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WO-2026096364-A1 - ENDOGENOUS TARGETING LIPID NANOPARTICLES (ENDO) FOR SYSTEMIC DELIVERY OF THERAPEUTIC AGENTS TO PANCREAS

WO2026096364A1WO 2026096364 A1WO2026096364 A1WO 2026096364A1WO-2026096364-A1

Abstract

Described herein are methods and lipid nanoparticle compositions for delivering therapeutic agents to the pancreas.

Inventors

  • ISAAC, Ivan
  • BHATTACHARYA, Chandrabali

Assignees

  • THE BOARD OF REGENTS OF THE NEVADA SYSTEM OF HIGHER EDUCATION ON BEHALF OF THE UNIVERSITY OF NEVADA, LAS VEGAS

Dates

Publication Date
20260507
Application Date
20251027
Priority Date
20241028

Claims (20)

  1. 1. A lipid nanoparticle composition comprising: one or more ionizable lipids; one or more non-ionizable lipids; one or more PEG-modified lipids; cholesterol or a derivative thereof; and about 5 mole percent (mol%) to about 25 mol% vitamin A, vitamin B, vitamin D, vitamin E, or vitamin K; or about 5 mol% to about 25 mol% a vitamin A receptor binder, a vitamin B receptor binder, a vitamin D receptor binder, a vitamin E receptor binder, or a vitamin K receptor binder.
  2. 2. The composition of claim 1 , wherein the composition comprises about 10 mol% to about 15 mol% vitamin D or a vitamin D receptor binder.
  3. 3. The composition of claim 1, wherein the vitamin D is vitamin D3 (cholecalciferol).
  4. 4. The composition of claim 1 , wherein the vitamin D receptor binder is a selective antagonist of the vitamin D receptor.
  5. 5. The composition of claim 1 , wherein the one or more ionizable lipids comprise cationic lipids selected from the group consisting of C12-200, SM-102, and combinations thereof.
  6. 6. The composition of claim 1 , wherein the one or more non-ionizable lipids comprise phospholipids.
  7. 7. The composition of claim 6, wherein the phospholipids are selected from the group consisting of 1 ,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), 1 ,2-distearoyl-sn- glycero-3-phosphocholine (DSPC), and combinations thereof.
  8. 8. The composition of claim 1 , wherein the one or more PEG-modified lipids are selected from the group consisting of 1 ,2-dimyristoyl-rac-glycero-3-methoxypolyethylene glycol- 2000 (DMG-PEG 2000), 1 ,2-distearoyl-sn-glycero-3-phosphoethanolamine-N- 208034-0009-W001 [amino(polyethylene glycol) (DSPE-PEG), 1 ,2-distearoyl-sn-glycero-3- phosphoethanolamine with conjugated methoxyl polyethylene glycol) (mPEG-DSPE), 1 ,2-dimyristoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)- 2000] (14:0 PEG2000 PE), and combinations thereof.
  9. 9. The composition of claim 1 , wherein the composition comprises: about 20 mol% to about 35 mol% ionizable lipids; about 15 mol% to about 17.5 mol% non-ionizable lipids; about 1 mol% to about 4 mol% PEG-modified lipids; and about 40 mol% to about 48 mol% cholesterol or a derivative thereof.
  10. 10. The composition of claim 1 , further comprising a therapeutic agent encapsulated in the lipid nanoparticle.
  11. 11. The composition of claim 10, wherein the therapeutic agent comprises one or more nucleic acid molecules.
  12. 12. The composition of claim 11 , wherein the one or more nucleic acid molecules comprise DNA, RNA, mRNA, or a combination thereof.
  13. 13. The composition of claim 11 , wherein the one or more nucleic acid molecules comprise one or more plasmid DNA, circular mRNA, Cas9 mRNA, guide RNA, or a combination thereof.
  14. 14. The composition of claim 1 , wherein the lipid nanoparticle has a diameter size of about 50 nm to about 200 nm.
  15. 15. The composition of claim 1 , wherein the lipid nanoparticle has a polydispersity index (PDI) of about 0.05 to about 0.3.
  16. 16. A method of delivering a lipid nanoparticle composition to a pancreas of a subject, the method comprising: administering to a subject a lipid nanoparticle composition comprising: one or more ionizable lipids; 208034-0009-W001 one or more non-ionizable lipids; one or more PEG-modified lipids; cholesterol or a derivative thereof; and about 5 mole percent (mol%) to about 25 mol% vitamin A, vitamin B, vitamin D, vitamin E, or vitamin K; or about 5 mol% to about 25 mol% a vitamin A receptor binder, a vitamin B receptor binder, a vitamin D receptor binder, a vitamin E receptor binder, or a vitamin K receptor binder.
  17. 17. The method of claim 16, wherein the lipid nanoparticle composition is administered to the subject by intravenous, intraperitoneal, or intramuscular injection.
  18. 18. The method of claim 16, wherein the vitamin D is vitamin D3 (cholecalciferol).
  19. 19. The method of claim 16, wherein the vitamin D receptor binder is a selective antagonist of the vitamin D receptor.
  20. 20. The method of claim 16, wherein the one or more ionizable lipids comprise cationic lipids selected from the group consisting of C12-200, SM-102, and combinations thereof.

Description

208034-0009-W001 ENDOGENOUS TARGETING LIPID NANOPARTICLES (ENDO) FOR SYSTEMIC DELIVERY OF THERAPEUTIC AGENTS TO PANCREAS CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63/800,917, filed on May 6, 2025, and U.S. Provisional Patent Application No. 63/712,809, filed on October 28, 2024, each of which is incorporated by reference herein in its entirety. BACKGROUND Lipid nanoparticles (LNPs) have revolutionized the field of nucleic acid delivery and have been extensively explored in gene therapy, protein replacement therapies, and immunotherapies for various diseases. Their clinical applications were notably demonstrated by their widespread use in delivering the SARS-CoV-2 vaccine during the COVID-19 pandemic. Despite their promise, targeting beyond the liver remains a significant challenge with the traditional LNPs, which are made up of four key components — ionizable lipid, phospholipid, cholesterol, and polyethylene glycol (PEG) lipid. The accumulation of LNPs in the liver primarily occurs because they associate with Apolipoprotein E (ApoE) in the blood, which is crucial for cholesterol transport and low-density lipoprotein receptor (LDLR)-mediated endocytosis. The mode of administration also plays a critical role in redirecting LNPs to extrahepatic sites. Previously, intraperitoneal administration effectively redirected nanoparticles to the pancreas with robust and specific protein expression via macrophage-mediated gene transfer. Another promising approach for redirecting LNPs to extrahepatic sites is incorporating a fifth component in the traditional LNP formulation. This strategy has been effective in achieving lung- and spleen-specific mRNA expression through interactions with plasma proteins, such as vitronectin (Vtn) and [32 glycoprotein 1 ( 2-GPI), using SORT LNPs containing a fifth component cationic or anionic lipid. Furthermore, the addition of an adjuvant lipidoid containing a Toll-like receptor (TLR) 7/8 agonist as a fifth component also successfully demonstrated transfection in the lymph nodes. This illustrates the potential of LNPs to target other hard-to-reach tissues with formulation design, overcoming the inherent limitations of classical four-component LNPs. What is needed are endogenous targeting lipid nanoparticles (ENDO) for systemic delivery of therapeutic agents to the pancreas and other tissues. 208034-0009-W001 SUMMARY One embodiment described herein is a lipid nanoparticle composition comprising: one or more ionizable lipids; one or more non-ionizable lipids; one or more PEG-modified lipids; cholesterol or a derivative thereof; and about 5 mole percent (mol%) to about 25 mol% vitamin A, vitamin B, vitamin D, vitamin E, or vitamin K; or about 5 mol% to about 25 mol% a vitamin A receptor binder, a vitamin B receptor binder, a vitamin D receptor binder, a vitamin E receptor binder, or a vitamin K receptor binder. In one aspect, the composition comprises about 10 mol% to about 15 mol% vitamin D or a vitamin D receptor binder. In another aspect, the vitamin D is vitamin D3 (cholecalciferol). In another aspect, the vitamin D receptor binder is a selective antagonist of the vitamin D receptor. In another aspect, the one or more ionizable lipids comprise cationic lipids selected from the group consisting of C12-200, SM-102, and combinations thereof. In another aspect, the one or more non-ionizable lipids comprise phospholipids. In another aspect, the phospholipids are selected from the group consisting of 1 ,2-dioleoyl-sn-glycero-3- phosphoethanolamine (DOPE), 1 ,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), and combinations thereof. In another aspect, the one or more PEG-modified lipids are selected from the group consisting of 1 ,2-dimyristoyl-rac-glycero-3-methoxypolyethylene glycol-2000 (DMG- PEG 2000), 1 ,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol) (DSPE-PEG), 1 ,2-distearoyl-sn-glycero-3-phosphoethanolamine with conjugated methoxyl polyethylene glycol) (mPEG-DSPE), 1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine-N- [methoxy(polyethylene glycol)-2000] (14:0 PEG2000 PE), and combinations thereof. In another aspect, the composition comprises: about 20 mol% to about 35 mol% ionizable lipids; about 15 mol% to about 17.5 mol% non-ionizable lipids; about 1 mol% to about 4 mol% PEG-modified lipids; and about 40 mol% to about 48 mol% cholesterol or a derivative thereof. In another aspect, the composition further comprises a therapeutic agent encapsulated in the lipid nanoparticle. In another aspect, the therapeutic agent comprises one or more nucleic acid molecules. In another aspect, the one or more nucleic acid molecules comprise DNA, RNA, mRNA, or a combination thereof. In another aspect, the one or more nucleic acid molecules comprise one or more plasmid DNA, circular mRNA, Cas9 mRNA, guide RNA, or a combination thereof. In another aspect, the lipid nanoparticle has a diameter size o