextrose will be used. These compositions can be sterilized by conventional sterilization techniques, such as filtration. The resulting aqueous solutions may be packaged for use or filtered under aseptic conditions and lyophilized, the lyophilized preparation being combined with a sterile aqueous solution prior to administration. The compositions may also contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions, such as pH adjusting and buffering agents, tonicity adjusting agents and the like, for example, sodium acetate, sodium lactate, sodium chloride, potassium chloride, calcium chloride, etc. Additionally, the composition may include lipid-protective agents, which protect lipids against free-radical and lipid-peroxidative damages on storage. Lipophilic free-radical quenchers, such as α-tocopherol and water-soluble iron-specific chelators, such as ferrioxamine, are suitable. The amount of active agent administered per dose is selected to be above the minimal therapeutic dose but below a toxic dose. The choice of amount per dose will depend on a number of factors, such as the medical history of the patient, the use of other therapies, and the nature of the disease. In addition, the amount of active agent administered may be adjusted throughout treatment, depending on the patient's response to treatment and the presence or severity of any treatment-associated side effects. In certain embodiments, the dosage of LNP composition or the frequency of administration is approximately the same as the dosage and schedule of treatment with the corresponding free active agent. However, it is understood that the dosage may be higher or more frequently administered as compared to free drug treatment, particularly where the LNP composition exhibits reduced toxicity. It is also understood that the dosage may be lower or less frequently administered as compared to free drug treatment, particularly where the LNP composition exhibits increased efficacy as compared to the free drug. Exemplary dosages and treatment for a variety of chemotherapy compounds (free drug) are known and available to those skilled in the art and are described in, e.g., Physician's Cancer Chemotherapy Drug Manual, E. Chu and V. Devita (Jones and Bartlett, 2002). Patients typically will receive at least two courses of such treatment, and potentially more, depending on the response of the patient to the treatment. In single agent regimens, total courses of treatment are determined by the patient and physician based on observed responses and toxicity. Combination Therapies In certain embodiments, LNP compositions of the instant disclosure can be administered in combination with one or more additional compounds or therapies, such as surgery, radiation treatment, chemotherapy, or other active agents, including any of those described above. LNP compositions may be administered in combination with a second active agent for a variety of reasons, including increased efficacy or to reduce undesirable side effects. The LNP composition may be administered prior to, subsequent to, or simultaneously with the additional treatment. Furthermore, where a LNP composition of the instant disclosure (which comprises a first active agent) is administered in combination with a second active agent, the second active agent may be administered as a free drug, as an independent LNP formulation, or as a component of the LNP composition comprising the first drug. In certain embodiments, multiple active agents are loaded into the same lipid nanoparticles. In other embodiments, lipid nanoparticles comprising an active agent are used in combination with one or more free drugs. In particular embodiments, LNP compositions comprising an active agent are formed individually and subsequently combined with other compounds for a single co-administration. Alternatively, certain therapies are administered sequentially in a predetermined order. Accordingly, LNP compositions of the instant disclosure may comprise one or more active agents. Other combination therapies known to those of skill in the art can be used in conjunction with the methods of the instant disclosure. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting. Reference will now be made in detail to exemplary embodiments of the disclosure. While the disclosure will be described in conjunction with the exemplary embodiments, it will be understood that it is not intended to limit the disclosure to those embodiments. To the contrary, it is intended to cover alternatives, modifications, and equivalents as may be included within the spirit and scope of the disclosure as defined by the appended claims. Standard techniques well known in the art or the techniques specifically described below were utilized.

[0051] EXAMPLES Example 1: Synthesis of SM-066

[0052] Step 1: tert-butyl N-[3-[[3-[3-(tert-butoxycarbonylamino)propylcarbamoyl]-5- c 1 2 Tert-butyl N-(3-aminopropyl)carbamate (3.54 g, 20.34 mmol, 3.55 mL, 1.8 eq) in DCM (30 mL) and TEA (2.29 g, 22.60 mmol, 3.15 mL, 2 eq) was added to a solution of benzene-1,3,5- tricarbonyl chloride (3 g, 11.30 mmol, 1 eq) in DCM (50 mL) dropwise at 0°C under N2, after addition, the mixture was stirred at 20°C for 16 hours. The compound tert-butyl N-[3-[[3-[3-(tert- butoxycarbonylamino)propylcarbamoyl]-5-chlorocarbonyl-benzoyl]amino]propyl]carbamate (6.1 g, crude) as yellow liquid was used directly in the next step. Step 2: tert-butyl N-[3-[[3-[3-(tert-butoxycarbonylamino)propylcarbamoyl]-5-[3- (dimethylamino)propylcarbamoyl]benzoyl]amino]propyl]carbamate (3): (EC5059-483 / 488) B TEA (2.85 g, 28.19 mmol, 3.92 mL, 2.5 eq) and N',N'-dimethylpropane-1,3-diamine (1.38 g, 13.53 mmol, 1.7 mL, 1.2 eq) were added to a solution of tert-butyl N-[3-[[3-[3-(tert- butoxycarbonylamino)propylcarbamoyl]-5-chlorocarbonyl-benzoyl]amino]propyl]carbamate (6.1 g, 11.27 mmol, 1 eq) in DCM (30 mL) at 0°C under N2. The mixture was stirred at 20°C for 16 hours. The reaction mixture was concentrated under reduced pressure to remove solvent to give crude product. The residue was purified by flash silica gel chromatography (80 g SepaFlash® Silica Flash Column, DCM : MeOH : 0~10%) to leave compound tert-butyl N-[[2-(2,6-dioxo-3- piperidyl)-1-oxo-isoindolin-5-yl]methyl]carbamate (2.1 g, 5.62 mmol, 52.5% yield) as a white solid. LCMS: [M+H]+: 607.6 Step 3: N1,N5-bis(3-aminopropyl)-N3-[3-(dimethylamino)propyl]benzene-1,3,5- tricarboxamide (4): (EC5059-491) B HCl / dioxane (4 M, 5 mL, 9.33 eq) was added to a solution of tert-butyl N-[3-[[3-[3-(tert- butoxycarbonylamino)propylcarbamoyl]-5-[3- (dimethylamino)propylcarbamoyl]benzoyl]amino]propyl]carbamate (1.3 g, 2.14 mmol, 1 eq) in DCM (5 mL). The mixture was stirred at 20°C for 16 hours. The reaction mixture was directly concentrated under reduced pressure to give crude product. The crude product was triturated with (PE / EtOAc = 3 / 1, 20 mL) at 20°C for 1 hour and filtered appropriately and dried to get compound N1,N5-bis(3-aminopropyl)-N3-[3-(dimethylamino)propyl]benzene-1,3,5-tricarboxamide (930 mg, crude, HCl) as a yellow solid. Step 4: 1-[3-[4-[3-[bis(2-hydroxydodecyl)amino]propyl]piperazin-1-yl]propyl-(2- hydroxydodecyl)amino]dodecan-2-ol (SM-066): (EC5059-495 / 498 / 499) NaBH3CN (680.91 mg, 10.84 mmol, 8 eq) was added to a solution of N1,N5-bis(3- aminopropyl)-N3-[3-(dimethylamino)propyl]benzene-1,3,5-tricarboxamide (600 mg, 1.35 mmol, 1 eq, HCl) and NaOAc (888.85 mg, 10.84 mmol, 8 eq) in MeOH (30 mL). After addition, the mixture was stirred at 25°C for 0.5 hours, and then 1-ethylhexyl 9-oxononanoate (2.31 g, 8.13 mmol, 6 eq) was added. The resulting mixture was stirred at 25°C for 15.5 hours. The reaction mixture was concentrated under reduced pressure to remove MeOH. The residue was diluted with H2O (60 mL) and extracted with EtOAc (50 mL * 3). The combined organic layers were washed with brine (60 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to leave a residue. The residue was purified by flash silica gel chromatography (40 g SepaFlash® Silica Flash Column, DCM : MeOH : 0~10%, twice) to give SM-066 (645 mg, 428.50 μmol, 48.8% yield, 98.34% purity) as colorless gum. LCMS: [M+H]+: 1480.8 1H NMR (400 MHz, CDCl3) δ = 8.20 (s, 3H), 8.06 - 7.98 (m, 3H), 4.83 - 4.76 (m, 4H), 3.63 -3.52 (m, 6H), 3.38 - 3.26 (m, 6H), 3.17 - 3.07 (m, 8H), 2.99 (s, 6H), 2.28 (t, J = 7.2 Hz, 8H), 2.21 - 2.12 (m, 6H), 1.78 - 1.68 (m, 8H), 1.65 - 1.55 (m, 14H), 1.54 - 1.48 (m, 10H), 1.39 - 1.25 (m, 56H), 0.90 - 0.85 (m, 24H). Alternative Syntheses of SM-066 Synthesis of SM-066 (method-2)

[0053] Step 1: 3,5-bis(methoxycarbonyl)benzoic acid To a solution of trimethyl benzene-1,3,5-tricarboxylate (27 g, 107.05 mmol, 1.0 eq) in MeOH (350 mL) was dropwise added a solution of NaOH (4.28 g, 107.05 mmol, 1.0 eq) in H2O (70 mL). The mixture was stirred at 60 °C for 2 h. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with DCM (300 mL) and extracted with saturation solution NaHCO3 (300 mL). The aqueous phase was acidified to pH = 1 with 5% hydrochloric acid and extracted with EtOAc (3 * 300 mL). The combined organic layers were dried over MgSO4, and concentrated under vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 330 g SepaFlash® Silica Flash Column, Eluent of 0 ~ 50% EtOAc / PE gradient @ 100 mL / min) to get compound 3,5-bis(methoxycarbonyl)benzoic acid (8 g, 33.59 mmol, 15.7% yield) as a white solid. 1H NMR (400 MHz, CD3OD-d4) δ = 8.73 - 8.68 (m, 2H), 8.66 - 8.62 (m, 1H), 3.96 (s, 6H). Step 2: dimethyl 5-[3-(dimethylamino)propylcarbamoyl]benzene-1,3-dicarboxylate To a solution of 3,5-bis(methoxycarbonyl)benzoic acid (6.9 g, 28.97 mmol, 1.0 eq) and N',N'-dimethylpropane-1,3-diamine (5.92 g, 57.94 mmol, 7.25 mL, 2.0 eq) in DCM (100 mL) were added EDCI (8.33 g, 43.45 mmol, 1.5 eq) and HOBt (5.87 g, 43.45 mmol, 1.5 eq). The mixture was stirred at 20 °C for 12 h. The reaction mixture was diluted with water (100mL) and extracted with DCM (100mL * 2). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0 ~ 10% MeOH / DCM gradient @ 100 mL / min) to get compound dimethyl 5-[3- (dimethylamino)propylcarbamoyl]benzene-1,3-dicarboxylate (6.1 g, 18.54 mmol, 64.0% yield, 98% purity) as a white solid. 1H NMR (400 MHz, CD3OD-d4) δ = 8.68 (d, J = 1.6 Hz, 1H), 8.64 (d, J = 1.6 Hz, 2H), 3.97 (s, 6H), 3.45 (t, J = 7.2 Hz, 2H), 2.53 - 2.40 (m, 2H), 2.29 (s, 6H), 1.90 - 175 (m, 2H). Step 3: 5-[3-(dimethylamino)propylcarbamoyl]benzene-1,3-dicarboxylic acid To a solution of dimethyl 5-[3-(dimethylamino)propylcarbamoyl]benzene-1,3- dicarboxylate (6.1 g, 18.92 mmol, 1.0 eq) in MeOH (100 mL) was added NaOH (1.67 g, 41.63 mmol, 2.2 eq) and H2O (20 mL). The mixture was stirred at 60 °C for 12 h. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with DCM (300 mL) and extracted with saturation solution NaHCO3(300 mL). The aqueous phase was acidified to pH = 1 with 5% hydrochloric acid and extracted with EtOAc (3 * 300 mL). The combined organic layers were dried over Mg2SO4, and concentrated under vacuum to give compound 5-[3-(dimethylamino)propylcarbamoyl]benzene-1,3-dicarboxylic acid (5 g, 15.12 mmol, 79.9% yield, HCl) as a white solid. 1H NMR (400 MHz, CD3OD-d4) δ = 8.73 (s, 1H), 8.50 (s, 2H), 3.52 (t, J = 6.4 Hz, 2H), 3.15 (t, J = 7.6 Hz, 2H), 2.84 (s, 6H), 2.16 - 2.00 (m, 2H). Step 4: tetra(octan-3-yl) 9,9',9'',9'''-((((5-((3- (dimethylamino)propyl)carbamoyl)isophthaloyl)bis(azanediyl))bis(propane-3,1- diyl))bis(azanetriyl))tetranonanoate To a solution of 5-[3-(dimethylamino)propylcarbamoyl]benzene-1,3-dicarboxylic acid (600 mg, 2.04 mmol, 1.0 eq) and 1-ethylhexyl 9-[3-aminopropyl-[9-(1-ethylhexoxy)-9-oxo- nonyl]amino]nonanoate (3.96 g, 6.12 mmol, 3.0 eq, HCl) in pyridine (20 mL) was added EDCI (1.37 g, 7.14 mmol, 3.5 eq). The mixture was stirred at 20 °C for 16 h under N2. The reaction mixture was directly concentrated under reduced pressure and the residual pyridine was co- evaporated with DCM to give residue. The residue was diluted with H2O (100 mL) and extracted with DCM (60 mL * 3). The combined organic layers were washed with brine (80 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give residue. The residue was purified by flash silica gel chromatography (40 g SepaFlash® Silica Flash Column, DCM : MeOH: 0~10%) and purified by prep-HPLC (column: Phenomenex luna C18150 * 25 mm * 10 um; mobile phase: [A / B water (FA) - ACN]; gradient: 65% - 95% B over 8 min) to give compound tetra(octan-3-yl) 9,9',9'',9'''-((((5-((3-(dimethylamino)propyl)carbamoyl)isophthaloyl)bis(azanediyl))bis(propane- 3,1-diyl))bis(azanetriyl))tetranonanoate (1.1 g, 739.62 μmol, 49.8% yield, 99.53% purity) as yellow gum. LCMS: [M+H]+: 1480.6 1H NMR (400 MHz, CDCl3) δ = 9.21 (s, 1H), 8.63 - 8.51 (m, 2H), 8.49 - 8.33 (m, 3H), 4.87 - 4.75 (m, 4H), 3.69 - 3.47 (m, 6H), 2.63 (t, J = 5.6 Hz, 4H), 2.58 - 2.45 (m, 10H), 2.38 (s, 6H), 2.31 - 2.22 (m, 8H), 1.78 (d, J = 2.8 Hz, 6H), 1.62 - 1.44 (m, 32H), 1.33 - 1.19 (m, 56H), 0.91 - 0.82 (m, 24H). Synthesis of SM-066 (method-3)

[0054] To a solution of (2,3,4,5,6-pentafluorophenyl) 3,5-bis[3-[bis[9-(1-ethylhexoxy)-9-oxo- nonyl]amino]propylcarbamoyl]benzoate (16.5 g, 10.56 mmol, 1.0 eq) in THF (300 mL) were added DIEA (6.83 g, 52.81 mmol, 9.20 mL, 5.0 eq) and N',N'-dimethylpropane-1,3-diamine (2.16 g, 21.12 mmol, 2.64 mL, 2.0 eq). The mixture was stirred at 20 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 330 g SepaFlash® Silica Flash Column, Eluent of 0~20% MeOH / DCM ether gradient @ 100 mL / min), prep-NP-HPLC (column: Welch Ultimate XB-CN 250 * 50 * 10 um; mobile phase: [A / B Hexane-EtOH (0.1% NH3.H2O) ]; gradient: 10%-40% B over 16 min) and prep-NP-HPLC (column: Welch Ultimate XB-Diol 250 * 50 * 10 um; mobile phase: [A / B Hexane-EtOH(0.1% NH3.H2O)]; gradient: 8%-35% of B over 16 min) to get SM-066, aka. tetra(octan-3-yl) 9,9',9'',9'''-((((5-((3- (dimethylamino)propyl)carbamoyl)isophthaloyl)bis(azanediyl)) bis(propane-3,1- diyl))bis(azanetriyl))tetranonanoate (23 g, 15.46 mmol, 76.3% yield, 99.51% purity) as a yellow oil. LCMS: [M+H]+: 1480.31H NMR (400 MHz, CDCl3) δ = 9.22 (s, 1H), 8.57 (t, J = 4.4 Hz, 2H), 8.44 - 8.28 (m, 3H), 4.87 - 4.80 (m, 4H), 3.65 - 3.50 (m, 6H), 2.62 (t, J = 6.0 Hz, 4H), 2.57 - 2.48 (m, 10H), 2.38 (s, 6H), 2.26 (t, J = 7.6 Hz, 8H), 1.77 - 1.74 (m, 6H), 1.61 - 1.44 (m, 32H), 1.33 - 1.21 (m, 56H), 0.94 - 0.82 (m, 24H). Example 2: Synthesis of SM-078 (aka 1-ethylhexyl 9-[3-[[3-[3-[bis[9-(1-ethylhexoxy)-9-oxo- nonyl]amino]propylcarbamoyl]-5-[4- (dimethylamino)butanoylamino]benzoyl]amino]propyl-[9-(1-ethylhexoxy)-9-oxo- nonyl]amino]nonanoate) tetra(octan-3-yl) 9,9',9'',9'''-((((5-(4- (dimethylamino)butanamido)isophthaloyl)bis(azanediyl))bis(propane-3,1- diyl))bis(azanetriyl))tetranonanoate.

[0055]

[0056] Step 1: tert-butyl N-[3-[[3-[3-(tert-butoxycarbonylamino)propylcarbamoyl]-5-nitro- benzoyl]amino]propyl]carbamate (2) To a solution of 5-nitrobenzene-1,3-dicarboxylic acid (7 g, 33.16 mmol, 1.0 eq) and tert- butyl N-(3-aminopropyl)carbamate (14.44 g, 82.89 mmol, 14.47 mL, 2.5 eq) in Py (100 mL) was added EDCI (15.89 g, 82.89 mmol, 2.5 eq) at 0 °C under N2. After addition, the mixture was stirred at 20 °C for 16 h. The reaction mixture was diluted with H2O (150 mL) and extracted with EtOAc (80 mL * 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give residue. The residue was purified by flash silica gel chromatography (120 g SepaFlash® Silica Flash Column, PE: EtOAc: 0 ~ 40%) to give compound tert-butyl N-[3-[[3-[3-(tert-butoxycarbonylamino)propylcarbamoyl]-5-nitro- benzoyl]amino]propyl]carbamate (8.5 g, 16.20 mmol, 49.3% yield, 99.8% purity) as white solid. 1H NMR (400 MHz, CDCl3) δ = 8.87 (s, 2H), 8.69 (s, 1H), 7.93 (s, 2H), 5.00 (s, 2H), 3.57 - 3.52 (m, 4H), 3.30 - 3.23 (m, 4H), 1.80 - 1.72 (m, 4H), 1.45 (s, 18H). Step 2: tert-butyl N-[3-[[3-amino-5-[3-(tert- butoxycarbonylamino)propylcarbamoyl]benzoyl]amino]propyl]carbamate (3) 23To a solution of tert-butyl N-[3-[[3-[3-(tert-butoxycarbonylamino)propylcarbamoyl]-5- nitro-benzoyl]amino]propyl]carbamate (8.5 g, 16.23 mmol, 1 eq) in MeOH (150 mL) was added Pd / C (17.28 g, 16.23 mmol, 10% purity) under N2. The suspension was degassed under vacuum and purged with H2several times. The mixture was stirred under H2(15 psi) at 40 °C for 16 h. The reaction mixture was filtered and the filter cake was washed with MeOH (30 mL * 2), the filtrate was concentrated under reduced pressure to give crude product. The crude product was triturated with (PE / EtOAc=10 / 1, 50 mL) at 20 °C for 0.5 h and filter. The filter cake was dried to afford pure compound tert-butyl N-[3-[[3-amino-5-[3-(tert- butoxycarbonylamino)propylcarbamoyl]benzoyl]amino]propyl]carbamate (7.5 g, 15.19 mmol, 93.6% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ = 8.27 (t, J = 5.6 Hz, 2H), 7.33 (s, 1H), 7.09 (s, 2H), 6.79 (t, J = 5.2 Hz, 2H), 5.40 (s, 2H), 3.21 (q, J = 6.4 Hz, 4H), 2.96 (q, J = 6.4 Hz, 4H), 1.65 - 1.56 (m, 4H), 1.37 (s, 18H). Step 3: tert-butyl N-[3-[[3-[3-(tert-butoxycarbonylamino)propylcarbamoyl]-5-[4- (dimethylamino)butanoylamino]benzoyl]amino]propyl]carbamate (4) B To a mixture of tert-butyl N-[3-[[3-amino-5-[3-(tert-butoxycarbonylamino) propylcarbamoyl]benzoyl]amino]propyl]carbamate (4 g, 8.10 mmol, 1.0 eq) and 4- (dimethylamino)butanoic acid (1.28 g, 9.72 mmol, 1.2 eq) in DMF (50 mL) were added HATU (3.70 g, 9.72 mmol, 1.2 eq) and DIPEA (2.09 g, 16.21 mmol, 2.82 mL, 2.0 eq). The mixture was stirred at 20 °C for 16 h under N2. The reaction mixture was diluted with H2O (120 mL) and extracted with EtOAc (60 mL * 3). The combined organic layers were washed with brine (80 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give residue. The residue was purified by flash silica gel chromatography (80 g SepaFlash® Silica Flash Column, DCM : MeOH : 0~15%) to give compound tert-butyl N-[3-[[3-[3-(tert- butoxycarbonylamino)propylcarbamoyl]-5-[4- (dimethylamino)butanoylamino]benzoyl]amino]propyl]carbamate (3.7 g, 6.10 mmol, 75.5% yield) as a yellow solid. Step 4: N1,N3-bis(3-aminopropyl)-5-[4-(dimethylamino)butanoylamino]benzene-1,3- dicarboxamide (5) B To a solution of tert-butyl N-[3-[[3-[3-(tert-butoxycarbonylamino)propylcarbamoyl]-5-[4- (dimethylamino)butanoylamino]benzoyl]amino]propyl]carbamate (1.5 g, 2.47 mmol, 1.0 eq) in DCM (10 mL) was added HCl / dioxane (4 M, 5 mL). The mixture was stirred at 20 °C for 16 h. The reaction mixture was directly concentrated under reduced pressure to give compound N1,N3- bis(3-aminopropyl)-5-[4-(dimethylamino)butanoylamino]benzene-1,3-dicarboxamide (1.05 g, crude, HCl) as yellow solid. The crude product was used for next step without further purification. 1H NMR (400 MHz, CD3OD-d4) δ = 8.29 - 8.26 (m, 2H), 8.18 - 8.15 (m, 1H), 3.55 (t, J = 6.4 Hz, 4H), 3.31 - 3.25 (m, 2H), 3.06 (t, J = 7.2 Hz, 4H), 2.96 (s, 6H), 2.65 (t, J = 6.4 Hz, 2H), 2.18 - 2.11 (m, 2H), 2.08 - 2.00 (m, 4H). Step 5: 1-ethylhexyl 9-[3-[[3-[3-[bis[9-(1-ethylhexoxy)-9-oxo- nonyl]amino]propylcarbamoyl]-5-[4- (dimethylamino)butanoylamino]benzoyl]amino]propyl-[9-(1-ethylhexoxy)-9-oxo- nonyl]amino]nonanoate (SM-078) To a solution of N1,N3-bis(3-aminopropyl)-5-[4- (dimethylamino)butanoylamino]benzene-1,3-dicarboxamide (500 mg, 1.13 mmol, 1.0 eq, HCl) and NaOAc (740.71 mg, 9.03 mmol, 8.0 eq) in MeOH (15 mL) was added NaBH3CN (567.43 mg, 9.03 mmol, 8.0 eq). After addition, the mixture was stirred at 20 °C for 0.5 h, and then 1-ethylhexyl 9-oxononanoate (2.57 g, 9.03 mmol, 8.0 eq) was added. The resulting mixture was stirred at 20 °C for 15.5 h. The reaction mixture was concentrated under reduced pressure to remove MeOH. The residue was diluted with H2O (60 mL) and extracted with EtOAc (50 mL * 3). The combined organic layers were washed with brine (60 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (40 g SepaFlash® Silica Flash Column, DCM : MeOH : 0~10%, 2% NH3•H2O in MeOH) and prep-HPLC (column: Welch Xtimate C1100 * 30 mm * 5 um; mobile phase: [water (FA)-MeOH]; gradient:63% - 93% B over 8 min) to give SM-078 (655 mg, 441.47 μmol, 38.44% yield, 99.77% purity) as light yellow oil. LCMS: [M+H]+: 1480.6 1H NMR (400 MHz, CDCl3) δ = 10.28 (s, 1H), 8.19 (s, 2H), 8.16 - 8.08 (m, 2H), 8.05 (s, 1H), 4.88 - 4.76 (m, 4H), 3.58 - 3.45 (m, 4H), 2.76 - 2.67 (m, 4H), 2.65 - 2.58 (m, 6H), 2.51 (br t, J = 6.8 Hz, 4H), 2.37 (s, 6H), 2.28 (t, J = 7.2 Hz, 8H), 1.92 - 1.84 (m, 4H), 1.63 - 1.48 (m, 32H), 1.35 - 1.23 (m, 60H), 0.90 - 0.85 (m, 24H). Example 3: Synthesis of SM-081 tetra(octan-3-yl) 9,9',9'',9'''-((((4-((3-(dimethylamino)propyl)carbamoyl)pyridine-2,6- dicarbonyl)bis(azanediyl))bis(propane-3,1-diyl))bis(azanetriyl))tetranonanoate.

[0057] Step 1: 2,6-dichloro-N-(3-(dimethylamino)propyl)isonicotinamide (2) To a solution of 2,6-dichloropyridine-4-carboxylic acid (30 g, 156.25 mmol, 1.0 eq) in DCM (300 mL) were added EDCI (44.93 g, 234.38 mmol, 1.5 eq), HOBt (31.67 g, 234.38 mmol, 1.5 eq) and TEA (47.43 g, 468.75 mmol, 65.24 mL, 3 eq), then N',N'-dimethylpropane-1,3-diamine (23.95 g, 234.38 mmol, 29.31 mL, 1.5 eq) was added into the mixture then the resulting mixture was stirred at 20 °C for 12 h. The reaction mixture was diluted with water (300 mL) and extracted with DCM / IPA (300 mL × 3). The combined organic layers were combined and concentrated under reduced pressure to give a residue. The residue was purified by reversed-phase HPLC (0.1%FA condition) to give the compound of 2,6-dichloro-N-(3- (dimethylamino)propyl)isonicotinamide (9.5 g, 34.29 mmol, 21.9% yield, 99.7% purity) as a yellow gum. 1H NMR (400 MHz, DMSO-d6) δ = 8.90 (s, 1H), 7.87 (s, 2H), 3.31 - 3.26 (m, 2H), 2.24 (t, J = 7.2 Hz, 2H), 2.12 (s, 6H), 1.70 - 1.58 (m, 2H). Step 2: dimethyl 4-[3-(dimethylamino)propylcarbamoyl]pyridine-2,6-dicarboxylate (3) To a solution of 2,6-dichloro-N-[3-(dimethylamino)propyl]pyridine-4-carboxamide (9 g, 32.59 mmol, 1 eq) in DMF (60 mL) and MeOH (40 mL) were added TEA (9.89 g, 97.77 mmol, 13.61 mL, 3.0 eq) and Pd(dppf)Cl2 (2.38 g, 3.26 mmol, 0.1 eq) under N2. The suspension was degassed under vacuum and purged with CO 3 times. The mixture was stirred under CO (50 psi) at 80 °C for 12 h. The reaction mixture was concentrated under reduced pressure to remove MeOH. The residue was diluted with water (150 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give crude product. The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, Eluent of 0~20% MeOH / DCM gradient @ 100 mL / min) to give a crude product, then the crude product was triturated with EtOAc at 20oC for 30 min to afford the desired compound of dimethyl 4-[3- (dimethylamino)propylcarbamoyl]pyridine-2,6-dicarboxylate (3.3 g, 10.01 mmol, 31.3% yield, 98.04% purity) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ= 9.28 (t, J = 5.2 Hz, 1H), 8.64 (s, 2H), 3.95 (s, 6H), 3.41 - 3.33 (m, 3H), 2.63 (s, 2H), 2.40 (s, 6H), 1.85 - 1.75 (m, 2H). Step 3: tert-butyl N-[3-[[6-[3-(tert-butoxycarbonylamino)propylcarbamoyl]-4-[3- (dimethylamino)propylcarbamoyl]pyridine-2-carbonyl]amino]propyl]carbamate (4) A mixture of dimethyl 4-[3-(dimethylamino)propylcarbamoyl]pyridine-2,6-dicarboxylate (2 g, 6.19 mmol, 1.0 eq) and tert-butyl N-(3-aminopropyl)carbamate (3.23 g, 18.56 mmol, 3.24 mL, 3.0 eq) in MeOH (20 mL) was stirred at 50 °C for 6 h. The reaction mixture was concentrated under reduced pressure to give a residue. The crude product was triturated with EtOA at 20oC for 30 min to afford the compound of tert-butyl N-[3-[[6-[3-(tert- butoxycarbonylamino)propylcarbamoyl]-4-[3-(dimethylamino)propylcarbamoyl]pyridine-2- carbonyl]amino]propyl]carbamate (3.03 g, 4.54 mmol, 73.3% yield, 90.9% purity) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ = 9.33 (t, J = 4.8 Hz, 2H), 9.26 - 9.16 (m, 1H), 8.56 (s, 2H), 7.00 - 6.75 (m, 2H), 3.41 - 3.35 (m, 4H), 3.30 (s, 4H), 3.04 - 2.95 (m, 4H), 2.14 (s, 6H), 1.74 - 1.62 (m, 6H), 1.37 (s, 18H). Step 4: N2,N6-bis(3-aminopropyl)-N4-[3-(dimethylamino)propyl]pyridine-2,4,6- tricarboxamide (5) To a solution of tert-butyl N-[3-[[6-[3-(tert-butoxycarbonylamino)propylcarbamoyl]-4-[3- (dimethylamino)propylcarbamoyl]pyridine-2-carbonyl]amino]propyl]carbamate (500 mg, 822.72 μmol, 1.0 eq) in DCM (2.5 mL) was added HCl / dioxane (4 M, 2.5 mL), then the mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give the crude product of N2,N6-bis(3-aminopropyl)-N4-[3-(dimethylamino)propyl]pyridine-2,4,6- tricarboxamide (590 mg, crude, 8HCl) as a white solid. The crude product was used into the next step without further purification. Step 5: SM-081 (AKA: 1-ethylhexyl 9-[3-[[6-[3-[bis[9-(1-ethylhexoxy)-9-oxo- nonyl]amino]propylcarbamoyl]-4-[3-(dimethylamino)propylcarbamoyl]pyridine-2- carbonyl]amino]propyl-[9-(1-ethylhexoxy)-9-oxo-nonyl]amino]nonanoate ) To a solution of N2,N6-bis(3-aminopropyl)-N4-[3-(dimethylamino)propyl]pyridine-2,4,6- tricarboxamide (590 mg, 843.83 μmol, 1.0 eq, 8 HCl) and NaOAc (830.67 mg, 10.13 mmol, 12.0 eq) in MeOH (15 mL) was added NaBH3CN (530.28 mg, 8.44 mmol, 10.0 eq). After addition, the mixture was stirred at 25 °C for 0.5 h, and then 1-ethylhexyl 9-oxononanoate (1.92 g, 6.75 mmol, 8.0 eq) was added. The resulting mixture was stirred at 25 °C for 15.5 h. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine 30 mL, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~10% DCM / MeOH gradient @ 80 mL / min) to give a crude product, then the crude product was purified by prep-HPLC (column: Welch Xtimate C1 100*30mm*5um; mobile phase: [water(FA)-MeOH]; gradient:63%-93% B over 8 min) to give SM-081 (305.92 mg, 204.71 μmol, 24.3% yield, 99.12% purity) as a light yellow oil. LCMS: [M+H]+: 1481.7 1H NMR (400 MHz, CDCl3) δ = 9.75 (d, J = 3.6 Hz, 1H), 8.68 (s, 2H), 8.34 - 8.24 (m, 1H), 4.86 - 4.77 (m, 4H), 3.66 - 3.52 (m, 6H), 2.63 - 2.52 (m, 6H), 2.49 - 2.42 (m, 4H), 2.41 (s, 6H), 2.28 (t, J = 7.5 Hz, 8H), 1.87 - 1.76 (m, 12H), 1.64 - 1.48 (m, 28H), 1.30 - 1.21 (m, 58H), 0.92 - 0.84 (m, 24H). Example 4: Synthesis of SM-082 tetra(octan-3-yl) 9,9',9'',9'''-((((5-((3-(4-methylpiperazin-1- yl)propyl)carbamoyl)isophthaloyl)bis(azanediyl))bis(propane-3,1- diyl))bis(azanetriyl))tetranonanoate.

[0058] Step 1: 3,5-bis(methoxycarbonyl)benzoic acid (2) To a solution of trimethyl benzene-1,3,5-tricarboxylate (20 g, 79.30 mmol, 1.0 eq) in MeOH (300 mL) and H2O (50 mL) was added NaOH (3.49 g, 87.23 mmol, 1.1 eq). The mixture was stirred at 60 °C for 16 h. The reaction mixture was concentrated under reduced pressure to remove EtOH. The residue was diluted with H2O (150 mL) and extracted with EtOAc (50 mL * 3). The aqueous phase pH was adjusted to 2 with 4M HCl and extracted with EtOAc (100 mL * 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give compound 3,5-bis(methoxycarbonyl)benzoic acid (14.6 g, 61.29 mmol, 77.3% yield) as white solid. The crude product was used for next step without further purification.1H NMR (400 MHz, DMSO-d6) δ = 13.64 - 13.50 (m, 1H), 8.59 - 8.5 (d, J = 1.6 Hz, 2H), 8.54 (d, J = 1.6 Hz, 1H), 3.91 (s, 6H). Step 2: dimethyl 5-[3-(4-methylpiperazin-1-yl)propylcarbamoyl]benzene-1,3-dicarboxylate (3) To a solution of 3,5-bis(methoxycarbonyl)benzoic acid (14.5 g, 60.87 mmol, 1.0 eq) in DCM (200 mL) were added HATU (27.78 g, 73.05 mmol, 1.2 eq) and DIPEA (9.44 g, 73.05 mmol, 12.72 mL, 1.2 eq) at 0 °C. After addition, the reaction mixture was stirred at 20 °C for 0.5 h. And then 3-(4-methylpiperazin-1-yl)propan-1-amine (11.49 g, 73.05 mmol, 1.2 eq) was added. The resulting mixture was stirred at 20 °C for 16 h under N2. The reaction mixture was diluted with H2O (150 mL) and extracted with DCM (100 mL * 3). The combined organic layers were washed with brine (150 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give residue. The residue was purified by flash silica gel chromatography (330 g SepaFlash® Silica Flash Column, DCM : MeOH : 0~10%, 2% NH3•H2O in MeOH ) to give compound dimethyl 5- [3-(4-methylpiperazin-1-yl)propylcarbamoyl]benzene-1,3-dicarboxylate (15.6 g, 39.77 mmol, 65.3% yield, 96.2% purity) as white solid. 1H NMR (400 MHz, DMSO-d6) δ = 8.95 (t, J = 5.2 Hz, 1H), 8.67 - 8.64 (m, 2H), 8.57- 8.53 (m, 1H), 3.93 (s, 6H), 3.36 - 3.30 (m, 2H), 2.74 - 2.50 (m, 8H), 2.46 (t, J = 7.2 Hz, 2H), 2.39 (s, 3H), 1.80 - 1.67 (m, 2H). Step 3: 5-[3-(4-methylpiperazin-1-yl)propylcarbamoyl]benzene-1,3-dicarboxylic acid (4) To a solution of dimethyl 5-[3-(4-methylpiperazin-1-yl)propylcarbamoyl]benzene-1,3- dicarboxylate (10 g, 26.49 mmol, 1.0 eq) in MeOH (60 mL) and H2O (15 mL) was added NaOH (3.18 g, 79.48 mmol, 3.0 eq). The mixture was stirred at 70 °C for 16 h. The reaction mixture was concentrated under reduced pressure to remove MeOH. The residue was diluted with H2O (30 mL) and extracted with EtOAc (30 mL * 3). The aqueous phase pH was adjusted to 2 with 4M HCl and concentrated under reduced pressure to give residue. The residue was triturated with (PE / EA = 1 / 1, 50 mL) at 20 °C for 0.5 h and filtered appropriately, the filter cake was dried to afford compound 5-[3-(4-methylpiperazin-1-yl)propylcarbamoyl]benzene-1,3-dicarboxylic acid (9.2 g, crude) as white solid. Step 4: tert-butyl N-[3-[[3-[3-(tert-butoxycarbonylamino)propylcarbamoyl]-5-[3-(4- methylpiperazin-1-yl)propylcarbamoyl]benzoyl]amino]propyl]carbamate (5) To a mixture of 5-[3-(4-methylpiperazin-1-yl)propylcarbamoyl]benzene-1,3-dicarboxylic acid (5 g, 14.31 mmol, 1.0 eq) and tert-butyl N-(3-aminopropyl)carbamate (7.48 g, 42.93 mmol, 7.50 mL, 3.0 eq) in Py (50 mL) was added EDCI (8.23 g, 42.93 mmol, 3.0 eq). The mixture was stirred at 20 °C for 16 h under N2. The reaction mixture was concentrated under reduced pressure to remove most of Py. The residue was diluted with saturated NH4Cl (50 mL) and extracted with DCM / MeOH (20 / 1, 50 mL * 5). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give residue. The residue was purified by flash silica gel chromatography (120 g SepaFlash® Silica Flash Column, DCM : MeOH : 0~15%, 2% NH3•H2O in MeOH) to give compound tert-butyl N-[3-[[3-[3-(tert- butoxycarbonylamino)propylcarbamoyl]-5-[3-(4-methylpiperazin-1- yl)propylcarbamoyl]benzoyl]amino]propyl]carbamate (6.9 g, 10.43 mmol, 72.6% yield) as yellow oil. Step 5: N1,N5-bis(3-aminopropyl)-N3-[3-(4-methylpiperazin-1-yl)propyl]benzene-1,3,5- tricarboxamide (6) To a solution of tert-butyl N-[3-[[3-[3-(tert-butoxycarbonylamino)propylcarbamoyl]-5-[3- (4-methylpiperazin-1-yl)propylcarbamoyl]benzoyl]amino]propyl]carbamate (4 g, 6.04 mmol, 1.0 eq) in DCM (15 mL) was added HCl / dioxane (4 M, 15 mL). The mixture was stirred at 20 °C for 2 h. The reaction mixture was directly concentrated under reduced pressure to give compound N1,N5-bis(3-aminopropyl)-N3-[3-(4-methylpiperazin-1-yl)propyl]benzene-1,3,5-tricarboxamide (3.1 g, crude, HCl) as black, brown solid. The crude product was used for next step without further purification. Step 6: (aka) 1-ethylhexyl 9-[3-[[3-[3-[bis[9-(1-ethylhexoxy)-9-oxo- nonyl]amino]propylcarbamoyl]-5-[3-(4-methylpiperazin-1- yl)propylcarbamoyl]benzoyl]amino]propyl-[9-(1-ethylhexoxy)-9-oxo- nonyl]amino]nonanoate (SM-082) To a solution of N1,N5-bis(3-aminopropyl)-N3-[3-(4-methylpiperazin-1- yl)propyl]benzene-1,3,5-tricarboxamide (600 mg, 1.20 mmol, 1.0 eq, HCl) in MeOH (15 mL) were added NaBH3CN (757.04 mg, 12.05 mmol, 10.0 eq) and NaOAc (988.24 mg, 12.05 mmol, 10.0 eq). After addition, the mixture was stirred at 25 °C for 0.5 h, and then 1-ethylhexyl 9- oxononanoate (2.74 g, 9.64 mmol, 8.0 eq) was added in the mixture. The resulting mixture was stirred at 25 °C for 15.5 h. The combined reaction mixture was concentrated under reduced pressure to remove MeOH. The residue was diluted with H2O (80 mL) and extracted with EtOAc (50 mL * 3). The combined organic layers were washed with brine (60 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (40 g SepaFlash® Silica Flash Column, DCM : MeOH : 0~10%, 2% NH3•H2O in MeOH) and prep-HPLC (column: Welch Xtimate C1100 * 30mm * 5um; mobile phase: [water(FA)-MeOH]; gradient:60%-90% B over 8 min) to give SM-082 (651 mg, 418.92 μmol, 35.7% yield, 98.80% purity) as yellow oil. LCMS: [M+H]+: 1535.8 1H NMR (400 MHz, CDCl3) δ = 8.62 - 8.55 (m, 1H), 8.54 - 8.52 (m, 1H), 8.46 - 8.43 (m, 1H), 8.33 (t, J = 4.8 Hz, 1H), 4.84 - 4.78 (m, 4H), 3.58 - 3.52 (m, 4H), 2.90 - 2.75 (m, 4H), 2.70 - 2.61 (m, 8H), 2.56 (t, J = 6.0 Hz, 2H), 2.36 (s, 3H), 2.30 - 2.22 (m, 10H), 1.92 - 1.88 (m, 2H), 1.84 - 1.78 (m, 2H), 1.65 - 1.47 (m, 36H), 1.34 - 1.21 (m, 62H), 0.89 - 0.85 (m, 24H).

[0059] tetra(octan-3-yl) 9,9',9'',9'''-((((5-(2-((3-(dimethylamino)propyl)amino)-2- oxoethyl)isophthaloyl)bis(azanediyl))bis(propane-3,1-diyl))bis(azanetriyl))tetranonanoate.

[0060] Step 1: 2-(3,5-dibromophenyl)-N-[3-(dimethylamino)propyl]acetamide (2) To a solution of 2-(3,5-dibromophenyl)acetic acid (500 mg, 1.70 mmol, 1.0 eq) in DMF (5 mL) were added HATU (711.46 mg, 1.87 mmol, 1.1 eq), N',N'-dimethylpropane-1,3-diamine (260.71 mg, 2.55 mmol, 319.11 μL, 1.5 eq) and DIEA (659.54 mg, 5.10 mmol, 888.87 μL, 3.0 eq). The mixture was stirred at 20 °C for 12 h under N2 atmosphere. The reaction mixture was quenched by addition H2O (20 mL) and filtered to give compound 2-(3,5-dibromophenyl)-N-[3- (dimethylamino)propyl]acetamide (435 mg, 1.13 mmol, 66.4% yield, 98.2% purity) as a white solid. Step 2: dimethyl 5-[2-[3-(dimethylamino)propylamino]-2-oxo-ethyl]benzene-1,3- dicarboxylate (3) To a solution of 2-(3,5-dibromophenyl)-N-[3-(dimethylamino)propyl]acetamide (13 g, 34.38 mmol, 1.0 eq) in DMF (78 mL) were added MeOH (52 mL), TEA (10.44 g, 103.15 mmol, 14.36 mL, 3.0 eq), Pd(dppf)Cl2(2.52 g, 3.44 mmol, 0.1 eq) under N2atmosphere. The suspension was degassed and purged with CO for 3 times. The mixture was stirred under CO (2 Mpa) at 80 °C for 16 h. The reaction mixture was poured into water (500 mL) and extracted with EtOAc (300 mL * 2). The combined organic layers were washed with brine (300 mL) dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (80 g SepaFlash® Silica Flash Column, EtOAc : MeOH : 0~20%) to give compound dimethyl 5-[2-[3-(dimethylamino)propylamino]-2-oxo-ethyl]benzene-1,3- dicarboxylate (3 g, 8.66 mmol, 25.2% yield, 97.0% purity) as a black, brown solid. 1H NMR (400 MHz, DMSO-d6) δ = 8.36 (s, 1H), 8.26 (s, 1H), 8.13 (s, 2H), 3.90 (s, 6H), 3.60 (s, 2H), 3.08 (q, J = 6.0 Hz, 2H), 2.41 (t, J = 6.8 Hz, 2H), 2.26 (s, 6H), 1.65 - 1.55 (m, 2H). Step 3: 5-[2-[3-(dimethylamino)propylamino]-2-oxo-ethyl]benzene-1,3-dicarboxylic acid (4) To a solution of dimethyl 5-[2-[3-(dimethylamino)propylamino]-2-oxo-ethyl]benzene-1,3- dicarboxylate (3 g, 8.92 mmol, 1.0 eq) in EtOH (4.75 mL) was added NaOH (1.78 g, 44.59 mmol, 5.0 eq) in H2O (0.25 mL). The mixture was stirred at 60 °C for 3 h The reaction mixture was poured into water (5 mL) and extracted with EtOAc (5 mL * 2). The water was concentrated under reduced pressure to give compound 5-[2-[3-(dimethylamino)propylamino]-2-oxo-ethyl]benzene- 1,3-dicarboxylic acid (1.7 g, crude) as a black, brown solid. The crude product was used for next step without further purification. Step 4: tert-butyl N-[3-[[3-[3-(tert-butoxycarbonylamino)propylcarbamoyl]-5-[2-[3- (dimethylamino)propylamino]-2-oxo-ethyl]benzoyl]amino]propyl]carbamate (5) A mixture of 5-[2-[3-(dimethylamino)propylamino]-2-oxo-ethyl]benzene-1,3- dicarboxylic acid (1.5 g, 4.86 mmol, 1.0 eq), tert-butyl N-(3-aminopropyl)carbamate (2.54 g, 14.59 mmol, 2.55 mL, 3.0 eq), HATU (4.07 g, 10.70 mmol, 2.2 eq), DIEA (3.77 g, 29.19 mmol, 5.08 mL, 6 eq) in DMF (15 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 20 °C for 12 h under N2atmosphere. The reaction mixture was diluted with H2O (150 mL) and extracted with EtOAc (50 mL * 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (80 g SepaFlash® Silica Flash Column, EtOAc : MeOH : 0~20% 0.15%NH3H2O in EtOAc and MeOH) to give compound tert-butyl N-[3-[[3-[3-(tert-butoxycarbonylamino)propylcarbamoyl]-5-[2-[3- (dimethylamino)propylamino]-2-oxo-ethyl]benzoyl]amino]propyl]carbamate (1.8 g, 2.88 mmol, 59.3% yield, 99.4% purity) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ = 8.52 (t, J = 5.2 Hz, 2H), 8.17 - 8.10 (m, 2H), 7.84 (s, 2H), 6.81 (t, J = 5.2 Hz, 2H), 3.50 (s, 2H), 3.26 (q, J = 6.4 Hz, 4H), 3.08 (q, J = 6.4 Hz, 2H), 2.97 (q, J = 6.4 Hz, 4H), 2.43 (t, J = 7.2 Hz, 2H), 2.28 (s, 6H), 1.68 - 1.57 (m, 6H), 1.37 (s, 18H). Step 5: N1,N3-bis(3-aminopropyl)-5-[2-[3-(dimethylamino)propylamino]-2-oxo- ethyl]benzene-1,3-dicarboxamide (6) To a solution of tert-butyl N-[3-[[3-[3-(tert-butoxycarbonylamino)propylcarbamoyl]-5-[2- [3-(dimethylamino)propylamino]-2-oxo-ethyl]benzoyl]amino]propyl]carbamate (1 g, 1.61 mmol, 1.0 eq) in DCM (10 mL) was added HCl / dioxane (4 M, 5.00 mL). The mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give compound N1,N3-bis(3-aminopropyl)-5-[2-[3-(dimethylamino)propylamino]-2-oxo-ethyl]benzene-1,3- dicarboxamide (1.25 g, crude, 10 HCl) as a pink solid. The crude product was used for next step without further purification. Step 6: (aka) 1-ethylhexyl 9-[3-[[3-[3-[bis[9-(1-ethylhexoxy)-9-oxo- nonyl]amino]propylcarbamoyl]-5-[2-[3-(dimethylamino)propylamino]-2-oxo- ethyl]benzoyl]amino]propyl-[9-(1-ethylhexoxy)-9-oxo-nonyl]amino]nonanoate (SM-084) To a solution of N1,N3-bis(3-aminopropyl)-5-[2-[3-(dimethylamino)propylamino]-2-oxo- ethyl]benzene-1,3-dicarboxamide (1.25 g, 1.59 mmol, 1.0 eq, 10 HCl) in MeOH (31 mL) were added NaOAc (1.83 g, 22.29 mmol, 14.0 eq) and NaBH3CN (1.00 g, 15.92 mmol, 10.0 eq). The mixture was stirred at 20 °C for 0.5 h, then 1-ethylhexyl 9-oxononanoate (3.62 g, 12.74 mmol, 8.0 eq) was added and the mixture was stirred at 20 °C for 14 h. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (30 mL * 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (40 g SepaFlash® Silica Flash Column, DCM : MeOH : 0~15%) and prep-HPLC (column: Welch Xtimate C1100 * 30mm * 5um; mobile phase: [water(FA)-MeOH];gradient: 63%-93% B over 8 min) to give SM-084 (448.31 mg, 293.86 μmol, 18.5% yield, 97.95% purity) as a yellow oil. LCMS: [M+H]+: 1494.8 1H NMR (400 MHz, CDCl3) δ = 8.31 (t, J = 4.8 Hz, 2H), 8.19 (s, 1H), 7.84 (d, J = 0.8 Hz, 2H), 7.37 (t, J = 4.8 Hz, 1H), 4.87 - 4.76 (m, 4H), 3.59 (s, 2H), 3.54 (q, J = 6.0 Hz, 4H), 3.31 (q, J = 6.0 Hz, 2H), 2.63 (t, J = 6.0 Hz, 4H), 2.55 - 2.45 (m, 8H), 2.28 (t, J = 7.6 Hz, 10H), 1.99 (s, 6H), 1.81 - 1.74 (m, 4H), 1.60 - 1.54 (m, 12H), 1.53 - 1.43 (m, 18H), 1.33 - 1.20 (m, 60H), 0.90 - 0.85 (m, 24H). Example 6: Synthesis of SM-089

[0061] Step 1: dimethyl 5-[3-(dimethylamino)propoxy]benzene-1,3-dicarboxylate (2) To a solution of dimethyl 5-hydroxybenzene-1,3-dicarboxylate (8 g, 38.06 mmol, 1.0 eq) and 3-chloro-N,N-dimethyl-propan-1-amine (5.55 g, 45.67 mmol, 1.2 eq) in MeCN (200 mL) were added K2CO3(7.89 g, 57.09 mmol, 1.5 eq), 18-C-6 (503.02 mg, 1.90 mmol, 0.05 eq) and KI (631.84 mg, 3.81 mmol, 0.1 eq). The mixture was stirred at 80 °C for 16 h. The reaction mixture was filtered and the filter cake was washed with EtOAc (50 mL * 2). The filtrate was concentrated under reduced pressure to give residue. The residue was purified by flash silica gel chromatography (120 g SepaFlash® Silica Flash Column, DCM : MeOH: 0~10%) to give compound dimethyl 5-[3-(dimethylamino)propoxy]benzene-1,3-dicarboxylate (14.8 g, 50.11 mmol, 66.1% yield) as yellow oil. 1H NMR (400 MHz, CDCl3) δ = 8.24 (s, 1H), 7.71 (s, 2H), 4.09 (t, J = 6.0 Hz, 2H), 3.92 (s, 6H), 2.56 (t, J = 7.6 Hz, 2H), 2.32 (s, 6H), 2.07 - 1.98 (m, 2H). Step 2: Compound 5-[3-(dimethylamino)propoxy]benzene-1,3-dicarboxylic acid (3) To a solution of dimethyl 5-[3-(dimethylamino)propoxy]benzene-1,3-dicarboxylate (7.5 g, 25.40 mmol, 1.0 eq) in MeOH (60 mL) and H2O (15 mL) was added NaOH (3.05 g, 76.19 mmol, 3.0 eq). The mixture was stirred at 60 °C for 16 h. The reaction mixture was concentrated under reduced pressure to remove MeOH. The residue was diluted with H2O (30 mL) and extracted with EtOAc (30 mL * 3). The aqueous phase pH was adjusted to 2 with 4M HCl and concentrated under reduced pressure to give residue. The residue was triturated with (PE / EtOAc = 5 / 1, 50 mL * 2) at 20 °C for 0.5 h and filtered appropriately. The filter cake was dried to afford compound 5-[3- (dimethylamino)propoxy]benzene-1,3-dicarboxylic acid (5.1 g, 19.08 mmol, 75.1% yield) as a yellow solid. Step 3: SM-089, aka. tetra(octan-3-yl) 9,9',9'',9'''-((((5-(3- (dimethylamino)propoxy)isophthaloyl)bis(azanediyl))bis(propane-3,1- diyl))bis(azanetriyl))tetranonanoate To a solution of 5-[3-(dimethylamino)propoxy]benzene-1,3-dicarboxylic acid (500 mg, 1.22 mmol, 1.0 eq) and 1-ethylhexyl 9-[3-aminopropyl-[9-(1-ethylhexoxy)-9-oxo- nonyl]amino]nonanoate (1.97 g, 3.04 mmol, 2.5 eq, HCl) in pyridine (15 mL) was added EDCI (582.75 mg, 3.04 mmol, 2.5 eq). The mixture was stirred at 20 °C for 16 h. The reaction mixture was directly concentrated under reduced pressure and the residual pyridine was co-evaporated with DCM to give residue. The residue was diluted with H2O (50 mL) and extracted with DCM (35 mL * 3). The combined organic layers were washed with brine (40 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give residue. The residue was purified by flash silica gel chromatography (20 g SepaFlash® Silica Flash Column, DCM : MeOH : 0~10%) and prep- HPLC (column: Welch Xtimate C1100 * 30 mm * 5um; mobile phase: [A / B water (FA)-MeOH]; gradient: 65%-95% B over 8 min) to give SM-089 (430 mg, 293.26 μmol, 25.07% yield, 99.11% purity) as light yellow oil. LCMS: [M+H]+: 1454.4 1H NMR (400 MHz, CDCl3) δ = 8.25 (s, 1H), 7.97 - 7.82 (m, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.49 (s, 1H), 4.81 (t, J = 6.0 Hz, 4H), 4.16 - 4.03 (m, 2H), 3.70 - 3.47 (m, 4H), 2.75 - 2.62 (m, 4H), 2.58 - 2.42 (m, 8H), 2.31 - 2.21 (m, 14H), 2.04 - 1.93 (m, 2H), 1.88 - 1.73 (m, 4H), 1.64 - 1.45 (m, 32H), 1.35 - 1.21 (m, 58H), 0.91 - 0.85 (m, 24H). Example 7: Synthesis of SM-090

[0062] Step 1: 2,6-dichloro-N-[2-(dimethylamino)ethyl]pyridine-4-carboxamide To a solution of 2,6-dichloropyridine-4-carboxylic acid (5 g, 26.04 mmol, 1.0 eq) in DCM (50 mL) was added SOCl2 (6.20 g, 52.08 mmol, 3.78 mL, 2.0 eq) at 0 °C. The mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give compound 2,6-dichloropyridine-4-carbonyl chloride (5.4 g, 25.66 mmol, 98.5% yield) as brown oil. To a solution of N',N'-dimethylethane-1,2-diamine (2.71 g, 30.79 mmol, 3.36 mL, 1.2 eq) and TEA (7.79 g, 76.98 mmol, 10.71 mL, 3.0 eq) in DCM (50 mL) was added 2,6-dichloropyridine-4- carbonyl chloride (5.4 g, 25.66 mmol, 1.0 eq) at 0 °C. The mixture was stirred at 25 °C for 12 h. The residue was diluted with water 50 mL and extracted with DCM (100 mL * 3). The combined organic layers were washed with water, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, DCM / MeOH = 1 / 0 to 20 / 1) to give compound 2,6-dichloro-N-[2-(dimethylamino)ethyl]pyridine- 4-carboxamide (6.6 g, 23.92 mmol, 93.2% yield, 94.9% purity) as yellow solid. 1H NMR (400 MHz, CDCl3) δ = 9.08 – 9.02 (m, 1H), 7.63 (s, 2H), 3.27 – 3.20 (m, 2H), 2.70 – 2.61 (m, 2H), 2.42 – 2.30 (m, 6H). Step 2: dimethyl 4-[2-(dimethylamino)ethylcarbamoyl]pyridine-2,6-dicarboxylate To a solution of 2,6-dichloro-N-[2-(dimethylamino)ethyl]pyridine-4-carboxamide (6.6 g, 25.18 mmol, 1.0 eq) in MeOH (70 mL) were added TEA (7.64 g, 75.53 mmol, 10.51 mL, 3.0 eq) and Pd(dppf)Cl2 (1.84 g, 2.52 mmol, 0.1 eq) under N2. The suspension was degassed under vacuum and purged with CO 3 times. The mixture was stirred under CO (50 psi) at 80 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0~5.3% MeOH / DCM gradient @ 60 mL / min) to give compound dimethyl 4-[2- (dimethylamino)ethylcarbamoyl]pyridine-2,6-dicarboxylate (7 g, 22.63 mmol, 89.9% yield) as brown solid. 1H NMR (400 MHz, DMSO-d6) δ = 9.56 (s, 1H), 8.69 (s, 2H), 3.95 (s, 6H), 3.70 – 3.67 (m, 2H), 3.28 – 3.26 (m, 2H), 2.81 – 2.78 (m, 6H). Step 3: tert-butyl N-[3-[[6-[3-(tert-butoxycarbonylamino)propylcarbamoyl]-4-[2- (dimethylamino)ethylcarbamoyl]pyridine-2-carbonyl]amino]propyl]carbamate To a solution of dimethyl 4-[2-(dimethylamino)ethylcarbamoyl]pyridine-2,6- dicarboxylate (1 g, 3.23 mmol, 1.0 eq) in MeOH (10 mL) was added tert-butyl N-(3- aminopropyl)carbamate (1.69 g, 9.70 mmol, 1.69 mL, 3.0 eq). The mixture was stirred at 50 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~5.3% MeOH / DCM gradient @ 60 mL / min) to give compound tert-butyl N- [3-[[6-[3-(tert-butoxycarbonylamino)propylcarbamoyl]-4-[2- (dimethylamino)ethylcarbamoyl]pyridine-2-carbonyl]amino]propyl]carbamate (1.9 g, 2.72 mmol, 84.1% yield, 85% purity) as brown solid. Step 4: N2, N6-bis(3-aminopropyl)-N4-[2-(dimethylamino)ethyl]pyridine-2,4,6- tricarboxamide To a solution of tert-butyl N-[3-[[6-[3-(tert-butoxycarbonylamino)propylcarbamoyl]-4-[2- (dimethylamino)ethylcarbamoyl]pyridine-2-carbonyl]amino]propyl]carbamate (1.9 g, 3.20 mmol, 1.0 eq) in DCM (15 mL) was added HCl / dioxane (4 M, 15 mL). The mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give a crude product. The crude product was triturated with PE / EtOAc = 10 / 1 for 30 min to give compound N2,N6- bis(3-aminopropyl)-N4-[2-(dimethylamino)ethyl]pyridine-2,4,6-tricarboxamide (1.3 g, 2.79 mmol, 87.1% yield, 2HCl) as gray solid. Step 5: tetra(octan-3-yl) 9,9',9'',9'''-((((4-((2-(dimethylamino)ethyl)carbamoyl)pyridine-2,6- dicarbonyl)bis(azanediyl))bis(propane-3,1-diyl))bis(azanetriyl))tetranonanoate: SM-090 To a solution of N2,N6-bis(3-aminopropyl)-N4-[2-(dimethylamino)ethyl]pyridine-2,4,6- tricarboxamide (409.94 mg, 878.94 μmol, 1.0 eq, 2HCl) and NaOAc (432.62 mg, 5.27 mmol, 6.0 eq) in MeOH (20 mL) was added NaBH3CN (331.41 mg, 5.27 mmol, 6.0 eq). After addition, the mixture was stirred at 25 °C for 0.5 h, and then 1-ethylhexyl 9-oxononanoate (1.5 g, 5.27 mmol, 6.0 eq) was added to the mixture. The mixture was stirred at 25 °C for 11.5 h. The reaction mixture was diluted with water (30 mL) and extracted with DCM (60 mL * 2). The combined organic layers were washed with water, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, DCM / MeOH = 40 / 1 to 20 / 1) and by prep-TLC (SiO2, DCM / MeOH = 10 / 1) and purified by prep- HPLC (column: Welch Xtimate C1100 * 30 mm * 5um; mobile phase: [A / B water (FA)-MeOH]; gradient: 63%-93% B over 8 min) to give compound tetra(octan-3-yl) 9,9',9'',9'''-((((4-((2- (dimethylamino)ethyl)carbamoyl)pyridine-2,6-dicarbonyl)bis(azanediyl))bis(propane-3,1- diyl))bis(azanetriyl))tetranonanoate (265.37 mg, 179.55 μmol, 20.43% yield, 99.27% purity) as colorless gum. LCMS: [M+H]+:1468.2 1H NMR (400 MHz, CDCl3) δ = 9.75 (s, 2H), 8.67 (s, 1H), 8.65 (s, 2H), 4.85 – 4.75 (m, 4H), 3.76 – 3.50 (m, 8H), 2.94 – 2.90 (m, 4H), 2.78 – 2.72 (m, 6H), 2.55 – 2.50 (m, 2H), 2.37 – 2.19 (m, 14H), 2.13 – 1.96 (m, 4H), 1.66 – 1.43 (m, 32H), 1.32 – 1.25 (m, 56H), 0.93 – 0.81 (m, 24H). Example 8: Synthesis of SM-091 Step 1: 2,6-dichloro-N-[4-(dimethylamino)butyl]pyridine-4-carboxamide To a solution of 2,6-dichloropyridine-4-carboxylic acid (10 g, 52.08 mmol, 1.0 eq) in DCM (100 mL) was added SOCl2(12.39 g, 104.17 mmol, 7.57 mL, 2.0 eq) at 0 °C. The mixture was stirred at 40 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give compound 2,6-dichloropyridine-4-carbonyl chloride (10.9 g, 51.79 mmol, 99.5% yield) as brown oil. To a solution of N',N'-dimethylbutane-1,4-diamine (7.22 g, 62.15 mmol, 1.2 eq) and TEA (15.72 g, 155.38 mmol, 21.63 mL, 3.0 eq) in DCM (100 mL) was added 2,6-dichloropyridine-4- carbonyl chloride (10.9 g, 51.79 mmol, 1.0 eq) at 0 °C. The mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, DCM / MeOH = 1 / 0 to 20 / 1) to give compound 2,6- dichloro-N-[4-(dimethylamino)butyl]pyridine-4-carboxamide (12.2 g, 42.04 mmol, 81.2% yield) as yellow solid. 1H NMR (400 MHz, DMSO-d6) δ = 9.26 - 9.21 (m, 1H), 7.97 (s, 2H), 3.31 - 3.25 (m, 2H), 3.03 - 2.96 (m, 2H), 2.67 (s, 6H), 1.75 - 1.50 (m, 4H). Step 2: dimethyl 4-[4-(dimethylamino)butylcarbamoyl]pyridine-2,6-dicarboxylate To a solution of 2,6-dichloro-N-[4-(dimethylamino)butyl]pyridine-4-carboxamide (12.2 g, 42.04 mmol, 1.0 eq) in MeOH (150 mL) were added TEA (12.76 g, 126.13 mmol, 17.55 mL, 3.0 eq) and Pd(dppf)Cl2 (3.08 g, 4.20 mmol, 0.1 eq) under N2. The suspension was degassed under vacuum and purged with CO three times. The mixture was stirred under CO (50 psi) at 80 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, DCM / MeOH = 40 / 1 to 10 / 1) and triturated with EtOAc for 1 h to give compound dimethyl 4-[4-(dimethylamino)butylcarbamoyl]pyridine-2,6- dicarboxylate (9.4 g, 27.86 mmol, 66.8% yield) as gray solid. 1H NMR (400 MHz, DMSO-d6) δ = 9.34 (s, 1H), 8.66 (s, 2H), 3.95 (s, 6H), 3.35 - 3.30 (m, 2H), 3.07 -3.00 (m, 2H), 2.70 (s, 6H), 1.75 - 1.54 (m, 4H). Step 3: tert-butyl N-[3-[[6-[3-(tert-butoxycarbonylamino)propylcarbamoyl]-4-[4- (dimethylamino)butylcarbamoyl]pyridine-2-carbonyl]amino]propyl]carbamate To a solution of dimethyl 4-[4-(dimethylamino)butylcarbamoyl]pyridine-2,6- dicarboxylate (2 g, 5.93 mmol, 1.0 eq) in MeOH (30 mL) was added tert-butyl N-(3- aminopropyl)carbamate (5.16 g, 29.64 mmol, 5.18 mL, 5.0 eq). The mixture was stirred at 50 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~5.3% MeOH / DCM gradient @ 60 mL / min) to give compound tert-butyl N- [3-[[6-[3-(tert-butoxycarbonylamino)propylcarbamoyl]-4-[4- (dimethylamino)butylcarbamoyl]pyridine-2-carbonyl]amino]propyl]carbamate (3.6 g, 5.56 mmol, 93.8% yield, 96% purity) as brown gum. Step 4: N2,N6-bis(3-aminopropyl)-N4-[4-(dimethylamino)butyl]pyridine-2,4,6- tricarboxamide To a solution of tert-butyl N-[3-[[6-[3-(tert-butoxycarbonylamino)propylcarbamoyl]-4-[4- (dimethylamino)butylcarbamoyl]pyridine-2-carbonyl]amino]propyl]carbamate (2 g, 3.22 mmol, 1.0 eq) in DCM (20 mL) was added HCl / dioxane (4 M, 20 mL). The mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give a crude product. The crude product was triturated with PE / EtOAc = 10 / 1 for 30 min to give compound N2,N6- bis(3-aminopropyl)-N4-[4-(dimethylamino)butyl]pyridine-2,4,6-tricarboxamide (1.5 g, 3.03 mmol, 94.3% yield, HCl salt) as gray solid. Step 5: tetra(octan-3-yl) 9,9',9'',9'''-((((4-((4-(dimethylamino)butyl)carbamoyl)pyridine-2,6- dicarbonyl)bis(azanediyl))bis(propane-3,1-diyl))bis(azanetriyl))tetranonanoate: SM-091 To a solution of N2,N6-bis(3-aminopropyl)-N4-[4-(dimethylamino)butyl]pyridine-2,4,6- tricarboxamide (434.60 mg, 878.94 μmol, 1.0 eq, 2HCl) and NaOAc (576.82 mg, 7.03 mmol, 8 eq) in MeOH (15 mL) was added NaBH3CN (441.88 mg, 7.03 mmol, 8.0 eq). After addition, the mixture was stirred at 25 °C for 0.5 h, and then 1-ethylhexyl 9-oxononanoate (2 g, 7.03 mmol, 8.0 eq) was added into the mixture. The mixture was stirred at 25 °C for 11.5 h. The reaction mixture was diluted with water (30 mL) and extracted with DCM (60 mL * 2). The combined organic layers were washed with water, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, DCM / MeOH = 40 / 1 to 20 / 1) and purified by prep-HPLC (column: Welch Xtimate C1100 * 30 mm * 5 um; mobile phase: [A / B water (FA)-MeOH]; gradient: 63%-93% B over 8 min) to give SM-091, aka. tetra(octan-3-yl) 9,9',9'',9'''-((((4-((4-(dimethylamino)butyl)carbamoyl)pyridine- 2,6-dicarbonyl)bis(azanediyl))bis(propane-3,1-diyl))bis(azanetriyl))tetranonanoate (312.02 mg, 205.42 μmol, 23.4% yield, 98.44% purity) as light yellow oil. LCMS: [M+H]+:1495.31H NMR (400 MHz, CDCl3) δ = 9.29 (s, 1H), 8.66 (s, 2H), 4.85 - 4.76 (m, 4H), 3.62 - 3.55 (m, 4H), 3.53 - 3.45 (m, 2H), 2.67 (s, 4H), 2.61 - 2.42 (m, 8H), 2.35 - 2.33 (m, 2H), 2.31 - 2.24 (m, 14H), 1.89 (s, 4H), 1.80 - 1.71 (m, 2H), 1.69 (s, 2H), 1.64 - 1.43 (m, 32H), 1.31 - 1.25 (m, 56H), 0.97 - 0.81 (m, 24H). Example 9: Synthesis of SM-092

[0063] Step 1: dimethyl 5-chlorocarbonylbenzene-1,3-dicarboxylate (2) To a solution of 3,5-bis(methoxycarbonyl)benzoic acid (3 g, 12.59 mmol, 1.0 eq) in DCM (30 mL) was added SOCl2(4.50 g, 37.78 mmol, 2.74 mL, 3.0 eq) at 0 °C under N2. After addition, the reaction mixture was stirred at 40 °C for 3 h. The reaction mixture was directly concentrated under reduced pressure to give compound dimethyl 5-chlorocarbonylbenzene-1,3-dicarboxylate (3.2 g, crude) as a yellow solid. The crude product was used for next step without further purification. Step 2: dimethyl 5-[(1-methyl-4-piperidyl)methylcarbamoyl]benzene-1,3-dicarboxylate (3) To a solution of (1-methyl-4-piperidyl)methanamine (1.92 g, 14.96 mmol, 1.2 eq) and TEA (3.15 g, 31.17 mmol, 4.34 mL, 2.5 eq) in DCM (30 mL) was added dropwise dimethyl 5- chlorocarbonylbenzene-1,3-dicarboxylate (3.2 g, 12.47 mmol, 1.0 eq) in DCM (20 mL) at 0 °C under N2. After addition, the resulting mixture was stirred at 20 °C for 3 h. The reaction mixture was directly concentrated under reduced pressure to give residue. The residue was triturated with (PE / EtOAc = 10 / 1, 50 mL * 3) at 20 °C for 0.5 h and filtered. The filter cake was dried to afford compound dimethyl 5-[(1-methyl-4-piperidyl)methylcarbamoyl]benzene-1,3-dicarboxylate (4.1 g, 11.77 mmol, 94.4% yield) as a yellow solid. Step 3: 5-[(1-methyl-4-piperidyl)methylcarbamoyl]benzene-1,3-dicarboxylic acid (4) To a solution of dimethyl 5-[(1-methyl-4-piperidyl)methylcarbamoyl]benzene-1,3- dicarboxylate (4.1 g, 11.77 mmol, 1.0 eq) in MeOH (60 mL) and H2O (15 mL) was added NaOH (1.41 g, 35.30 mmol, 3.0 eq). The mixture was stirred at 60 °C for 16 h. The reaction mixture was concentrated under reduced pressure to remove MeOH. The residue was diluted with H2O (30 mL) and extracted with EtOAc (30 mL * 3). The aqueous phase pH was adjusted to 2 with 4M HCl and concentrated under reduced pressure to give residue. The residue was triturated with (PE / EtOAc = 1 / 1, 50 mL * 3) at 20 °C for 0.5 h and filtered appropriately. The filter cake was dried to afford compound 5-[(1-methyl-4-piperidyl)methylcarbamoyl]benzene-1,3-dicarboxylic acid (2.9 g, 9.05 mmol, 76.9% yield) as a white solid. Step 4: SM-092, aka. tetra(octan-3-yl) 9,9',9'',9'''-((((5-(((1-methylpiperidin-4- yl)methyl)carbamoyl)isophthaloyl)bis(azanediyl))bis(propane-3,1- diyl))bis(azanetriyl))tetranonanoate To a solution of 5-[(1-methyl-4-piperidyl)methylcarbamoyl]benzene-1,3-dicarboxylic acid (400 mg, 1.25 mmol, 1.0 eq) and 1-ethylhexyl 9-[3-aminopropyl-[9-(1-ethylhexoxy)-9-oxo- nonyl]amino]nonanoate (2.02 g, 3.12 mmol, 2.5 eq, HCl) in pyridine (15 mL) was added EDCI (598.43 mg, 3.12 mmol, 2.5 eq). The mixture was stirred at 20 °C for 16 h. The reaction mixture was directly concentrated under reduced pressure and the residual pyridine was co-evaporated with DCM to give residue. The residue was diluted with water (50 mL) and extracted with DCM (35 mL * 3). The combined organic layers were washed with brine (40 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give residue. The residue was purified by flash silica gel chromatography (20 g SepaFlash® Silica Flash Column, DCM : MeOH : 0~10%) and prep-HPLC (column: Welch Xtimate C1100 * 30 mm * 5 um; mobile phase: [A / B water (FA)- MeOH]; gradient: 60%-90% of MeOH over 8 min) to give SM-092 (430 mg, 0.29 mmol, 25.1% yield, 99.11% purity) as light yellow oil. LCMS: [M+H]+: 1506.6 1H NMR (400 MHz, CDCl3) δ = 8.65 - 8.57 (m, 2H), 8.49 - 8.41 (m, 3H), 7.10 - 6.85 (m, 1H), 4.84 - 4.75 (m, 4H), 3.63 - 3.52 (m, 4H), 3.37 (t, J = 6.0 Hz, 2H), 2.87 (d, J = 11.2 Hz, 2H), 2.75 - 2.66 (m, 4H), 2.62 - 2.48 (m, 8H), 2.30 - 2.24 (m, 10H), 1.95 (t, J = 10.8 Hz, 2H), 1.89 - 1.72 (m, 6H), 1.64 - 1.46 (m, 32H), 1.35 - 1.20 (m, 60H), 0.90 - 0.83 (m, 24H). Example 10: Synthesis of SM-093

[0064] Step 1: 9-[3-(tert-butoxycarbonylamino)propyl-[9-(2-hexyloctanoyloxy)nonyl]amino]nonyl 2-hexyloctanoate To a solution of tert-butyl N-(3-aminopropyl)carbamate (1.5 g, 8.61 mmol, 1.50 mL, 1.0 eq) in MeOH (90 mL) were added HOAc (1.5 g, 25.8 mmol, 1.5 mL, 3.0 eq) and NaBH3CN (1.62 g, 25.83 mmol, 3.0 eq). The mixture was stirred at 20 °C for 0.5 h. After that, 9-oxononyl 2- hexyloctanoate (9.52 g, 25.83 mmol, 3.0 eq) [see Int_5 for preparation], was added to the mixture and stirred at 20 °C for 11.5 h. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with water (100 mL) and extracted with DCM (100 mL * 2). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 120g SepaFlash® Silica Flash Column, Eluent of 0~50% EtOAc / PE, gradient @ 100 mL / min) to get compound 9-[3-(tert-butoxycarbonylamino)propyl-[9-(2- hexyloctanoyloxy)nonyl]amino]nonyl 2-hexyloctanoate (6.9 g, 7.34 mmol, 85.2% yield, 93.5% purity) as a yellow gum. 1H NMR (400 MHz, CDCl3) δ = 5.11 (s, 1H), 4.06 (t, J = 6.4 Hz, 4H), 3.24 (q, J = 6.0 Hz, 2H), 3.13 - 3.01 (m, 2H), 3.01 - 2.83 (m, 4H), 2.38 - 2.22 (m, 2H), 2.06 - 1.91 (m, 2H), 1.82 - 1.52 (m, 12H), 1.49 - 1.39 (m, 13H), 1.39 - 1.17 (m, 52H), 0.88 (t, J = 6.8 Hz, 12H) Step 2: 9-[3-aminopropyl-[9-(2-hexyloctanoyloxy)nonyl]amino]nonyl 2-hexyloctanoate To a solution of 9-[3-(tert-butoxycarbonylamino)propyl-[9-(2- hexyloctanoyloxy)nonyl]amino]nonyl 2-hexyloctanoate (6.9 g, 7.85 mmol, 1.0 eq) in DCM (40 mL) was added HCl / dioxane (4 M, 10 mL, 5.1 eq). The mixture was stirred at 20 °C for 12 h. The reaction mixture was concentrated under reduced pressure to get compound 9-[3-aminopropyl-[9- (2-hexyloctanoyloxy)nonyl]amino]nonyl 2-hexyloctanoate (6.4 g, 7.77 mmol, 99.1% yield, 99.1% purity, HCl) as a light yellow gum. 1H NMR (400 MHz, CDCl3) δ = 4.06 (t, J = 6.8 Hz, 4H), 3.48 - 3.24 (m, 4H), 3.21 - 2.97 (m, 4H), 2.42 - 2.36 (s, 2H), 2.35 - 2.25 (m, 2H), 2.17 - 1.98 (m, 2H), 1.85 - 1.69 (m, 4H), 1.86 - 1.69 (m, 6H), 1.46 - 1.41 (m, 4H), 1.39 - 1.17 (m, 52H), 0.88 (t, J = 6.4 Hz, 12H). Step 3: 3,5-bis(methoxycarbonyl)benzoic acid To a solution of trimethyl benzene-1,3,5-tricarboxylate (27 g, 107.05 mmol, 1.0 eq) in MeOH (350 mL) was dropwise added a solution of NaOH (4.28 g, 107.05 mmol, 1.0 eq) in H2O (70 mL). The mixture was stirred at 60 °C for 2 h. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with DCM (300 mL) and extracted with saturation solution NaHCO3 (300 mL). The aqueous phase was acidified to pH=1 with 5% hydrochloric acid and extracted with EtOAc (3 × 300 mL). The combined organic layers were dried over MgSO4, and concentrated under vacuum to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 330 g SepaFlash® Silica Flash Column, Eluent of 0~50% EtOAc / PE gradient @ 100 mL / min) to get compound 3,5-bis(methoxycarbonyl)benzoic acid (8 g, 33.59 mmol, 15.7% yield) as a white solid. 1H NMR (400 MHz, CD3OD-d4) δ = 8.73 - 8.68 (m, 2H), 8.66 - 8.62 (m, 1H), 3.96 (s, 6H). Step 4: dimethyl 5-[3-(dimethylamino)propylcarbamoyl]benzene-1,3-dicarboxylate To a solution of 3,5-bis(methoxycarbonyl)benzoic acid (6.9 g, 28.97 mmol, 1.0 eq) and N',N'-dimethylpropane-1,3-diamine (5.92 g, 57.94 mmol, 7.25 mL, 2.0 eq) in DCM (100 mL) were added EDCI (8.33 g, 43.45 mmol, 1.5 eq) and HOBt (5.87 g, 43.45 mmol, 1.5 eq). The mixture was stirred at 20 °C for 12 h. The reaction mixture was diluted with water (100mL) and extracted with DCM (100mL * 2). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0~10% MeOH / DCM gradient @ 100 mL / min) to get compound dimethyl 5-[3- (dimethylamino)propylcarbamoyl]benzene-1,3-dicarboxylate (6.1 g, 18.54 mmol, 64.0% yield, 98% purity) as a white solid. 1H NMR (400 MHz, CD3OD-d4) δ = 8.68 (d, J = 1.6 Hz, 1H), 8.64 (d, J = 1.6 Hz, 2H), 3.97 (s, 6H), 3.45 (t, J = 7.2 Hz, 2H), 2.53 - 2.40 (m, 2H), 2.29 (s, 6H), 1.90 - 175 (m, 2H). Step 5: 5-[3-(dimethylamino)propylcarbamoyl]benzene-1,3-dicarboxylic acid To a solution of dimethyl 5-[3-(dimethylamino)propylcarbamoyl]benzene-1,3- dicarboxylate (6.1 g, 18.92 mmol, 1.0 eq) in MeOH (100 mL) were added NaOH (1.67 g, 41.63 mmol, 2.2 eq) and H2O (20 mL). The mixture was stirred at 60 °C for 12 h. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with DCM (300 mL) and extracted with saturation solution NaHCO3(300 mL). The aqueous phase was acidified to pH=1 with 5% hydrochloric acid and extracted with EtOAc (3 * 300 mL). The combined organic layers were dried over Mg2SO4, and concentrated under vacuum to give compound 5-[3-(dimethylamino)propylcarbamoyl]benzene-1,3-dicarboxylic acid (5 g, 15.12 mmol, 79.9% yield, HCl) as a white solid. 1H NMR (400 MHz, CD3OD-d4) δ = 8.73 (s, 1H), 8.50 (s, 2H), 3.52 (t, J = 6.4 Hz, 2H), 3.15 (t, J = 7.6 Hz, 2H), 2.84 (s, 6H), 2.16 - 2.00 (m, 2H). Step 6: SM-093, aka. ((((5-((3- (dimethylamino)propyl)carbamoyl)isophthaloyl)bis(azanediyl))bis(propane-3,1- diyl))bis(azanetriyl))tetrakis(nonane-9,1-diyl) tetrakis(2-hexyloctanoate) To a solution of 5-[3-(dimethylamino)propylcarbamoyl]benzene-1,3-dicarboxylic acid (400 mg, 1.36 mmol, 1.0 eq) and 9-[3-aminopropyl-[9-(2-hexyloctanoyloxy)nonyl]amino]nonyl 2-hexyloctanoate (2.77 g, 3.40 mmol, 2.5 eq, HCl) in pyridine (30 mL) was added EDCI (651.38 mg, 3.40 mmol, 2.5 eq). The mixture was stirred at 20 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~10% MeOH / DCM gradient @ 80 mL / min) and prep-HPLC (column: Welch Xtimate C1100 * 30mm * 5 um; mobile phase: [A / B water (FA)-MeOH]; gradient:70%-100% B over 8 min) to give SM-093, ((((5-((3- (dimethylamino)propyl)carbamoyl)isophthaloyl)bis(azanediyl))bis(propane-3,1- diyl))bis(azanetriyl))tetrakis(nonane-9,1-diyl) tetrakis(2-hexyloctanoate) (824.97 mg, 452.65 μmol, 41.1% yield, 99.69% purity) as a light yellow oil. LCMS: [M+H]+: 1817.5 1H NMR (400 MHz, CDCl3) δ = 9.28 (s, 1H), 8.59 (s, 2H), 8.42 (s, 3H), 4.05 (t, J = 6.8 Hz, 8H), 3.67 - 3.51 (m, 6H), 2.75 - 2.6 (m, 4H), 2.60 - 2.47 (m, 10H), 2.39 (s, 6H), 2.34 - 2.27 (m, 4H), 1.85 - 1.72 (m, 6H), 1.63 - 1.54 (m, 16H), 1.50 - 1.36 (m, 16H), 1.33 - 1.18 (m, 104H), 0.87 (t, J = 6.8 Hz, 24H). Example 11: Synthesis of SM-094 Step 1: dimethyl 5-chlorocarbonylbenzene-1,3-dicarboxylate To a solution of 3,5-bis(methoxycarbonyl)benzoic acid (2.5 g, 10.50 mmol, 1.0 eq) in DCM (20 mL) were added DMF (153.43 mg, 2.10 mmol, 161.51 μL, 0.2 eq), SOCl2 (1.50 g, 12.59 mmol, 914.78 μL, 1.2 eq) at 0 °C. Then the mixture was warmed to 20 °C and stirred at 40 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give compound dimethyl 5- chlorocarbonylbenzene-1,3-dicarboxylate (2.69 g, crude) as a yellow oil. Step 2: dimethyl 5-[2-(1-methyl-4-piperidyl)ethylcarbamoyl]benzene-1,3-dicarboxylate To a solution of 2-(1-methyl-4-piperidyl)ethanamine (1.49 g, 10.48 mmol, 1.2 eq) in DCM (30 mL) were added TEA (3.18 g, 31.44 mmol, 4.38 mL, 3.0 eq) and dimethyl 5- chlorocarbonylbenzene-1,3-dicarboxylate (2.69 g, 10.48 mmol, 1.0 eq) at 0 °C. The mixture was stirred at 20 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue. The crude product was triturated with EtOAc (10 mL) at 20 °C for 20 min to get compound dimethyl 5-[2-(1-methyl-4-piperidyl)ethylcarbamoyl]benzene-1,3-dicarboxylate (3.8 g, 9.96 mmol, 95.1% yield, 95.0% purity) as a brown solid. 1H NMR (400 MHz, CD3OD-d4) δ = 8.73 - 8.70 (m, 1H), 8.69 - 8.65 (m, 2H), 3.98 (s, 6H), 3.54 - 3.44 (m, 4H), 3.09 - 2.94 (m, 2H), 2.84 (s, 3H), 2.15 - 2.03 (m, 2H), 1.77 - 1.69 (m, 1H), 1.69 - 1.63 (m, 2H), 1.61 - 1.47 (m, 2H). Step 3: 5-[2-(1-methyl-4-piperidyl)ethylcarbamoyl]benzene-1,3-dicarboxylic acid To a solution of dimethyl 5-[2-(1-methyl-4-piperidyl)ethylcarbamoyl]benzene-1,3- dicarboxylate (3.8 g, 10.49 mmol, 1.0 eq) in MeOH (35 mL) was dropwise added a solution of NaOH (922.69 mg, 23.07 mmol, 2.2 eq) in H2O (7.0 mL). The mixture was stirred at 60 °C for 2 h. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with DCM (300 mL) and extracted with saturation solution NaHCO3 (300 mL). The aqueous phase was acidified to pH=1 with 5% hydrochloric acid and extracted with EtOAc (3 × 300 mL). The combined organic layers were dried over Na2SO4, and concentrated under vacuum to give a residue. The crude product was triturated with EtOAc (10 mL) at 20 °C for 0.5 h to get compound 5-[2-(1-methyl-4-piperidyl)ethylcarbamoyl]benzene-1,3-dicarboxylic acid (1.5 g, 4.44 mmol, 42.4% yield, 99.0% purity) as an off-white solid.1H NMR (400 MHz, CD3OD-d4) δ = 8.76 (s, 1H), 8.67 (s, 2H), 3.56 - 3.45 (m, 4H), 2.99 (t, J = 12.0 Hz, 2H), 2.85 (s, 3H), 2.10 (d, J = 14.4 Hz, 2H), 1.77 - 1.69 (m, 1H), 1.69 - 1.61 (m, 2H), 1.58 - 1.42 (m, 2H). Step 4: SM-094, aka. tetra(octan-3-yl) 9,9',9'',9'''-((((5-((2-(1-methylpiperidin-4- yl)ethyl)carbamoyl)isophthaloyl)bis(azanediyl))bis(propane-3,1- diyl))bis(azanetriyl))tetranonanoate To a solution of 5-[2-(1-methyl-4-piperidyl)ethylcarbamoyl]benzene-1,3-dicarboxylic acid (400 mg, 1.20 mmol, 1.0 eq) and 1-ethylhexyl 9-[3-aminopropyl-[9-(1-ethylhexoxy)-9-oxo- nonyl]amino]nonanoate (2.05 g, 2.99 mmol, 2.5 eq, 2HCl) in pyridine (30 mL) was added EDCI (573.33 mg, 2.99 mmol, 2.5 eq). The mixture was stirred at 20 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~20% MeOH / DCM gradient @ 80 mL / min) and prep-HPLC (column: Welch Xtimate C1100 * 30mm * 5um; mobile phase: [A / B water(FA) - MeOH]; gradient:63%-93% B over 8 min) to get compound SM-094, tetra(octan-3-yl) 9,9',9'',9'''-((((5-((2-(1-methylpiperidin-4- yl)ethyl)carbamoyl)isophthaloyl)bis(azanediyl))bis(propane-3,1- diyl))bis(azanetriyl))tetranonanoate (537.1 mg, 352.41 μmol, 38.3% yield, 99.76% purity) as a light yellow oil. LCMS: [M+H]+: 1520.0 1H NMR (400 MHz, CDCl3) δ = 8.64 (s, 1H), 8.60 - 8.35 (m, 5H), 4.90 -4.65 (m, 4H), 3.63 - 3.54 (m, 4H), 3.54 - 3.48 (m, 2H), 2.95 - 2.86 (m, 2H), 2.83 - 2.70 (m, 4H), 2.68 - 2.50 (m, 8H), 2.34 - 2.21 (m, 11H), 2.05 - 1.94 (m, 2H), 1.93 - 1.81 (m, 4H), 1.81 - 1.74 (m, 2H), 1.65 - 1.43 (m, 35H), 1.38 - 1.34 (m, 2H), 1.34 - 1.2 (m, 56H), 0.92 - 0.80 (m, 24H). Example 12: Synthesis of SM-095

[0065]

[0066] Step 1: dimethyl 5-chlorocarbonylbenzene-1,3-dicarboxylate (2) To a solution of 3,5-bis(methoxycarbonyl)benzoic acid (2.5 g, 10.50 mmol, 1.0 eq) in DCM (20 mL) were added DMF (76.72 mg, 1.05 mmol, 80.75 μL, 0.1 eq), SOCl2(1.50 g, 12.59 mmol, 914.78 μL, 1.2 eq) at 0 °C. Then the mixture was warmed to 20 °C and stirred at 40 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give compound dimethyl 5- chlorocarbonylbenzene-1,3-dicarboxylate (2.69 g, crude) as a yellow oil. Step 2: dimethyl 5-[(1-methyl-4-piperidyl)carbamoyl]benzene-1,3-dicarboxylate To a solution of 1-methylpiperidin-4-amine (1.32 g, 11.53 mmol, 1.1 eq) in DCM (30 mL) were added TEA (3.18 g, 31.44 mmol, 4.38 mL, 3.0 eq) and dimethyl 5-chlorocarbonylbenzene- 1,3-dicarboxylate (2.69 g, 10.48 mmol, 1.0 eq) at 0 °C. The mixture was stirred at 20 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue. The crude product was triturated with EtOAc (10 mL) at 20 °C for 20 min to get compound dimethyl 5-[(1-methyl- 4-piperidyl)carbamoyl]benzene-1,3-dicarboxylate (3.5 g, 9.45 mmol, 90.2% yield, 90.3% purity) as an orange solid. 1H NMR (400 MHz, CDCl3) δ = 8.75 (s, 1H), 8.60 (d, J = 1.6 Hz, 2H), 4.16 - 4.01 (m, 1H), 3.95 (s, 6H), 3.03 - 2.96 (m, 2H), 2.42 (s, 3H), 2.34 (t, J = 11.6 Hz, 2H), 2.09 (d, J = 10.8 Hz, 2H), 1.91 - 1.73 (m, 2H). Step 3: 5-[(1-methyl-4-piperidyl)carbamoyl]benzene-1,3-dicarboxylic acid To a solution of dimethyl 5-[(1-methyl-4-piperidyl)carbamoyl]benzene-1,3-dicarboxylate (3.5 g, 10.47 mmol, 1.0 eq) in MeOH (50 mL) was dropwise added a solution of NaOH (1.05 g, 26.17 mmol, 2.5 eq) in H2O (10 mL). The mixture was stirred at 60 °C for 2 h. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with DCM (300 mL) and extracted with saturation solution NaHCO3 (300 mL). The aqueous phase was acidified to pH=1 with 5% hydrochloric acid and concentrated under vacuum to give a residue. The crude product was triturated with PE / EtOAc = 3 / 1 (10 mL) at 20 °C for 30 min to get compound 5-[(1-methyl-4-piperidyl)carbamoyl]benzene-1,3-dicarboxylic acid (2.3 g, 7.31 mmol, 69.8% yield, 97.3% purity) as a white solid 1H NMR (400 MHz, CD3OD-d4) δ = 8.67 (t, J = 1.6 Hz, 1H), 8.39 (d, J = 1.6 Hz, 2H), 4.04 - 3.79 (m, 1H), 2.91 (d, J = 12.0 Hz, 2H), 2.30 (s, 3H), 2.18 (t, J = 11.2 Hz, 2H), 1.97 (d, J = 10.4 Hz, 2H), 1.80 - 1.61 (m, 2H). Step 4: SM-095, aka. tetra(octan-3-yl) 9,9',9'',9'''-((((5-((1-methylpiperidin-4- yl)carbamoyl)isophthaloyl)bis(azanediyl))bis(propane-3,1- diyl))bis(azanetriyl))tetranonanoate To a solution of 1-ethylhexyl 9-[3-aminopropyl-[9-(1-ethylhexoxy)-9-oxo- nonyl]amino]nonanoate (2.23 g, 3.26 mmol, 2.5 eq, 2HCl) in pyridine (30 mL) were added EDCI (625.84 mg, 3.26 mmol, 2.5 eq) and 5-[(1-methyl-4-piperidyl)carbamoyl]benzene-1,3- dicarboxylic acid (400 mg, 1.31 mmol, 1.0 eq). The mixture was stirred at 20 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® S...

Claims

We Claim: 1 ( oX is CH or N; a and b are independently 2-5; m1, m2, m3, and m4are independently 4-10; E1, E2, E3, and E4 are independently -O(CO)O-, -(CO)O- or -O(CO)-; T1, T2, T3, and T4 are independently branched or unbranched C5-C22 alkyl, C5-C22 alkenyl, or C5-C22alkynyl; R1and R2are independently H, C1-C6alkyl, C2-C6alkenyl, or C2-C6alkynyl; R3 is independently H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or; G is O, -(CO)NR3-, -NR3(CO)-, -(CO)O-, or -CH2(CO)NR3-; L is a bond or optionally substituted C1-C4alkyl; Z is CH or N, and R4 and R5 are independently H, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl,form an optionally substituted 3-7 membered ring comprising 0-2 heteroatoms, or R4 and R5 together with L form a substituted 3-7 membered ring.

2. The compound of Formula I of claim 1, or salt or isomer thereof, wherein one or more of R1and R2, a and b, m1-m4, E1-E4, and T1-T4are the same.

3. The compound of Formula I of claim 1, or salt or isomer thereof, wherein one or more of R1 and R2, a and b, m1-m4, E1-E4, and T1-T4 are different.

4. The compound of Formula I of claim 1, or salt or isomer thereof, wherein R1and R2, a and b, m1-m4, E1-E4, and T1-T4are all the same.

5. The compound of Formula I of claim 1, or salt or isomer thereof, wherein R1 and R2 are H.

6. The compound of Formula I of claim 1, or salt or isomer thereof, wherein a and b are independently 3, 4, or 5.

7. The compound of Formula I of claim 1, or salt or isomer thereof, wherein a and b are 3.

8. The compound of Formula I of claim 1, or salt or isomer thereof, wherein m1, m2, m3, and m4 are independently 6, 7, 8, or 9.

9. The compound of Formula I of claim 1, or salt or isomer thereof, wherein m1, m2, m3, and m4are 8.

10. The compound of Formula I of claim 1, or salt or isomer thereof, wherein E1, E2, E3, and E4are -(CO)O-.

11. The compound of Formula I of claim 1, or salt or isomer thereof, wherein E1, E2, E3, and E4 are -O(CO)- or -O(CO)O-.

12. The compound of Formula I of claim 1, or salt or isomer thereof, wherein T1, T2, T3, or T4 are independently selected from the group consisting of C5-C18alkyl, C5-C18alkenyl, and C5-C18alkynyl, each of which is optionally substituted, optionally wherein T1, T2, T3, and T4 are independently selected from the group consisting of C5-C18 alkyl, C5-C18 alkenyl, and C5-C18 alkynyl, each of which is optionally substituted.

13. The compound of Formula I of claim 1, or salt or isomer thereof, wherein T1, T2, T3, or T4are independently selected from the group consisting of C5-C12 alkyl, C5-C12 alkenyl, and C5-C12 alkynyl, each of which is optionally substituted, optionally wherein T1, T2, T3, and T4are independently selected from the group consisting of C5-C12alkyl, C5-C12alkenyl, and C5-C12alkynyl, each of which is optionally substituted.

14. The compound of Formula I of claim 1, or salt or isomer thereof, wherein T1, T2, T3, or T4are independently selected from the group consisting of C5-C10alkyl, C5-C10alkenyl, and C5-C10alkynyl, each of which is optionally substituted, optionally wherein T1, T2, T3, and T4 are independently selected from the group consisting of C5-C10 alkyl, C5-C10 alkenyl, and C5-C10 alkynyl, each of which is optionally substituted.

15. The compound of Formula I of claim 1, or salt or isomer thereof, wherein T1, T2, T3, or T4 are independently selected from the group consisting of C5-C8 alkyl, C5-C8 alkenyl, and C5-C8 alkynyl, each of which is optionally substituted, optionally wherein T1, T2, T3, and T4are independently selected from the group consisting of C5-C8 alkyl, C5-C8 alkenyl, and C5-C8 alkynyl, each of which is optionally substituted.

16. The compound of Formula I of claim 1, or salt or isomer thereof, wherein T1, T2, T3, or T4are independently selected from the group consisting of C6-C8alkyl, C6-C8alkenyl, and C6-C8alkynyl, each of which is optionally substituted, optionally wherein T1, T2, T3, and T4 are independently selected from the group consisting of C6-C8alkyl, C6-C8alkenyl, and C6-C8alkynyl, each of which is optionally substituted.

17. The compound of Formula I of claim 1, or salt or isomer thereof, wherein T1, T2, T3, or T4 are independently selected from the group consisting of C7 or C8 alkyl, C7 or C8 alkenyl, and C7 or C8alkynyl, each of which is optionally substituted, optionally wherein T1, T2, T3, and T4are independently selected from the group consisting of C7 or C8 alkyl, C7 or C8 alkenyl, and C7 or C8 alkynyl, each of which is optionally substituted.

18. The compound of Formula I of claim 1, or salt or isomer thereof, wherein G is O, - (CO)NR3-, and -NR3(CO)-.

19. The compound of Formula of claim 1, or salt or isomer thereof, wherein R3 is H or methyl.

20. The compound of Formula of claim 1, or salt or isomer thereof, wherein R3is.

21. The compound of Formula I of claim 1, or salt or isomer thereof, wherein L is a bond.

22. The compound of Formula I of claim 1, or salt or isomer thereof, wherein L is C1 alkyl.

23. The compound of Formula I of claim 1, or salt or isomer thereof, wherein L is C2alkyl.

24. The compound of Formula I of claim 1, or salt or isomer thereof, wherein L is C3alkyl.

25. The compound of Formula I of claim 1, or salt or isomer thereof, wherein L is C4 alkyl.

26. The compound of Formula I of claim 1, or salt or isomer thereof, wherein R4, R5, or R4 and R5are absent or H.

27. The compound of Formula I of claim 1, or salt or isomer thereof, wherein R4, R5, or R4 and28. The compound of Formula I of claim 1, or salt or isomer thereof, wherein R4and R5are independently C1, C2, or C3 alkyl.

29. The compound of Formula I of claim 1, or salt or isomer thereof, wherein R4 and R5 form an optionally substituted 6 membered ring comprising 1 or 2 heteroatoms.

30. The compound of Formula I of claim 29, or salt or isomer thereof, wherein at least one of the 1 or 2 heteroatoms is N.

31. The compound of Formula I of claim 29, or salt or isomer thereof, wherein a hydrogen of at least one atom of the 6 membered ring is substituted with a methyl group.

32. The compound of Formula I of claim 29, or salt or isomer thereof, wherein the at least one atom is a N atom.

33. The compound of Formula I of claim 29, or salt or isomer thereof, wherein the 6 membered ring includes 1, 2, or 3 double bonds, optionally wherein the 6 membered ring includes three double bonds.

34. The compound of Formula I of claim 1, or salt or isomer thereof, wherein R4and R5are methyl.

35. The compound of Formula of claim 1, or salt or isomer thereof, wherein R4 and R5 form an optionally substituted 5 membered ring comprising 1 or 2 heteroatoms and 1 or 2 double bonds.

36. The compound of Formula I of claim 35, or salt or isomer thereof, wherein at least one of the 1 or 2 heteroatoms is N.

37. The compound of Formula I of claim 1, or salt or isomer thereof, wherein T1, T2, T3, and T4 are independently an alkyl selected from the group consisting of butane, pentane, hexane, heptane, octane, nonane, decane, undecane, dodecane, and tridecane, each of which is optionally substituted.

38. The compound of Formula I of claim 1, or salt or isomer thereof, wherein T1, T2, T3, and T4 are octane or tridecane.

39. The compound of Formula I of claim 1, or salt or isomer thereof, wherein T1, T2, T3, and T4are independently an alkenyl selected from the group consisting of but-1-ene, but-2-ene, pent- 1-ene, pent-2-ene, hex-1-ene, hex-2-ene, hex3-ene, hept-1-ene, hept-2-ene, hept-3-ene, oct-1-ene, oct-2-ene, oct-3-ene, oct-4-ene, non-1-ene, non-2-ene, non-3-ene, non-4-ene, non-5-ene, dec-1- ene, dec-2-ene, dec-3-ene, dec-4-ene, dec-5-ene, dec-6-ene, undec-1-ene, undec-2-ene, undec-3- ene, undec-4-ene, undec-5-ene, undec-6-ene, undec-7-ene, dodec-1-ene, dodec-2-ene, dodec-3- ene, dodec-4-ene, dodec-5-ene, dodec-6-ene, dodec-8-ene, and an alkenyl group comprising two or more double bonds, each of which is optionally substituted.

40. The compound of Formula I of claim 1, or salt or isomer thereof, wherein T1, T2, T3, and T4 are independently an alkynyl selected from the group consisting of but-1-yne, but-2-yne, pent- 1-yne, pent-2-yne, hex-1-yne, hex-2-yne, hex3-yne, hept-1-yne, hept-2-yne, hept-3-yne, oct-1- yne, oct-2-yne, oct-3-yne, oct-4-yne, non-1-yne, non-2-yne, non-3-yne, non-4-yne, non-5-yne, dec-1-yne, dec-2-yne, dec-3-yne, dec-4-yne, dec-5-yne, dec-6-yne, undec-1-yne, undec-2-yne, undec-3-yne, undec-4-yne, undec-5-yne, undec-6-yne, undec-7-yne, dodec-1-yne, dodec-2-yne, dodec-3-yne, dodec-4-yne, dodec-5-yne, dodec-6-yne, dodec-8-yne, and an alkynyl group comprising two or more triple bonds, each of which is optionally substituted.

41. The compound of Formula I of claim 1, or salt or isomer thereof, wherein X is N.

42. A compound selected from the group consisting of:( ( ( (( (( ( ( (( (( ( ( (( ( ( (( ( ((SM-155),( ( ( (43. A pharmaceutical composition comprising a lipid of Formula I:(or a salt or isomer thereof, where X is CH or N; a and b are independently 2-5; m1, m2, m3, and m4are independently 4-10;E1, E2, E3, and E4 are independently -O(CO)O-, -(CO)O- or -O(CO)-; T1, T2, T3, and T4 are independently branched or unbranched C5-C22 alkyl, C5-C22 alkenyl, or C5-C22alkynyl; R1 and R2 are independently H or C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; R3 is independently H or C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl orG is O, -(CO)NR3-, -NR3(CO)-, -(CO)O-, or -CH2(CO)NR3-; L is a bond or optionally substituted C1-C4alkyl; Z is CH or N, and R4 and R5 are independently H, C1-C3 alkyl, C2-C3 alkenyl, or C2-C3 alkynyl, orform an optionally substituted 3-7 membered ring comprising 0-2 heteroatoms, or R4 and R5 together with L form a substituted 3-7 membered ring.

44. The pharmaceutical composition of claim 43, including Formula I or salt or isomer thereof, wherein one or more of R1and R2, a and b, m1-m4, E1-E4, and T1-T4are the same.

45. The pharmaceutical composition of claim 43, including Formula I or salt or isomer thereof, wherein one or more of R1 and R2, a and b, m1-m4, E1-E4, and T1-T4 are different.

46. The pharmaceutical composition of claim 43, including Formula I or salt or isomer thereof, wherein R1 and R2, a and b, m1-m4, E1-E4, and T1-T4 are all the same.

47. The pharmaceutical composition of claim 43, including Formula I or salt or isomer thereof, wherein R1and R2are H.

48. The pharmaceutical composition of claim 43, including Formula I or salt or isomer thereof, wherein a and b are independently 3, 4, or 5.

49. The pharmaceutical composition of claim 43, including Formula I or salt or isomer thereof, wherein a and b are 3.

50. The pharmaceutical composition of claim 43, including Formula I or salt or isomer thereof, wherein m1, m2, m3, and m4 are independently 6, 7, 8, or 9.

51. The pharmaceutical composition of claim 43, including Formula I or salt or isomer thereof, wherein m1, m2, m3, and m4are 8.

52. The pharmaceutical composition of claim 43, including Formula I or salt or isomer thereof, wherein E1, E2, E3, and E4 are -(CO)O-.

53. The pharmaceutical composition of claim 43, including Formula I or salt or isomer thereof, wherein E1, E2, E3, and E4are -O(CO)- or -O(CO)O-.

54. The pharmaceutical composition of claim 43, including Formula I or salt or isomer thereof, wherein T1, T2, T3, or T4 are independently selected from the group consisting of C5-C18 alkyl, C5- C18alkenyl, and C5-C18alkynyl, each of which is optionally substituted, optionally wherein T1, T2, T3, and T4 are independently selected from the group consisting of C5-C18 alkyl, C5-C18 alkenyl, and C5-C18 alkynyl, each of which is optionally substituted.

55. The pharmaceutical composition of claim 43, including Formula I or salt or isomer thereof, wherein T1, T2, T3, or T4are independently selected from the group consisting of C5-C12alkyl, C5- C12 alkenyl, and C5-C12 alkynyl, each of which is optionally substituted, optionally wherein T1, T2, T3, and T4are independently selected from the group consisting of C5-C12alkyl, C5-C12alkenyl, and C5-C12alkynyl, each of which is optionally substituted.

56. The pharmaceutical composition of claim 43, including Formula I or salt or isomer thereof, wherein T1, T2, T3, or T4are independently selected from the group consisting of C5-C10alkyl, C5- C10alkenyl, and C5-C10alkynyl, each of which is optionally substituted, optionally wherein T1, T2, T3, and T4 are independently selected from the group consisting of C5-C10 alkyl, C5-C10 alkenyl, and C5-C10 alkynyl, each of which is optionally substituted.

57. The pharmaceutical composition of claim 43, including Formula I or salt or isomer thereof, wherein T1, T2, T3, or T4 are independently selected from the group consisting of C5-C8 alkyl, C5-C8 alkenyl, and C5-C8 alkynyl, each of which is optionally substituted, optionally wherein T1, T2, T3, and T4 are independently selected from the group consisting of C5-C8 alkyl, C5-C8 alkenyl, and C5-C8alkynyl, each of which is optionally substituted.

58. The pharmaceutical composition of claim 43, including Formula I or salt or isomer thereof, wherein T1, T2, T3, or T4 are independently selected from the group consisting of C6-C8 alkyl, C6- C8alkenyl, and C6-C8alkynyl, each of which is optionally substituted, optionally wherein T1, T2, T3, and T4are independently selected from the group consisting of C6-C8alkyl, C6-C8alkenyl, and C6-C8 alkynyl, each of which is optionally substituted.

59. The pharmaceutical composition of claim 43, including Formula I or salt or isomer thereof, wherein T1, T2, T3, or T4are independently selected from the group consisting of C7or C8alkyl, C7 or C8 alkenyl, and C7 or C8 alkynyl, each of which is optionally substituted, optionally wherein T1, T2, T3, and T4 are independently selected from the group consisting of C7 or C8 alkyl, C7 or C8 alkenyl, and C7or C8alkynyl, each of which is optionally substituted.

60. The pharmaceutical composition of claim 43, including Formula I or salt or isomer thereof, wherein G is O, -(CO)NR3-, and -NR3(CO)-.

61. The pharmaceutical composition of claim 43, including Formula I or salt or isomer thereof, wherein R3is H or methyl.

62. The pharmaceutical composition of claim 43, including Formula I or salt or isomer thereof, wherein63. The pharmaceutical composition of claim 43, including Formula I or salt or isomer thereof, wherein L is a bond.

64. The pharmaceutical composition of claim 43, including Formula I or salt or isomer thereof, wherein L is C1alkyl.

65. The pharmaceutical composition of claim 43, including Formula I or salt or isomer thereof, wherein L is C2 alkyl.

22. The compound of Formula I of claim 1, or salt or isomer thereof, wherein L is C3alkyl.

66. The pharmaceutical composition of claim 43, including Formula I or salt or isomer thereof, wherein L is C4 alkyl.

67. The pharmaceutical composition of claim 43, including Formula I or salt or isomer thereof, wherein R4, R5, or R4and R5are absent or H.

68. The pharmaceutical composition of claim 43, including Formula I or salt or isomer thereof,.

69. The pharmaceutical composition of claim 43, including Formula I or salt or isomer thereof, wherein R4and R5are independently C1, C2, or C3alkyl.

70. The pharmaceutical composition of claim 43, including Formula I or salt or isomer thereof, wherein R4and R5form an optionally substituted 6 membered ring comprising 1 or 2 heteroatoms.

71. The pharmaceutical composition of claim 70, including Formula I or salt or isomer thereof, wherein at least one of the 1 or 2 heteroatoms is N.

72. The pharmaceutical composition of claim 70, including Formula I or salt or isomer thereof, wherein a hydrogen of at least one atom of the 6 membered ring is substituted with a methyl group.

73. The pharmaceutical composition of claim 72, including Formula I or salt or isomer thereof, wherein the at least one atom is a N atom.

74. The pharmaceutical composition of claim 70, including Formula I or salt or isomer thereof, wherein the 6 membered ring includes 1, 2, or 3 double bonds, optionally wherein the 6 membered ring includes three double bonds.

75. The pharmaceutical composition of claim 43, including Formula I or salt or isomer thereof, wherein R4and R5are methyl.

76. The pharmaceutical composition of claim 43, including Formula I or salt or isomer thereof, wherein R4and R5form an optionally substituted 5 membered ring comprising 1 or 2 heteroatoms and 1 or 2 double bonds.

77. The pharmaceutical composition of claim 76, including Formula I or salt or isomer thereof, wherein at least one of the 1 or 2 heteroatoms is N.

78. The pharmaceutical composition of claim 43, including Formula I or salt or isomer thereof, wherein T1, T2, T3, and T4 are independently an alkyl selected from the group consisting of butane, pentane, hexane, heptane, octane, nonane, decane, undecane, dodecane, and tridecane, each of which is optionally substituted.

79. The pharmaceutical composition of claim 43, including Formula I or salt or isomer thereof, wherein T1, T2, T3, and T4 are octane or tridecane.

80. The pharmaceutical composition of claim 43, including Formula I or salt or isomer thereof, wherein T1, T2, T3, and T4are independently an alkenyl selected from the group consisting of but- 1-ene, but-2-ene, pent-1-ene, pent-2-ene, hex-1-ene, hex-2-ene, hex3-ene, hept-1-ene, hept-2-ene, hept-3-ene, oct-1-ene, oct-2-ene, oct-3-ene, oct-4-ene, non-1-ene, non-2-ene, non-3-ene, non-4- ene, non-5-ene, dec-1-ene, dec-2-ene, dec-3-ene, dec-4-ene, dec-5-ene, dec-6-ene, undec-1-ene, undec-2-ene, undec-3-ene, undec-4-ene, undec-5-ene, undec-6-ene, undec-7-ene, dodec-1-ene, dodec-2-ene, dodec-3-ene, dodec-4-ene, dodec-5-ene, dodec-6-ene, dodec-8-ene, and an alkenyl group comprising two or more double bonds, each of which is optionally substituted.

81. The pharmaceutical composition of claim 43, including Formula I or salt or isomer thereof, wherein T1, T2, T3, and T4 are independently an alkynyl selected from the group consisting of but- 1-yne, but-2-yne, pent-1-yne, pent-2-yne, hex-1-yne, hex-2-yne, hex3-yne, hept-1-yne, hept-2- yne, hept-3-yne, oct-1-yne, oct-2-yne, oct-3-yne, oct-4-yne, non-1-yne, non-2-yne, non-3-yne, non-4-yne, non-5-yne, dec-1-yne, dec-2-yne, dec-3-yne, dec-4-yne, dec-5-yne, dec-6-yne, undec- 1-yne, undec-2-yne, undec-3-yne, undec-4-yne, undec-5-yne, undec-6-yne, undec-7-yne, dodec- 1-yne, dodec-2-yne, dodec-3-yne, dodec-4-yne, dodec-5-yne, dodec-6-yne, dodec-8-yne, and an alkynyl group comprising two or more triple bonds, each of which is optionally substituted.

82. The pharmaceutical composition of claim 43, including Formula I or salt or isomer thereof, wherein X is N.

83. A lipid particle comprising a compound of claims 1-82.

84. The lipid particle of claim 83, further comprising a therapeutic agent.

85. The lipid particle of claim 84, wherein the therapeutic agent is a nucleic acid.

86. A pharmaceutical composition comprising a lipid particle of claim 83 and a pharmaceutically acceptable excipient, carrier, or diluent.

87. A compound of Formula VII:(VII) or a salt or isomer thereof, wherein L6 is -O(CO)-, -CH2-O(CO)-, -CH2(CO)O-, or -O(CO)-NH-, n6 and n7 are independently 1, 2, 3, 4, 5, 6, 7, or 8, G5and G6are independently a bond; -(CO)O-; or -O(CO)-, and R11and R12are independently, optionally substituted, C5-C20alkyl or C5-C20alkenyl.

88. The compound of claim 87, or salt or isomer thereof, wherein R11 and R12 are the same.

89. The compound of claim 87, or salt or isomer thereof, wherein R11 and R12 are different.

90. The compound of claim 87, or salt or isomer thereof, wherein R11or R12are independently selected from the group consisting of optionally substituted C8-C20 alkyl and C8-C20 alkenyl, optionally wherein R11 and R12 are independently selected from the group consisting of optionally substituted C8-C20alkyl and C8-C20alkenyl.

91. The compound of claim 90, or salt or isomer thereof, wherein n6 and n7 are independently 4, 5, 6, 7, or 8.

92. The compound of claim 91, or salt or isomer thereof, wherein R11or R12include 1, 2, 3, 4, 5, 6, or more sites of unsaturation.

93. The compound of claim 87, or salt or isomer thereof, wherein R11 or R12 are independently selected from the group consisting of optionally substitutedC8-C17alkyl and C8-C17alkenyl, optionally wherein R11and R12are independently selected from the group consisting of optionally substitutedC8-C17 alkyl and C8-C17 alkenyl.

94. The compound of claim 93, or salt or isomer thereof, wherein n6and n7are independently 5, 6, or 7.

95. The compound of claim 94, or salt or isomer thereof, wherein R11 or R12 include 1, 2, 3, 4, 5, 6, or more sites of unsaturation.

96. The compound of claim 87, or salt or isomer thereof, wherein R11or R12are independently selected from the group consisting of optionally substitutedC10-C17 alkyl and C10-C17 alkenyl, optionally wherein R11 and R12 are independently selected from the group consisting of optionally substitutedC10-C17alkyl and C10-C17alkenyl.

97. The compound of claim 96, or salt or isomer thereof, wherein n6and n7are independently 5, 6, or 7.

98. The compound of claim 96, or salt or isomer thereof, wherein R11or R12include 1, 2, 3, 4, 5, 6, or more sites of unsaturation.

99. The compound of claim 87, or salt or isomer thereof, wherein R11 or R12 are independently selected from the group consisting of optionally substituted C12-C17alkyl and C12-C17alkenyl, optionally wherein R11and R12are independently selected from the group consisting of optionally substitutedC12-C17 alkyl and C12-C17 alkenyl.

100. The compound of claim 99, or salt or isomer thereof, wherein n6 and n7 are independently 5, 6, or 7.

101. The compound of claim 99, or salt or isomer thereof, wherein R11 or R12 include 1, 2, 3, 4, 5, 6, or more sites of unsaturation.

102. The compound of claim 87, or salt or isomer thereof, wherein R11is selected from the group consisting of optionally substituted C8-C17 alkyl and C8-C17 alkenyl, and R12 is selected from the group consisting of optionally substituted C8-C17 alkyl and C8-C17 alkenyl.

103. The compound of claim 102, or salt or isomer thereof, wherein n6and n7are 5.

104. The compound of claim 87, wherein G5and G6are the same.

105. The compound of claim 87, wherein G5 and G6 are different.

106. The compound of claim 102, or salt or isomer thereof, wherein G5is a bond and G6is - (CO)O-.

107. The compound of claim 87, or salt or isomer thereof, wherein R11 or R12 are independently selected from the group consisting of optionally substitutedC8, C12, C15, or C17 alkyl and C8, C12, C15, or C17alkenyl, optionally wherein R11and R12are independently selected from the group consisting of optionally substituted C8, C12, C15, or C17 alkyl and C8, C12, C15, or C17 alkenyl.

108. The compound of claim 87, or salt or isomer thereof, wherein R11 and R12 are independently an alkyl selected from the group consisting of octane, nonane, decane, undecane, and dodecane, each of which is optionally substituted.

109. The compound of claim 87, or salt or isomer thereof, wherein R11 and R12 are independently an alkyl selected from the group consisting of octane, nonane, decane, undecane, dodecane, tridecane, tetradecane, pentadecane, hexadecane, heptadecane, octadecane, nonadecane, and icosane.

110. The compound of claim 87, or salt or isomer thereof, wherein R11and R12are independently an alkenyl selected from the group consisting of oct-1-ene, oct-2-ene, oct-3-ene, oct-4-ene, non-1- ene, non-2-ene, non-3-ene, non-4-ene, non-5-ene, dec-1-ene, dec-2-ene, dec-3-ene, dec-4-ene, dec-5-ene, dec-6-ene, undec-1-ene, undec-2-ene, undec-3-ene, undec-4-ene, undec-5-ene, undec- 6-ene, undec-7-ene, dodec-1-ene, dodec-2-ene, dodec-3-ene, dodec-4-ene, dodec-5-ene, dodec-6-ene, tridec-1-ene, tridec-2-ene, tridec-3-ene, tridec-4-ene, tridec-5-ene, tridec-6-ene, tridec-7-ene, tetradec-1-ene, tetradec-2-ene, tetradec-3-ene, tetradec-4-ene, tetradec-5-ene, tetradec-6-ene, tetradec-7-ene, pentadec-1-ene, pentadec-2-ene, pentadec-3-ene, pentadec-4-ene, pentadec-5-ene, pentadec-6-ene, pentadec-7-ene, hexadec-1-ene, hexadec-2-ene, hexadec-3-ene, hexadec-4-ene, hexadec-5-ene, hexadec-6-ene, hexadec-7-ene, hexadec-8-ene, heptadec-1-ene, heptadec-2-ene, heptadec-3-ene, heptadec-4-ene, heptadec-5-ene, heptadec-6-ene, heptadec-7-ene, heptadec-8- ene, octadec-1-ene, octadec-2-ene, octadec-3-ene, octadec-4-ene, octadec-5-ene, octadec-6-ene, octadec-7-ene, octadec-8-ene, octadec-9-ene, nonadec-1-ene, nonadec-2-ene, nonadec-3-ene, nonadec-4-ene, nonadec-5-ene, nonadec-6-ene, nonadec-7-ene, nonadec-8-ene, nonadec-9-ene, icos-1-ene, icos-2-ene, icos-3-ene, icos-4-ene, icos-5-ene, icos-6-ene, icos-7-ene, icos-8-ene, and icos-9-ene.

111. The compound of claim 110, or salt or isomer thereof, wherein at least one of R11 and R12 comprises one or more additional double bonds.

112. A compound selected from the group consisting of: O O(9,9'-di(heptadecan-9-yl) O'1,O1-((((((piperazine-1,4-diylbis(2-oxoethane-2,1- diyl))bis(piperidine-1,4-diyl))bis(ethane-2,1-diyl))bis(oxy))bis(2-oxoethane-2,1-diyl))bis(4,1- phenylene)) di(nonanedioate), SM-048);O O((((((piperazine-1,4-diylbis(2-oxoethane-2,1-diyl))bis(piperidine-1,4-diyl))bis(ethane-2,1- diyl))bis(oxy))bis(2-oxoethane-2,1-diyl))bis(4,1-phenylene) dioleate, SM-074);(9,9'-bis(2-butyloctyl) O'1,O1-((((((piperazine-1,4-diylbis(2-oxoethane-2,1-diyl))bis(piperidine- 1,4-diyl))bis(ethane-2,1-diyl))bis(oxy))bis(2-oxoethane-2,1-diyl))bis(4,1-phenylene)) di(nonanedioate), SM-076);(1-(heptadecan-9-yl) 9-(4-(2-(2-(1-(2-(4-(2-(4-(2-(2-(4- (oleoyloxy)phenyl)acetoxy)ethyl)piperidin-1-yl)acetyl)piperazin-1-yl)-2-oxoethyl)piperidin-4- yl)ethoxy)-2-oxoethyl)phenyl) nonanedioate, SM-077); O O((((((piperazine-1,4-diylbis(2-oxoethane-2,1-diyl))bis(piperidine-1,4-diyl))bis(ethane-2,1- diyl))bis(oxy))bis(2-oxoethane-2,1-diyl))bis(4,1-phenylene) bis(9-((2- heptylnonanoyl)oxy)nonanoate), SM-079); O O(9,9'-bis(2-ethylhexyl) O'1,O1-((((((piperazine-1,4-diylbis(2-oxoethane-2,1-diyl))bis(piperidine- 1,4-diyl))bis(ethane-2,1-diyl))bis(oxy))bis(2-oxoethane-2,1-diyl))bis(4,1-phenylene)) di(nonanedioate), SM-083);O O(di(heptadecan-9-yl) 9,9'-(((((((((piperazine-1,4-diylbis(2-oxoethane-2,1-diyl))bis(piperidine-1,4- diyl))bis(ethane-2,1-diyl))bis(oxy))bis(2-oxoethane-2,1-diyl))bis(4,1- phenylene))bis(oxy))bis(carbonyl))bis(azanediyl))dinonanoate; SM-085); and O O(9,9'-di(heptadecan-9-yl) O'1,O1-(((((((piperazine-1,4-diylbis(2-oxoethane-2,1- diyl))bis(piperidine-1,4-diyl))bis(ethane-2,1-diyl))bis(oxy))bis(2-oxoethane-2,1-diyl))bis(4,1- phenylene))bis(methylene)) di(nonanedioate); SM-088),O O(7,7'-dinonyl O'1,O1-((((((piperazine-1,4-diylbis(2-oxoethane-2,1-diyl))bis(piperidine-1,4- diyl))bis(ethane-2,1-diyl))bis(oxy))bis(2-oxoethane-2,1-diyl))bis(4,1-phenylene)) di(heptanedioate); SM-100)((di(heptadecan-9-yl) 9,9'-((2,2'-((((((piperazine-1,4-diylbis(2-oxoethane-2,1- diyl))bis(piperidine-1,4-diyl))bis(ethane-2,1-diyl))bis(oxy))bis(2-oxoethane-2,1-diyl))bis(4,1- phenylene))bis(acetyl))bis(oxy))dinonanoate); SM-109)O O(di(heptadecan-9-yl) O,O'-((((((piperazine-1,4-diylbis(2-oxoethane-2,1-diyl))bis(piperidine-1,4- diyl))bis(ethane-2,1-diyl))bis(oxy))bis(2-oxoethane-2,1-diyl))bis(4,1-phenylene)) diglutarate); SM-113)(bis(9-(heptadecan-9-yloxy)-9-oxononyl) O,O'-(((piperazine-1,4-diylbis(2-oxoethane-2,1- diyl))bis(piperidine-1,4-diyl))bis(ethane-2,1-diyl)) diterephthalate); SM-125).and salts and isomers thereof.

113. A lipid particle comprising a compound of claims 87-112.

114. The lipid particle of claim 113, further comprising a therapeutic agent.

115. The lipid particle of claim 114, wherein the therapeutic agent is a nucleic acid.

116. A pharmaceutical composition comprising a lipid particle of claim 113 and a pharmaceutically acceptable excipient, carrier, or diluent.

117. A nucleic acid-lipid particle for delivering a nucleic acid cargo to a subject, the nucleic acid-lipid particle comprising a compound selected from the group consisting of: O O(9,9'-di(heptadecan-9-yl) O'1,O1-((((((piperazine-1,4-diylbis(2-oxoethane-2,1- diyl))bis(piperidine-1,4-diyl))bis(ethane-2,1-diyl))bis(oxy))bis(2-oxoethane-2,1-diyl))bis(4,1- phenylene)) di(nonanedioate), SM-048); O O((((((piperazine-1,4-diylbis(2-oxoethane-2,1-diyl))bis(piperidine-1,4-diyl))bis(ethane-2,1- diyl))bis(oxy))bis(2-oxoethane-2,1-diyl))bis(4,1-phenylene) dioleate, SM-074);O O(9,9'-bis(2-butyloctyl) O'1,O1-((((((piperazine-1,4-diylbis(2-oxoethane-2,1-diyl))bis(piperidine- 1,4-diyl))bis(ethane-2,1-diyl))bis(oxy))bis(2-oxoethane-2,1-diyl))bis(4,1-phenylene)) di(nonanedioate), SM-076);(1-(heptadecan-9-yl) 9-(4-(2-(2-(1-(2-(4-(2-(4-(2-(2-(4- (oleoyloxy)phenyl)acetoxy)ethyl)piperidin-1-yl)acetyl)piperazin-1-yl)-2-oxoethyl)piperidin-4- yl)ethoxy)-2-oxoethyl)phenyl) nonanedioate, SM-077); O O((((((piperazine-1,4-diylbis(2-oxoethane-2,1-diyl))bis(piperidine-1,4-diyl))bis(ethane-2,1- diyl))bis(oxy))bis(2-oxoethane-2,1-diyl))bis(4,1-phenylene) bis(9-((2- heptylnonanoyl)oxy)nonanoate), SM-079); O O(9,9'-bis(2-ethylhexyl) O'1,O1-((((((piperazine-1,4-diylbis(2-oxoethane-2,1-diyl))bis(piperidine- 1,4-diyl))bis(ethane-2,1-diyl))bis(oxy))bis(2-oxoethane-2,1-diyl))bis(4,1-phenylene)) di(nonanedioate), SM-083);(di(heptadecan-9-yl) 9,9'-(((((((((piperazine-1,4-diylbis(2-oxoethane-2,1-diyl))bis(piperidine-1,4- diyl))bis(ethane-2,1-diyl))bis(oxy))bis(2-oxoethane-2,1-diyl))bis(4,1- phenylene))bis(oxy))bis(carbonyl))bis(azanediyl))dinonanoate; SM-085);O O(9,9'-di(heptadecan-9-yl) O'1,O1-(((((((piperazine-1,4-diylbis(2-oxoethane-2,1- diyl))bis(piperidine-1,4-diyl))bis(ethane-2,1-diyl))bis(oxy))bis(2-oxoethane-2,1-diyl))bis(4,1- phenylene))bis(methylene)) di(nonanedioate); SM-088); O O(7,7'-dinonyl O'1,O1-((((((piperazine-1,4-diylbis(2-oxoethane-2,1-diyl))bis(piperidine-1,4- diyl))bis(ethane-2,1-diyl))bis(oxy))bis(2-oxoethane-2,1-diyl))bis(4,1-phenylene)) di(heptanedioate); SM-100);((di(heptadecan-9-yl) 9,9'-((2,2'-((((((piperazine-1,4-diylbis(2-oxoethane-2,1- diyl))bis(piperidine-1,4-diyl))bis(ethane-2,1-diyl))bis(oxy))bis(2-oxoethane-2,1-diyl))bis(4,1- phenylene))bis(acetyl))bis(oxy))dinonanoate); SM-109); O O(di(heptadecan-9-yl) O,O'-((((((piperazine-1,4-diylbis(2-oxoethane-2,1-diyl))bis(piperidine-1,4- diyl))bis(ethane-2,1-diyl))bis(oxy))bis(2-oxoethane-2,1-diyl))bis(4,1-phenylene)) diglutarate); SM-113); and(bis(9-(heptadecan-9-yloxy)-9-oxononyl) O,O'-(((piperazine-1,4-diylbis(2-oxoethane-2,1- diyl))bis(piperidine-1,4-diyl))bis(ethane-2,1-diyl)) diterephthalate); SM-125) further comprising about 30-70 mol % or about 40-60 mol % or about 50 mol % of the total lipid present in the nucleic acid-lipid particle, optionally comprising 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, or 55 mol % of the total lipid present in the nucleic acid-lipid particle.

118. The nucleic acid-lipid particle of claim 116, comprising a conjugated lipid that inhibits aggregation of particles comprising from 0.01 to 2% of the total lipid present, optionally wherein the conjugated lipid comprises a polyethyleneglycol (PEG)-lipid conjugate, optionally wherein the PEG of the PEG-lipid conjugate has an average molecular weight of from 550 Daltons to 5000 Daltons, optionally wherein the PEG-lipid conjugate is a PEG5000-lipid conjugate, optionally wherein the PEG-lipid conjugate is a PEG2000-lipid conjugate, optionally wherein the PEG2000- lipid conjugate comprises one or more of 1,2-dimyristoyl-rac-glycero-3-methoxypolyethylene glycol-2000 (DMG-PEG2k) and 1,2-distearoyl-rac-glycero-3-methoxypolyethylene glycol-2000 (DSG-PEG2k), optionally wherein the PEG2000-lipid conjugate is 1,2-Dimyristoyl-rac–glycero- 3-methoxypolyethylene glycol-2000 (DMG-PEG2k), optionally wherein the PEG2000-lipid conjugate is 1,2-Dioleoyl-sn–glycero-3-phosphoethanolamine (DOPE)-polyethylene glycol methoxy (DOPE-mPEG2k), optionally wherein the PEG2000-lipid conjugate is 1,2-Distearoyl- sn-Glycero-3-Phosphoethanolamine with conjugated methoxyl poly(ethylene glycol) (DSPE- mPEG2k), optionally wherein the nucleic acid-lipid particle comprises a PEG-lipid conjugate at a concentration selected from the group consisting of about 0.5 mol % of the total lipid present in the nucleic acid-lipid particle, about 1.0 mol % of the total lipid present in the nucleic acid-lipid particle, and about 0.5-3.0 mol % of the total lipid present in the nucleic acid-lipid particle.

119. The nucleic acid-lipid particle of claim 118, wherein the PEG-lipid conjugate is DMG- PEG2k comprising about 1.5 mol % of the total lipid present in the nucleic acid-lipid particle.

120. The nucleic acid-lipid particle of claims 117-119, comprising one or more non-cationic lipids comprising from 20 mol % to 80 mol % of the total lipid present in the lipid-nucleic acid particle, optionally wherein the one or more non-cationic lipids comprise cholesterol or a derivative thereof.

121. The nucleic acid-lipid particle of claim 120, comprising cholesterol or a derivative thereof at a concentration range selected from the group consisting of 35 mol % to 45 mol % of the total lipid present in the nucleic acid-lipid particle, 45 mol % to 55 mol % of the total lipid present in the nucleic acid-lipid particle, and 55 mol % to 65 mol % of the total lipid present in the nucleic acid-lipid particle, optionally wherein the cholesterol or a derivative thereof is about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, or about 45% of the total lipid present in the nucleic acid-lipid particle, optionally wherein the cholesterol or a derivative thereof is about 40% of the total lipid present in the nucleic acid- lipid particle.

122. The nucleic acid-lipid particle of claims 117-121, comprising one or more non-cationic lipid other than cholesterol or a derivative thereof, optionally wherein the one or more non-cationic lipid other than cholesterol or a derivative thereof comprises from 5 mol % to 20 mol % of the total lipid present in the lipid-nucleic acid particle, optionally wherein the one or more non-cationic lipid other than cholesterol or a derivative thereof comprises about 10 mol % of the total lipid present in the nucleic acid-lipid particle.

123. The nucleic acid-lipid particle of claim 122, wherein the one or more non-cationic lipid other than cholesterol or a derivative thereof comprises a non-cationic lipid selected from the group consisting of 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2-Distearoyl-sn-glycero-3- phosphocholine (DSPC), 1,2-Dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), 1,2- Distearoyl-sn-glycero-3-phosphoethanolamine (DSPE), and β-sitosterol, optionally wherein the one or more non-cationic lipid other than cholesterol or a derivative thereof is DOPE.

124. The nucleic acid-lipid particle of claims 117-123, wherein the nucleic acid cargo comprises a synthetic or naturally occurring RNA or DNA, or derivatives thereof, optionally wherein the nucleic acid cargo is a modified RNA, optionally wherein the modified RNA is selected from the group consisting of a modified mRNA, a modified antisense oligonucleotide and a modified siRNA, optionally wherein the modified mRNA encodes a nucleic acid modulating controller.

125. The nucleic acid-lipid particle of claims 117-124, wherein the nucleic acid cargo comprises one or more modifications selected from the group consisting of 2′-O-methyl modified nucleotides, a nucleotide comprising a 5′-phosphorothioate group, a terminal nucleotide linked to a cholesterylderivative, a 2′-deoxy-2′-fluoro modified nucleotide, a 5′-methoxy-modified nucleotide (e.g., 5′- methoxyuridine), a 2′-deoxy-modified nucleotide, a locked nucleotide, an abasic nucleotide, a 2′- amino-modified nucleotide, a 2′-alkyl-modified nucleotide, a morpholino nucleotide, a phosphoramidate, a non-natural base comprising nucleotide; internucleoside linkages or backbones including phosphorothioates, chiral phosphorothioates, phosphorodithioates, phosphotriesters, aminoalkylphosphotriesters, methyl and other alkyl phosphonates including 3′- alkylene phosphonates and chiral phosphonates, phosphinates, phosphoramidates including 3′- amino phosphoramidate and aminoalkylphosphoramidates, thionophosphoramidates, thionoalkylphosphonates, thionoalkylphosphotriesters, and boranophosphates having normal 3′-5′ linkages, 2′-5′ linked analogs of these, and those having inverted polarity wherein the adjacent pairs of nucleoside units are linked 3′-5′ to 5′-3′ or 2′-5′ to 5′-2′.

126. The nucleic acid-lipid particle of claims 117-125, wherein the nucleic acid-lipid particle comprises SM-048, SM-074, SM-076, SM-077, SM-079, SM-083, SM-085, SM-088, SM-100, SM-109, SM-113, or SM-125 at about 50 mol % of the total lipid present in the nucleic acid-lipid particle, cholesterol at about 38.5 mol % of the total lipid present in the nucleic acid-lipid particle, DOPE at about 10 mol % of the total lipid present in the nucleic acid-lipid particle, and DMG- PEG2k at about 1.5 mol % of the total lipid present in the nucleic acid-lipid particle.

127. A compound selected from the group consisting of:.

128. A compound of Formula IX:(IX) or a salt or isomer thereof, where X2, X3, and X4are independently CH or N; G8, G9, and G10 are independently O, -(CO)O-, -CH2O(CO)-, -(CH2)2(CO)NR15-, - (CH2)O(CO)NR15-, CH2(CO)NR15-, -(CO)NR15-, -NR15(CO)-, or NR15(CO)O-, wherein if X2, X3, and X4are all CH, then not all of G8, G9, and G10 are -(CO)NR15-; a1, b1, and c1 are independently 0, 1, 2, 3, or 4; m6, m7, and m8are independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;E5, E6, and E7 are independently -(CO)O- or -O(CO)-; T5, T6, and T7 are independently C5-C22 alkyl, C5-C22 alkenyl, or C5-C22 alkynyl; and R1is H, C1-C6alkyl, C2-C6alkenyl, or C2-C6alkynyl.

129. The compound of Formula IX of claim 128, or salt or isomer thereof, wherein two or more of m6-m8, E5-E7, and T5-T7 are the same.

130. The compound of Formula IX of claim 128, or salt or isomer thereof, wherein one or more of m6-m8, E5-E7, and T5-T7 are different.

131. The compound of Formula IX of claim 128, or salt or isomer thereof, wherein two of m6- m8, E5-E7, and T5-T7are the same.

132. The compound of Formula IX of claim 128, or salt or isomer thereof, wherein a1, b1, or c1are 2, 3, or 4.

133. The compound of Formula IX of claim 128, or salt or isomer thereof, wherein a1, b1, and c1are 2, 3, or 4.

134. The compound of Formula IX of claim 128, or salt or isomer thereof, wherein a1, b1, or c1 are 3 or 4.

135. The compound of Formula IX of claim 128, or salt or isomer thereof, wherein a1and b1are 3 and c1 is 4.

136. The compound of Formula IX of claim 128, or salt or isomer thereof, wherein a1, b1, and c1are 3.

137. The compound of Formula IX of claim 128, or salt or isomer thereof, wherein m6, m7, or m8 are 1-8.

138. The compound of Formula IX of claim 128, or salt or isomer thereof, wherein m6, m7, or m8are 5-8, optionally wherein m6, m7, and m8are 5-8.

139. The compound of Formula IX of claim 128, or salt or isomer thereof, wherein m1, m2, or m3 are 5-6, optionally wherein m6, m7, and m8 are 5-6.

140. The compound of Formula IX of claim 128, or salt or isomer thereof, wherein m1, m2, or m3 are 6, optionally wherein m6, m7, and m8 are 6.

141. The compound of Formula IX of claim 128, or salt or isomer thereof, wherein one of X2, X3, or X4is N, optionally wherein two of X2, X3, or X4are N.

142. The compound of Formula IX of claim 128, or salt or isomer thereof, wherein X2, X3, and X4are CH.

143. The compound of Formula IX of claim 128, or salt or isomer thereof, wherein two of G8, G9, or G10are the same-, optionally wherein all G8, G9, and G10are the same.

144. The compound of Formula IX of claim 128, or salt or isomer thereof, wherein one or more of G8, G9, or G10 are different.

145. The compound of Formula IX of claim 128, or salt or isomer thereof, wherein one of X2, X3, or X4is N, and G8, G9, and G10 are -(CO)NR15-.

146. The compound of Formula IX of claim 128, or salt or isomer thereof, wherein G8, G9, and G10are -(CO)O-.

147. The compound of Formula IX of claim 128, or salt or isomer thereof, wherein two of G8, G9, and G10 are -(CO)NR15-.

148. The compound of Formula IX of claim 128, or salt or isomer thereof, wherein one of G8, G9, and G10is -NR15(CO)-.

149. The compound of Formula IX of claim 128, or salt or isomer thereof, wherein all of G8, G9, and G10are -NR15(CO)-.

150. The compound of Formula IX of claim 128, or salt or isomer thereof, wherein one of G8, G9, and G10 is -(CO)NR15- and two of G8, G9, and G10 are -NR15(CO)-.

151. The compound of Formula IX of claim 128, or salt or isomer thereof, wherein one of G8, G9, and G10 is -(CO)NR15- and two of G8, G9, and G10 are O.

152. The compound of Formula IX of claim 128, or salt or isomer thereof, wherein T5, T6, or T7are independently selected from the group consisting of C5-C18 alkyl, C5-C18 alkenyl, and C5-C18 alkynyl, each of which is optionally substituted, optionally wherein T5, T6, and T7 are independently selected from the group consisting of C5-C18alkyl, C5-C18alkenyl, and C5-C18alkynyl, each of which is optionally substituted.

153. The compound of Formula IX of claim 128, or salt or isomer thereof, wherein T5, T6, or T7 are independently selected from the group consisting of C5-C12alkyl, C5-C12alkenyl, and C5-C12alkynyl, each of which is optionally substituted, optionally wherein T5, T6, and T7are independently selected from the group consisting of C5-C12 alkyl, C5-C12 alkenyl, and C5-C12 alkynyl, each of which is optionally substituted.

154. The compound of Formula IX of claim 128, or salt or isomer thereof, wherein T5, T6, or T7are independently selected from the group consisting of C5-C10 alkyl, C5-C10 alkenyl, and C5-C10 alkynyl, each of which is optionally substituted, optionally wherein T5, T6, and T7 are independently selected from the group consisting of C5-C10alkyl, C5-C10alkenyl, and C5-C10alkynyl, each of which is optionally substituted.

155. The compound of Formula IX of claim 128, or salt or isomer thereof, wherein T5, T6, or T7 are independently selected from the group consisting of C5-C8alkyl, C5-C8alkenyl, and C5-C8alkynyl, each of which is optionally substituted, optionally wherein T5, T6, and T7are independently selected from the group consisting of C5-C8 alkyl, C5-C8 alkenyl, and C5-C8 alkynyl, each of which is optionally substituted.

156. The compound of Formula IX of claim 128, or salt or isomer thereof, wherein T5, T6, or T7are independently selected from the group consisting of C6-C8 alkyl, C6-C8 alkenyl, and C6-C8 alkynyl, each of which is optionally substituted, optionally wherein T5, T6, and T7 are independently selected from the group consisting of C6-C8alkyl, C6-C8alkenyl, and C6-C8alkynyl, each of which is optionally substituted.

157. The compound of Formula IX of claim 128, or salt or isomer thereof, wherein T5, T6, or T7 are independently selected from the group consisting of C7 or C8 alkyl, C7 or C8 alkenyl, and C7 or C8alkynyl, each of which is optionally substituted, optionally wherein T5, T6, and T7are independently selected from the group consisting of C7 or C8 alkyl, C7 or C8 alkenyl, and C7 or C8 alkynyl, each of which is optionally substituted.

158. The compound of Formula IX of claim 128, or salt or isomer thereof, wherein T5, T6, or T7are independently C8alkyl, C8alkenyl, or C8alkynyl, each of which is optionally substituted, optionally wherein T5, T6, and T7 are C8 alkyl, C8 alkenyl, or C8 alkynyl, each of which is optionally substituted.

159. The compound of Formula IX of claim 128, or salt or isomer thereof, wherein E5, E6, or E7are -(CO)O-, optionally wherein E5, E6, and E7 are -(CO)O-.

160. The compound of Formula IX of claim 128, or salt or isomer thereof, wherein T5, T6, and T7are independently an alkyl selected from the group consisting of butane, pentane, hexane, heptane, octane, nonane, decane, undecane, dodecane, and tridecane, each of which is optionally substituted.

161. The compound of Formula IX of claim 128, or salt or isomer thereof, wherein T5, T6, and T7are octane or tridecane.

162. The compound of Formula IX of claim 128, or salt or isomer thereof, wherein T5, T6, and T7are independently an alkenyl selected from the group consisting of but-1-ene, but-2-ene, pent- 1-ene, pent-2-ene, hex-1-ene, hex-2-ene, hex3-ene, hept-1-ene, hept-2-ene, hept-3-ene, oct-1-ene, oct-2-ene, oct-3-ene, oct-4-ene, non-1-ene, non-2-ene, non-3-ene, non-4-ene, non-5-ene, dec-1- ene, dec-2-ene, dec-3-ene, dec-4-ene, dec-5-ene, dec-6-ene, undec-1-ene, undec-2-ene, undec-3- ene, undec-4-ene, undec-5-ene, undec-6-ene, undec-7-ene, dodec-1-ene, dodec-2-ene, dodec-3- ene, dodec-4-ene, dodec-5-ene, dodec-6-ene, dodec-8-ene, and an alkenyl group comprising two or more double bonds, each of which is optionally substituted.

163. The compound of Formula IX of claim 128, or salt or isomer thereof, wherein T5, T6, and T7 are independently an alkynyl selected from the group consisting of but-1-yne, but-2-yne, pent- 1-yne, pent-2-yne, hex-1-yne, hex-2-yne, hex3-yne, hept-1-yne, hept-2-yne, hept-3-yne, oct-1-yne, oct-2-yne, oct-3-yne, oct-4-yne, non-1-yne, non-2-yne, non-3-yne, non-4-yne, non-5-yne, dec-1-yne, dec-2-yne, dec-3-yne, dec-4-yne, dec-5-yne, dec-6-yne, undec-1-yne, undec-2-yne, undec-3-yne, undec-4-yne, undec-5-yne, undec-6-yne, undec-7-yne, dodec-1-yne, dodec-2-yne, dodec-3-yne, dodec-4-yne, dodec-5-yne, dodec-6-yne, dodec-8-yne, and an alkynyl group comprising two or more triple bonds, each of which is optionally substituted.

164. The compound of Formula IX of claim 128, or salt or isomer thereof, wherein R1is H.

165. A compound selected from the group consisting of:(SM-016; 1-ethylhexyl 9-[3-[[3,5-bis[3-[bis[9-(1-ethylhexoxy)-9-oxo- nonyl]amino]propylcarbamoyl]benzoyl]amino]propyl-[9-(1-ethylhexoxy)-9-oxo- nonyl]amino]nonanoate)(SM-062; hexa(octan-3-yl) 9,9',9'',9''',9'''',9'''''-((((pyridine-2,4,6- tricarbonyl)tris(azanediyl))tris(propane-3,1-diyl))tris(azanetriyl))hexanonanoate),(SM-065; tris(3-(bis(9-(octan-3-yloxy)-9-oxononyl)amino)propyl) benzene-1,3,5-tricarboxylate),(SM-067; tetra(octan-3-yl) 9,9',9'',9'''-((((5-(4-(bis(9-(octan-3-yloxy)-9- oxononyl)amino)butanamido)isophthaloyl)bis(azanediyl))bis(propane-3,1- diyl))bis(azanetriyl))tetranonanoate),(SM-68; hexa(octan-3-yl) 9,9',9'',9''',9'''',9'''''-(((benzene-1,3,5-triyltris(azanediyl))tris(4- oxobutane-4,1-diyl))tris(azanetriyl))hexanonanoate),(SM-070; tetra(octan-3-yl) 9,9',9'',9'''-((((5-((3-(bis(9-(octan-3-yloxy)-9- oxononyl)amino)propyl)carbamoyl)-1,3-phenylene)bis(azanediyl))bis(4-oxobutane-4,1- diyl))bis(azanetriyl))tetranonanoate),(SM-072; tetra(octan-3-yl) 9,9',9'',9'''-((((5-((3-(bis(9-(octan-3-yloxy)-9- oxononyl)amino)propyl)carbamoyl)-1,3-phenylene)bis(oxy))bis(propane-3,1- diyl))bis(azanetriyl))tetranonanoate),(SM-073; tetra(octan-3-yl) 9,9',9'',9'''-((((5-(2-((3-(bis(9-(octan-3-yloxy)-9- oxononyl)amino)propyl)amino)-2-oxoethyl)isophthaloyl)bis(azanediyl))bis(propane-3,1-oxononyl)amino)propyl)amino)-3-oxopropyl)isophthaloyl)bis(azanediyl))bis(propane-3,1-oxononyl)amino)pentanoyl)oxy)methyl)isophthaloyl)bis(azanediyl))bis(propane-3,1- d(SM-112; tetra(octan-3-yl) 9,9',9'',9'''-((((5-(19-ethyl-8-(9-(octan-3-yloxy)-9-oxononyl)-3,17-dioxo-2,18-dioxa-4,8-diazatetracosyl)isophthaloyl)bis(azanediyl))bis(propane-3,1- diyl))bis(azanetriyl))tetranonanoate).

166. A pharmaceutical composition comprising a lipid of Formula IX: (or a salt or isomer thereof, where X2, X3, and X4are independently CH or N; G8, G9, and G10are independently O, -(CO)O-, -CH2O(CO)-, -(CH2)2(CO)NR15-, - (CH2)O(CO)NR15-, CH2(CO)NR15-, -(CO)NR15-, -NR15(CO)-, or NR15(CO)O-, wherein if X2, X3, and X4are all CH, then not all of G8, G9, and G10are -(CO)NR15-;a1, b1, and c1 are independently 0, 1, 2, 3, or 4; m6, m7, and m8 are independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; E5, E6, and E7are independently -(CO)O- or -O(CO)-; T5, T6, and T7 are independently C5-C22 alkyl, C5-C22 alkenyl, or C5-C22 alkynyl; and R1 is H, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl.

167. The pharmaceutical composition comprising a lipid of Formula IX of claim 166, or salt or isomer thereof, wherein two or more of m6-m8, E5-E7, and T5-T7 are the same.

168. The pharmaceutical composition comprising a lipid of Formula IX of claim 166, or salt or isomer thereof, wherein one or more of m6-m8, E5-E7, and T5-T7are different.

169. The pharmaceutical composition comprising a lipid of Formula IX of claim 166, or salt or isomer thereof, wherein two of m6-m8, E5-E7, and T5-T7 are the same.

170. The pharmaceutical composition comprising a lipid of Formula IX of claim 166, or salt or isomer thereof, wherein a1, b1, or c1are 2, 3, or 4.

171. The pharmaceutical composition comprising a lipid of Formula IX of claim 166, or salt or isomer thereof, wherein a1, b1, and c1 are 2, 3, or 4.

172. The pharmaceutical composition comprising a lipid of Formula IX of claim 166, or salt or isomer thereof, wherein a1, b1, or c1 are 3 or 4.

173. The pharmaceutical composition comprising a lipid of Formula IX of claim 166, or salt or isomer thereof, wherein a1and b1are 3 and c1is 4.

174. The pharmaceutical composition comprising a lipid of Formula IX of claim 166, or salt or isomer thereof, wherein a1, b1, and c1 are 3.

175. The pharmaceutical composition comprising a lipid of Formula IX of claim 166, or salt or isomer thereof, wherein m1, m2, or m3 are 1-8.

176. The pharmaceutical composition comprising a lipid of Formula IX of claim 166, or salt or isomer thereof, wherein m1, m2, or m3 are 5-8, optionally wherein m6, m7, and m8 are 5-8.

177. The pharmaceutical composition comprising a lipid of Formula IX of claim 166, or salt or isomer thereof, wherein m1, m2, or m3are 5-6, optionally wherein m6, m7, and m8are 5-6.

178. The pharmaceutical composition comprising a lipid of Formula IX of claim 166, or salt or isomer thereof, wherein m1, m2, or m3 are 6, optionally wherein m6, m7, and m8 are 6.

179. The pharmaceutical composition comprising a lipid of Formula IX of claim 166, or salt or isomer thereof, wherein one of X2, X3, or X4is N, optionally wherein two of X2, X3, or X4are N.

180. The pharmaceutical composition comprising a lipid of Formula IX of claim 166, or salt or isomer thereof, wherein X2, X3, and X4are CH.

181. The pharmaceutical composition comprising a lipid of Formula IX of claim 166, or salt or isomer thereof, wherein two of G8, G9, or G10 are the same, optionally wherein all G8, G9, and G10 are the same.

182. The pharmaceutical composition comprising a lipid of Formula IX of claim 166, or salt or isomer thereof, wherein one or more of G8, G9, or G10are different.

183. The pharmaceutical composition comprising a lipid of Formula IX of claim 166, or salt or isomer thereof, wherein one of X2, X3, or X4is N, and G8, G9, and G10are -(CO)NR15-.

184. The pharmaceutical composition comprising a lipid of Formula IX of claim 166, or salt or isomer thereof, wherein G8, G9, and G10 are -(CO)O-.

185. The pharmaceutical composition comprising a lipid of Formula IX of claim 166, or salt or isomer thereof, wherein two of G8, G9, and G10are -(CO)NR15-.

186. The pharmaceutical composition comprising a lipid of Formula IX of claim 166, or salt or isomer thereof, wherein one of G8, G9, and G10 is -NR15(CO)-.

187. The pharmaceutical composition comprising a lipid of Formula IX of claim 166, or salt or isomer thereof, wherein all of G8, G9, and G10 are -NR15(CO)-.

188. The pharmaceutical composition comprising a lipid of Formula IX of claim 166, or salt or isomer thereof, wherein one of G8, G9, and G10 is -(CO)NR15- and two of G8, G9, and G10 are - NR15(CO)-.

189. The pharmaceutical composition comprising a lipid of Formula IX of claim 166, or salt or isomer thereof, wherein one of G8, G9, and G10is -(CO)NR15- and two of G8, G9, and G10are O.

190. The pharmaceutical composition comprising a lipid of Formula IX of claim 166, or salt or isomer thereof, wherein T5, T6, or T7are independently selected from the group consisting of C5- C18alkyl, C5-C18alkenyl, and C5-C18alkynyl, each of which is optionally substituted, optionally wherein T5, T6, and T7 are independently selected from the group consisting of C5-C18 alkyl, C5- C18 alkenyl, and C5-C18 alkynyl, each of which is optionally substituted.

191. The pharmaceutical composition comprising a lipid of Formula IX of claim 166, or salt or isomer thereof, wherein T5, T6, or T7 are independently selected from the group consisting of C5- C12 alkyl, C5-C12 alkenyl, and C5-C12 alkynyl, each of which is optionally substituted, optionally wherein T5, T6, and T7are independently selected from the group consisting of C5-C12alkyl, C5- C12alkenyl, and C5-C12alkynyl, each of which is optionally substituted.

192. The pharmaceutical composition comprising a lipid of Formula IX of claim 166, or salt or isomer thereof, wherein T5, T6, or T7are independently selected from the group consisting of C5- C10alkyl, C5-C10alkenyl, and C5-C10alkynyl, each of which is optionally substituted, optionally wherein T5, T6, and T7 are independently selected from the group consisting of C5-C10 alkyl, C5- C10alkenyl, and C5-C10alkynyl, each of which is optionally substituted.

193. The pharmaceutical composition comprising a lipid of Formula IX of claim 166, or salt or isomer thereof, wherein T5, T6, or T7 are independently selected from the group consisting of C5- C8 alkyl, C5-C8 alkenyl, and C5-C8 alkynyl, each of which is optionally substituted, optionally wherein T5, T6, and T7are independently selected from the group consisting of C5-C8alkyl, C5-C8alkenyl, and C5-C8 alkynyl, each of which is optionally substituted.

194. The pharmaceutical composition comprising a lipid of Formula IX of claim 166, or salt or isomer thereof, wherein T5, T6, or T7 are independently selected from the group consisting of C6- C8alkyl, C6-C8alkenyl, and C6-C8alkynyl, each of which is optionally substituted, optionally wherein T5, T6, and T7 are independently selected from the group consisting of C6-C8 alkyl, C6-C8 alkenyl, and C6-C8 alkynyl, each of which is optionally substituted.

195. The pharmaceutical composition comprising a lipid of Formula IX of claim 166, or salt or isomer thereof, wherein T5, T6, or T7are independently selected from the group consisting of C7or C8 alkyl, C7 or C8 alkenyl, and C7 or C8 alkynyl, each of which is optionally substituted, optionally wherein T5, T6, and T7are independently selected from the group consisting of C7or C8alkyl, C7or C8alkenyl, and C7or C8alkynyl, each of which is optionally substituted.

196. The pharmaceutical composition comprising a lipid of Formula IX of claim 166, or salt or isomer thereof, wherein T5, T6, or T7 are independently C8 alkyl, C8 alkenyl, or C8 alkynyl, each of which is optionally substituted, optionally wherein T5, T6, and T7are C8alkyl, C8alkenyl, or C8alkynyl, each of which is optionally substituted.

197. The pharmaceutical composition comprising a lipid of Formula IX of claim 166, or salt or isomer thereof, wherein E5, E6, or E7are -(CO)O-, optionally wherein E5, E6, and E7are -(CO)O-.

198. The pharmaceutical composition comprising a lipid of Formula IX of claim 166, or salt or isomer thereof, wherein T5, T6, and T7 are independently an alkyl selected from the group consisting of butane, pentane, hexane, heptane, octane, nonane, decane, undecane, dodecane, and tridecane, each of which is optionally substituted.

199. The pharmaceutical composition comprising a lipid of Formula IX of claim 166, or salt or isomer thereof, wherein T5, T6, and T7are octane or tridecane.

200. The pharmaceutical composition comprising a lipid of Formula IX of claim 166, or salt or isomer thereof, wherein T5, T6, and T7 are independently an alkenyl selected from the group consisting of but-1-ene, but-2-ene, pent-1-ene, pent-2-ene, hex-1-ene, hex-2-ene, hex3-ene, hept- 1-ene, hept-2-ene, hept-3-ene, oct-1-ene, oct-2-ene, oct-3-ene, oct-4-ene, non-1-ene, non-2-ene, non-3-ene, non-4-ene, non-5-ene, dec-1-ene, dec-2-ene, dec-3-ene, dec-4-ene, dec-5-ene, dec-6- ene, undec-1-ene, undec-2-ene, undec-3-ene, undec-4-ene, undec-5-ene, undec-6-ene, undec-7-ene, dodec-1-ene, dodec-2-ene, dodec-3-ene, dodec-4-ene, dodec-5-ene, dodec-6-ene, dodec-8- ene, and an alkenyl group comprising two or more double bonds, each of which is optionally substituted.

201. The pharmaceutical composition comprising a lipid of Formula IX of claim 166, or salt or isomer thereof, wherein T5, T6, and T7 are independently an alkynyl selected from the group consisting of but-1-yne, but-2-yne, pent-1-yne, pent-2-yne, hex-1-yne, hex-2-yne, hex3-yne, hept- 1-yne, hept-2-yne, hept-3-yne, oct-1-yne, oct-2-yne, oct-3-yne, oct-4-yne, non-1-yne, non-2-yne, non-3-yne, non-4-yne, non-5-yne, dec-1-yne, dec-2-yne, dec-3-yne, dec-4-yne, dec-5-yne, dec-6- yne, undec-1-yne, undec-2-yne, undec-3-yne, undec-4-yne, undec-5-yne, undec-6-yne, undec-7- yne, dodec-1-yne, dodec-2-yne, dodec-3-yne, dodec-4-yne, dodec-5-yne, dodec-6-yne, dodec-8- yne, and an alkynyl group comprising two or more triple bonds, each of which is optionally substituted.

202. The pharmaceutical composition comprising a lipid of Formula IX of claim 166, or salt or isomer thereof, wherein R1 is H.

203. The pharmaceutical composition comprising a lipid selected from the group consisting of:(SM-016; 1-ethylhexyl 9-[3-[[3,5-bis[3-[bis[9-(1-ethylhexoxy)-9-oxo- nonyl]amino]propylcarbamoyl]benzoyl]amino]propyl-[9-(1-ethylhexoxy)-9-oxo- nonyl]amino]nonanoate)(SM-062; hexa(octan-3-yl) 9,9',9'',9''',9'''',9'''''-((((pyridine-2,4,6- tricarbonyl)tris(azanediyl))tris(propane-3,1-diyl))tris(azanetriyl))hexanonanoate),(SM-065; tris(3-(bis(9-(octan-3-yloxy)-9-oxononyl)amino)propyl) benzene-1,3,5-tricarboxylate),(SM-067; tetra(octan-3-yl) 9,9',9'',9'''-((((5-(4-(bis(9-(octan-3-yloxy)-9- oxononyl)amino)butanamido)isophthaloyl)bis(azanediyl))bis(propane-3,1- diyl))bis(azanetriyl))tetranonanoate),(SM-068; hexa(octan-3-yl) 9,9',9'',9''',9'''',9'''''-(((benzene-1,3,5-triyltris(azanediyl))tris(4- oxobutane-4,1-diyl))tris(azanetriyl))hexanonanoate),(SM-070; tetra(octan-3-yl) 9,9',9'',9'''-((((5-((3-(bis(9-(octan-3-yloxy)-9- oxononyl)amino)propyl)carbamoyl)-1,3-phenylene)bis(azanediyl))bis(4-oxobutane-4,1- diyl))bis(azanetriyl))tetranonanoate),(SM-072; tetra(octan-3-yl) 9,9',9'',9'''-((((5-((3-(bis(9-(octan-3-yloxy)-9- oxononyl)amino)propyl)carbamoyl)-1,3-phenylene)bis(oxy))bis(propane-3,1- diyl))bis(azanetriyl))tetranonanoate),(SM-073; tetra(octan-3-yl) 9,9',9'',9'''-((((5-(2-((3-(bis(9-(octan-3-yloxy)-9- oxononyl)amino)propyl)amino)-2-oxoethyl)isophthaloyl)bis(azanediyl))bis(propane-3,1-oxononyl)amino)propyl)amino)-3-oxopropyl)isophthaloyl)bis(azanediyl))bis(propane-3,1-oxononyl)amino)pentanoyl)oxy)methyl)isophthaloyl)bis(azanediyl))bis(propane-3,1- d(SM-112; tetra(octan-3-yl) 9,9',9'',9'''-((((5-(19-ethyl-8-(9-(octan-3-yloxy)-9-oxononyl)-3,17- dioxo-2,18-dioxa-4,8-diazatetracosyl)isophthaloyl)bis(azanediyl))bis(propane-3,1- diyl))bis(azanetriyl))tetranonanoate).

204. A lipid particle comprising a compound of claims 128-165.

205. The lipid particle of claim 204, further comprising a therapeutic agent.

206. The lipid particle of claim 204, wherein the therapeutic agent is a nucleic acid.

207. A pharmaceutical composition comprising a lipid particle of claim 204 and a pharmaceutically acceptable excipient, carrier, or diluent.

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