Discovery of Ketal-Ester Ionizable Lipid Nanoparticle with Reduced Hepatotoxicity, Enhanced Spleen Tropism for mRNA Vaccine Delivery.

ABSTRACT: The safety and efficacy of the lipid nanoparticle (LNP) delivery system are crucial for the successful development of messenger RNA vaccines. We designed and synthesized a series of ketal ester lipids (KELs), featuring a biodegradable ketal moiety in the linker and ester segments in the tail. Through iterative optimization of the head and tail groups of KELs, we tuned the pKa and molecular shapes, and identified (4S)-KEL12 as a safe and efficient ionizable lipid for mRNA delivery. (4S)-KEL12 LNP showed significantly higher delivery efficacy and lower toxicity than the DLin-MC3-DMA LNP. In comparison to SM-102 LNP, (4S)-KEL12 LNP exhibited better spleen tropism, reduced liver tropism, and hepatotoxicity. Additionally, (4S)-KEL12 demonstrated good biodegradability following intramuscular or

SUBMITTER: Lv K 

PROVIDER: S-EPMC11615764 | biostudies-literature | 2024 Dec

REPOSITORIES: biostudies-literature