EP-4734960-A1 - STEROL ANALOGS IN LIPID NANOPARTICLE FORMULATIONS

EP4734960A1EP 4734960 A1EP4734960 A1EP 4734960A1EP-4734960-A1

Abstract

Provided are lipid nanoparticles for delivering nucleic acids molecules such as mRNA. Also provided are methods of making and using thereof.

Inventors

DEROSA, FRANK
KARVE, Shrirang
KAUSHAL, Neha
MA, Younan
PARANDE, Dipen

Assignees

Sanofi Pasteur Inc.

Dates

Publication Date: 20260506
Application Date: 20240628

Claims (1)

CLAIMS 1. A composition comprising a lipid nanoparticle (LNP), wherein the LNP comprises: (I) an ionizable lipid; (II) a structural lipid selected from the group consisting of α-amyrin, β-amyrin, α- boswellic acid, β-boswellic acid, 11-keto-β-boswellic acid, 3-O-acetyl-11-keto-β-boswellic acid, taraxasterol, senegenin, arjungenin, cycloastrogenol, β-elemonic acid, ganoderic acid A, ganoderic acid B, ganoderic acid D, ganoderic acid F, ganoderic acid H, yamogenin, steviol, brusatol, γ-oryzanol, phytolaccagenin, hecogenin, pristimerin, erythrodiol, guggulsterone Z, corosolic acid, soyasapogenol B, gitogenin, or a combination thereof; (III) optionally, cholesterol; (IV) a helper lipid; and (V) a stealth lipid. 2. The composition of claim 1, wherein the LNP comprises: (I) an ionizable lipid; (II) a structural lipid selected from the group consisting of α-amyrin, β-amyrin, α- boswellic acid, β-boswellic acid, 11-keto-β-boswellic acid, taraxasterol, senegenin, arjungenin, cycloastrogenol, β-elemonic acid, ganoderic acid B, ganoderic acid D, ganoderic acid H, yamogenin, steviol, brusatol, γ-oryzanol, or a combination thereof; (III) optionally, cholesterol; (IV) a helper lipid; and (V) a stealth lipid. 3. A composition comprising a lipid nanoparticle (LNP), wherein the LNP comprises: (I) an ionizable lipid, wherein: (a) the ionizable lipid has a structure according to Formula CAT-I: R 6 R 7 N p or a pharmaceutically acceptable salt thereof, wherein: p is an integer of between 1 and 9, inclusive; each instance of R 2 is independently hydrogen or optionally substituted C 1-6 alkyl; each instance of L is independently an optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted heteroalkylene, optionally substituted heteroalkenylene, optionally substituted heteroalkynylene, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, or optionally substituted heteroarylene, or combination thereof; each instance of R 6 and R 7 is independently a group of formula (i), (ii), or (iii); Formulae (i), (ii), and (iii) are: R' R L YR P , each instance of R′ is independently hydrogen or optionally substituted alkyl; X is O, S, or NR X , wherein R X is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group; Y is O, S, or NR Y , wherein R Y is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or a nitrogen protecting group; R P is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, or a nitrogen protecting group when attached to a nitrogen atom; and R L is optionally substituted C 1-50 alkyl, optionally substituted C 2-50 alkenyl, optionally substituted C 2-50 alkynyl, optionally substituted heteroC 1-50 alkyl, optionally substituted heteroC 2- 50 alkenyl, optionally substituted heteroC 2-50 alkynyl, or a polymer; or (b) the ionizable lipid has a structure according to Formula CAT-II: HO R 1B or a pharmaceutically acceptable salt thereof, wherein: O O S A 1 is selected S S , wherein the left hand side of each depicted structure O O S Z 1 is selected O S S , wherein the right hand side of each depicted R 1A and R 1B are each independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted acyl, and -W 1 -X 1 -Y 1 ; each W 1 is independently selected from optionally substituted alkyl and optionally substituted alkenyl; each X 1 is independently selected from -*O-(C=O)-optionally substituted alkyl, -(*C=O)- O-optionally substituted alkyl, -*O-(C=O)-optionally substituted alkenyl, and -(*C=O)-O- optionally substituted alkenyl, wherein the atom marked with a * is connected to W 1 , each Y 1 is independently selected from hydrogen, -*O-(C=O)-optionally substituted alkyl, -(*C=O)-O-optionally substituted alkyl, -*O-(C=O)-optionally substituted alkenyl, and - (*C=O)-O-optionally substituted alkenyl, wherein the atom marked with a * is connected to X 1 ; b is 1, 2, 3, 4, or 5; and each a is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; (II) a structural lipid, wherein said structural lipid is a sterol or sterol analog other than cholesterol; (III) optionally, cholesterol; (IV) a helper lipid; and (V) a stealth lipid. 4. The composition of claim 3, wherein the LNP comprises: (I) an ionizable lipid, wherein: (a) the ionizable lipid has a structure according to Formula CAT-I; or (b) the ionizable lipid has a structure according to Formula CAT-II; (II) a structural lipid, wherein: (a) the structural lipid has a structure according to Formula STR-I or STR-II: s8b s8a s8b s8a a R R s9 s7b s9a R R R R R R s2a and R s2b are each, independently, optionally substituted C 1-6 alkyl or COOH; R s3a and R s3b are each, independently, H, OH, or optionally substituted C 1-6 alkyl; R s4a and R s4b are each, independently H, optionally substituted C 1-6 alkyl, or R s4a and R s4b are taken together with the carbon atom to which they are attached to form C=O; R s5 is H, optionally substituted C 1-6 alkyl, or COOH; R s6a and R s6b are each, independently, H, optionally substituted C 1-6 alkyl, or COOH; R s7a and R s7b are each, independently, H, OH, or optionally substituted C 1-6 alkyl; R s8a and R s8b are each, independently, H, OH, optionally substituted C 1-6 alkyl, or R s8a and R s8b are taken together with the carbon atom to which they are attached to form C=CH 2 ; and R s9a and R s9b are each, independently, H, OH, or optionally substituted C 1-6 alkyl; (b) the structural lipid has a structure according to Formula STR-III, STR-IV, or STR-V: R s13 R s14 R s14 R s14 R s11a is H, and R s11b is OH, or R s11a and R s11b are taken together with the carbon atom to which they are attached to form C=O; R s12a is H, and R s12b is OH, or R s12a and R s12b are taken together with the carbon atom to which they are attached to form C=O; R s13 is H or OC(O)C 1-6 alkyl; R s14a ; substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, or COOH; and R s14b is optionally substituted C 7-10 alkyl, optionally substituted C 6-10 alkenyl; optionally substituted C 7-10 alkynyl; or C 1-5 alkyl-C(O)-C 1-5 alkyl-COOH; or (c) the structural lipid is selected from the group consisting of cycloastrogenol, β- elemonic acid, diosgenin, yamogenin, steviol, brusatol, and γ-oryzanol; (III) optionally, cholesterol; (IV) a helper lipid; and (V) a stealth lipid. 5. The composition of claim 3, wherein the LNP comprises: (I) an ionizable lipid, wherein: (a) the ionizable lipid has a structure according to Formula CAT-I; or (b) the ionizable lipid has a structure according to Formula CAT-II; (II) a structural lipid, wherein: (a) the structural lipid has a structure according to Formula STR-I or STR-II; (b) the structural lipid has a structure according to Formula STR-III, STR-IV, or STR-V; or (c) the structural lipid is selected from the group consisting of 3-O-acetyl-11-keto- β-boswellic acid, cycloastrogenol, β-elemonic acid, ganoderic acid A, diosgenin, yamogenin, steviol, brusatol, γ-oryzanol, phytolaccagenin, hecogenin, pristimerin, guggulsterone Z, corosolic acid, and soyasapogenol B; (III) optionally, cholesterol; (IV) a helper lipid; and (V) a stealth lipid. 6. The composition of any one of claims 1-5, wherein the ionizable lipid has a structure according to Formula CAT-Ib: R 6 R 7 N or a pharmaceutically acceptable salt thereof, wherein q is an integer between 1 and 10, inclusive. 7. The composition of any one of claims 1-5, wherein the ionizable lipid has a structure according to Formula CAT-IIa: R 1B B or a pharmaceutically acceptable salt thereof. 8. A composition comprising a lipid nanoparticle (LNP), wherein the LNP comprises: (I) an ionizable lipid having a structure according to Formula CAT-V: ), or a pharmaceutically a wherein L 1 is a bond, (C 1 -C 6 ) alkylene or (C 2 -C 6 ) alkenylene; wherein X is O or S; wherein R 1 , R 2 , R 3 , R 4 and R 5 are each independently selected from H, OH, optionally substituted (C 1 -C 6 ) alkyl, optionally substituted (C 2 -C 6 ) alkenyl, optionally substituted (C 2 -C 6 ) alkynyl, optionally substituted (C 1 -C 6 ) alkoxy and -OC(O)R’; wherein at least one of R 1 , R 2 , R 3 , R 4 or R 5 is -OC(O)R’; wherein each R’ is independently selected from ; ; each independently 0, 1, 2, 3, 4 or 5; wherein each R 7 is independently selected from H, optionally substituted (C 1 -C 6 ) alkyl, optionally substituted (C 2 -C 6 ) alkenyl, optionally substituted (C 2 -C 6 ) alkynyl, optionally substituted (C 1 -C 6 ) acyl, –(CH 2 ) k R A or -(CH 2 ) k CH(OR 11 )R A ; wherein each R 8 is independently selected from H, optionally substituted (C 1 -C 6 ) alkyl, optionally substituted (C 2 -C 6 ) alkenyl, optionally substituted (C 2 -C 6 ) alkynyl, optionally substituted (C 1 -C 6 ) acyl, –(CH 2 ) n R B or -(CH 2 ) n CH(OR 12 )R B ; wherein R 9 is selected from H, optionally substituted (C 1 -C 6 ) alkyl, optionally substituted (C 2 -C 6 ) alkenyl, optionally substituted (C 2 -C 6 ) alkynyl, optionally substituted (C 1 -C 6 ) acyl, - (CH 2 ) q R C or -(CH 2 ) q CH(OR 13 )R C ; wherein R 10 is selected from H, optionally substituted (C 1 -C 6 ) alkyl, optionally substituted (C 2 -C 6 ) alkenyl, optionally substituted (C 2 -C 6 ) alkynyl, optionally substituted (C 1 - C 6 )acyl, -(CH 2 ) r R D or -(CH 2 ) r CH(OR 14 )R D ; wherein k, n, q and r are each independently 1,2,3,4 or 5; or wherein (i) R 7 and R 8 or (ii) R 9 and R 10 together form an optionally substituted 5- or 6- membered heterocycloalkyl or heteroaryl wherein the heterocycloalkyl or heteroaryl comprises 1 to 3 heteroatoms selected from N, O and S; wherein R 11 , R 12 , R 13 and R 14 are each independently selected from H, methyl, ethyl or propyl; wherein R A , R B , R C and R D are each independently selected from optionally substituted (C 6 -C 20 ) alkyl, optionally substituted (C 6 -C 20 ) alkenyl, optionally substituted (C 6 -C 20 ) alkynyl, optionally substituted (C 6 -C 20 ) acyl, optionally substituted –OC(O) alkyl, optionally substituted – OC(O) alkenyl, optionally substituted (C 1 -C 6 ) monoalkylamino, optionally substituted (C 1 -C 6 ) dialkylamino, optionally substituted (C 1 -C 6 ) alkoxy, -OH, -NH 2 ; wherein at least one of R 7 , R 8 , R 9 , R 10 comprises a R A , R B , R C or R D moiety respectively wherein that R A , R B , R C or R D is independently selected from optionally substituted (C 6 -C 20 ) alkyl, optionally substituted (C 6 -C 20 ) alkenyl, optionally substituted (C 6 -C 20 ) alkynyl, optionally substituted (C 6 -C 20 ) acyl, optionally substituted –OC(O)(C 6 -C 20 ) alkyl or optionally substituted – OC(O)(C 6 -C 20 ) alkenyl. (II) a structural lipid, wherein said structural lipid is a sterol or sterol analog other than cholesterol; (III) optionally, cholesterol; (IV) a helper lipid; and (V) a stealth lipid. 9. The composition of claim 8, wherein the LNP comprises: (I) an ionizable lipid having a structure according to Formula CAT-V; (II) a structural lipid, wherein: (a) the structural lipid has a structure according to Formula STR-I or STR-II; (b) the structural lipid has a structure according to Formula STR-III, STR-IV, or STR-V; or (c) the structural lipid is selected from the group consisting of 3-O-acetyl-11-keto- β-boswellic acid, cycloastrogenol, β-elemonic acid, ganoderic acid A, diosgenin, yamogenin, steviol, brusatol, γ-oryzanol, phytolaccagenin, hecogenin, pristimerin, guggulsterone Z, corosolic acid, and soyasapogenol B; (III) optionally, cholesterol; (IV) a helper lipid; and (V) a stealth lipid. 10. The composition of claim 8 or claim 9, wherein the ionizable lipid has a structure according to Formula CAT-Vd O or a pharmaceutically 11. The composition of any one of claims 8-10, wherein the ionizable lipid has the following structure: N O OH O , or a 12. The composition of any one of claims 3-11, wherein the structural lipid is α-amyrin, β- amyrin, α-boswellic acid, β-boswellic acid, 11-keto-β-boswellic acid, 3-O-acetyl-11-keto-β- boswellic acid, taraxasterol, senegenin, arjungenin, β-sitosterol, campesterol, fucosterol, Δ-5- avenasterol, Δ-7-avenasterol, α-spinasterol, cycloartenol, cycloastrogenol, β-elemonic acid, ganoderic acid A, ganoderic acid B, ganoderic acid D, ganoderic acid F, ganoderic acid H, diosgenin, yamogenin, steviol, brusatol, γ-oryzanol, phytolaccagenin, hecogenin, pristimerin, erythrodiol, guggulsterone Z, corosolic acid, soyasapogenol B, madecassic acid, asiatic acid, gitogenin, or a combination thereof. 13. The composition of claim 12, wherein the structural lipid is α-amyrin, β-amyrin, α- boswellic acid, β-boswellic acid, 11-keto-β-boswellic acid, taraxasterol, arjungenin, β-sitosterol, Δ-5-avenasterol, Δ-7-avenasterol, α-spinasterol, ganoderic acid A, ganoderic acid B, ganoderic acid D, ganoderic acid F, ganoderic acid H, diosgenin, yamogenin, γ-oryzanol, soyasapogenol B, or a combination thereof. 14. The composition of any one of claims 3-11, wherein the structural lipid is α-amyrin, β- amyrin, α-boswellic acid, β-boswellic acid, 11-keto-β-boswellic acid, taraxasterol, senegenin, arjungenin, β-sitosterol, campesterol, fucosterol, Δ-5-avenasterol, α-spinasterol, cycloartenol, cycloastrogenol, β-elemonic acid, ganoderic acid B, ganoderic acid D, ganoderic acid H, diosgenin, yamogenin, steviol, brusatol, γ-oryzanol, or a combination thereof, preferably the structural lipid is β-amyrin, β-boswellic acid, taraxasterol, β-sitosterol, campesterol, fucosterol, α-spinasterol, cycloartenol, diosgenin, yamogenin, γ-oryzanol, or a combination thereof, more preferably the structural lipid is β-amyrin, β-boswellic acid, taraxasterol, α-spinasterol, cycloartenol, diosgenin, yamogenin, γ-oryzanol, or a combination thereof. 15. The composition of any one of claims 3-11, wherein: (a) the structural lipid has a structure according to Formula STR-I: R s8b Rs8a R s9a R s7b wherein: R s2a and R s2b are each, independently, optionally substituted C 1-6 alkyl or COOH; R s3a is H or C 1-6 alkyl; R s4a and R s4b are each, independently, H or R s4a and R s4b are taken together with the carbon atom to which they are attached to form C=O; R s5 is C 1-6 alkyl or COOH; R s6a and R s6b are each, independently, H; R s7a and R s7b are each, independently, H; R s8a and R s8b are each, independently, H, C 1-6 alkyl, or R s8a and R s8b are taken together with the carbon atom to which they are attached to form C=CH 2 ; and R s9a and R s9b are each, independently, H, OH, or C 1-6 alkyl; (b) the structural lipid has a structure according to Formula STR-II: R s8b R s8a R s9a R s7b wherein: R s1 is optionally substituted C 1-6 alkyl or COOH; R s3a and R s3b are each, independently, H or C 1-6 alkyl; R s4a and R s4b are each, independently H or optionally substituted C 1-6 alkyl; R s5 is H; R s6a and R s6b are each, independently, C 1-6 alkyl or COOH; R s7a and R s7b are each, independently, H, OH, or C 1-6 alkyl; R s8a and R s8b are each, independently, H, OH, or C 1-6 alkyl; and R s9a and R s9b are each, independently, H or C1-6 alkyl; (c) the structural lipid has a structure according to Formula STR-III: R s14 wherein: R s10a and R s10b are each, independently, H or optionally substituted C 1-6 alkyl; R s14a ; substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, or COOH; and R s14b is optionally substituted C 7-10 alkyl, optionally substituted C 6-10 alkenyl; optionally substituted C 7-10 alkynyl; or C 1-5 alkyl-C(O)-C 1-5 alkyl-COOH; (d) the structural lipid has a structure according to Formula STR-IV: R s14 wherein: R s10a and R s10b are each, independently, H or optionally substituted C 1-6 alkyl; R s14a ; substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, or COOH; and R s14b is optionally substituted C 7-10 alkyl, optionally substituted C 6-10 alkenyl; optionally substituted C 7-10 alkynyl; or C 1-5 alkyl-C(O)-C 1-5 alkyl-COOH; or (e) the structural lipid has a structure according to Formula STR-V: R s13 R s14 wherein: R s10a and R s10b are each, independently, H or optionally substituted C 1-6 alkyl; R s11a is H, and R s11b is OH, or R s11a and R s11b are taken together with the carbon atom to which they are attached to form C=O; R s12a is H, and R s12b is OH, or R s12a and R s12b are taken together with the carbon atom to which they are attached to form C=O; R s13 is H or OC(O)C 1-6 alkyl; R s14a ; substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, or COOH; and R s14b is optionally substituted C 7-10 alkyl, optionally substituted C 6-10 alkenyl; optionally substituted C 7-10 alkynyl; or C 1-5 alkyl-C(O)-C 1-5 alkyl-COOH. 16. The composition of any one of claims 1-15, wherein the ratio of structural lipid to cholesterol is between 1:9 and 9:1. 17. The composition of any one of claims 1-16, wherein the helper lipid is 1,2-dioleoyl-SN- glycero-3-phosphoethanolamine (DOPE); 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC); 1,2-dioleoyl-sn-glycero-3-phospho-L-serine (DOPS); 1,2-dielaidoyl-sn-glycero-3- phosphoethanolamine (DEPE); and 1,2-dioleoyl-sn-glycero-3-phosphocholine (DPOC), dipalmitoylphosphatidylcholine (DPPC), 1,2-dilauroyl-sn-glycero-3-phosphocholine (DLPC), 1,2-Distearoylphosphatidylethanolamine (DSPE), or 1,2-dilauroyl-sn-glycero-3- phosphoethanolamine (DLPE). 18. The composition of any one of claims 1-17, wherein the stealth lipid is a polyethylene glycol-conjugated (PEGylated) lipid selected from the group consisting of 1,2-dimyristoyl-rac- glycero-3-methoxypolyethylene glycol (DMG-PEG), 1,2-distearoyl-sn-glycero-3- phosphoethanolamine-polyethylene glycol (DSPE-PEG), 1,2-dilauroyl-sn-glycero-3- phosphoethanolamine-polyethylene glycol (DLPE-PEG), and 1,2-distearoyl-rac-glycero- polyethelene glycol (DSG-PEG). 19. The composition of any one of claims 1-18, wherein the LNP comprises: the ionizable lipid at a molar ratio between 35% and 45%, the structural lipid and cholesterol at a combined molar ratio between 20% and 35%, the stealth lipid at a molar ratio between 0.25% and 8.75%, and the helper lipid at a molar ratio between 25% and 35%. 20. The composition of claim any one of the preceding claims, further comprising a nucleic acid molecule, wherein the nucleic acid molecule is encapsulated in the LNP, wherein the nucleic acid molecule is an mRNA molecule. 21. The composition of claim 20, wherein the mRNA molecule encodes an antigen, optionally a viral antigen or a bacterial antigen. 22. Use of the composition of claim 20 or claim 21 for the manufacture of a medicament for eliciting an immune response in a subject. 23. Use of the composition of claim 20 or claim 21 for the manufacture of a medicament for preventing an infection or reducing one or more symptoms of an infection in a subject. 24. A method of eliciting an immune response in a subject in need thereof, said method comprising administering to the subject a therapeutically effective amount of the composition of claim 20 or claim 21. 25. A method of preventing an infection or reducing one or more symptoms of an infection in a subject in need thereof, said method comprising administering to the subject a therapeutically effective amount of the composition of claim 20 or claim 21.

Description

Sterol Analogs in Lipid Nanoparticle Formulations CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to European Patent Application No.23306050.8, filed June 28, 2023, the disclosure of which is incorporated herein by reference in its entirety. BACKGROUND Effective targeted delivery of biologically active substances such as nucleic acid molecules (e.g., mRNA) represents a continuing medical challenge. In particular, the delivery of nucleic acids to cells is made difficult by their low in vivo stability, propensity toward rapid degradation, and low cell permeability. Thus, there exists a need to develop methods and compositions to facilitate the delivery of therapeutic and/or prophylactics such as nucleic acids to cells. Lipid-containing nanoparticle compositions have proven effective as transport vehicles into cells and/or intracellular compartments for biologically active substances such as small molecule drugs, proteins, and nucleic acids. Such compositions generally include one or more ionizable (e.g., cationic) lipids, phospholipids including polyunsaturated lipids, cholesterol-based lipids, and/or lipids containing polyethylene glycol (PEGylated lipids). Though a variety of such lipid-containing nanoparticle compositions have been demonstrated, there remains a need for lipid nanoparticle formulations having improved efficacy. SUMMARY The present disclosure provides, inter alia, a composition comprising a lipid nanoparticle (LNP), wherein the LNP comprises: (I) an ionizable lipid; (II) a structural lipid selected from the group consisting of α-amyrin, β-amyrin, α-boswellic acid, β-boswellic acid, 11-keto-β-boswellic acid, taraxasterol, senegenin, arjungenin, cycloastrogenol, β-elemonic acid, ganoderic acid B, ganoderic acid D, ganoderic acid H, yamogenin, steviol, brusatol, γ-oryzanol, and combinations thereof; and (III) optionally, cholesterol. In some embodiments, the LNP comprises: (I) an ionizable lipid; (II) a structural lipid selected from the group consisting of α-amyrin, β-amyrin, α-boswellic acid, β-boswellic acid, 11- keto-β-boswellic acid, taraxasterol, senegenin, arjungenin, cycloastrogenol, β-elemonic acid, ganoderic acid B, ganoderic acid D, ganoderic acid H, yamogenin, steviol, brusatol, γ-oryzanol, or a combination thereof; (III) optionally, cholesterol; (IV) a helper lipid; and (V) a stealth lipid. In some embodiments, the LNP comprises: (I) an ionizable lipid; (II) a structural lipid selected from the group consisting of α-amyrin, β-amyrin, α-boswellic acid, β-boswellic acid, 11- keto-β-boswellic acid, taraxasterol, senegenin, arjungenin, cycloastrogenol, β-elemonic acid, yamogenin, steviol, brusatol, γ-oryzanol, and a combination thereof; (III) cholesterol; (IV) a helper lipid; and (V) a stealth lipid. The present disclosure further provides a composition comprising a lipid nanoparticle (LNP), wherein the LNP comprises: (I) an ionizable lipid having a structure according to Formula CAT-I or CAT-II, as defined herein; (II) a structural lipid, wherein said structural lipid is a sterol or sterol analog other than cholesterol; and (III) optionally, cholesterol. In some embodiments, the LNP comprises: (I) an ionizable lipid having a structure according to Formula CAT-I or CAT-II, as defined herein; (II) a structural lipid, wherein said structural lipid is a sterol or sterol analog other than cholesterol; (III) optionally, cholesterol; (IV) a helper lipid; and (V) a stealth lipid. In some embodiments, the LNP comprises: (I) an ionizable lipid having a structure according to Formula CAT-I or CAT-II, as defined herein; (II) a structural lipid, wherein said structural lipid is a sterol or sterol analog other than cholesterol; (III) cholesterol; (IV) a helper lipid; and (V) a stealth lipid. The present disclosure further provides a composition comprising a lipid nanoparticle (LNP), wherein the LNP comprises: (I) an ionizable lipid having a structure according to Formula CAT-I or CAT-II, as defined herein; (II) a structural lipid having a structure according to Formula STR-I, STR-II, SRT-III, STR-IV, or STR-V, or selected from the group consisting of cycloastrogenol, β-elemonic acid, diosgenin, yamogenin, steviol, brusatol, and γ-oryzanol, or a combination thereof; and (III) optionally, cholesterol. In some embodiments, the LNP comprises: (I) an ionizable lipid having a structure according to Formula CAT-I or CAT-II, as defined herein; (II) a structural lipid having a structure according to Formula STR-I, STR-II, SRT-III, STR-IV, or STR-V, or selected from the group consisting of cycloastrogenol, β-elemonic acid, diosgenin, yamogenin, steviol, brusatol, and γ-oryzanol, or a combination thereof; (III) optionally, cholesterol; (IV) a helper lipid; and (V) a stealth lipid. In some embodiments, the LNP comprises: (I) an ionizable lipid having a structure according to Formula CAT-I or CAT-II, as defined herein; (II) a structural lipid having a structure according to Formula