Ligand-tethered lipid nanoparticles for targeted RNA delivery to treat liver fibrosis

Lipid nanoparticle-mediated RNA delivery holds great potential to treat various liver diseases. However, targeted delivery of RNA therapeutics to activated liver-resident fibroblasts for liver fibrosis treatment remains challenging. Here, we develop a combinatorial library of anisamide ligand-tethered lipidoids (AA-lipidoids) using a one-pot, two-step modular synthetic method and adopt a two-round screening strategy to identify AA-lipidoids with both high potency and selectivity to deliver RNA payloads to activated fibroblasts. The lead AA-lipidoid AA-T3A-C12 mediates greater RNA delivery and transfection of activated fibroblasts than its analog without anisamide and the FDA-approved MC3 ionizable lipid. In a…

• NS
  National Science Foundation

  Awards: CBET-2145491, 1845298, CAREER, 2145491
• UO
  University of Pennsylvania
• NI
  National Institutes of Health

  Awards: NIDDK R01 DK123049, DP2 TR002776, R01 DK123049, NCI R01 CA241661, NCI R01, NCI R37 CA244911, NIDDK R01
• NC
  National Cancer Institute

  Awards: R37 CA244911, R01 CA241661
• NI
  National Institute of Diabetes and Digestive and Kidney Diseases

  Award: R01 DK123049
• DO
  Division of Chemical, Bioengineering, Environmental, and Transport Systems

  Awards: CBET-2145491, 2145491