Photochemistry-Based Development of Ionizable Lipid Library for mRNA-Lipid Nanoparticle Delivery In Vivo

Abstract Ionizable lipid is a key component of lipid nanoparticle (LNP) for mRNA delivery. However, the discovery of new lipid scaffolds remains constrained by the limited availability of efficient synthetic platforms capable of generating structurally diverse libraries. Here, we report a photochemistry-based ionizable lipid library (PILL) platform that enables the rapid discovery of ionizable lipids for mRNA delivery. Using a visible-light-driven multicomponent reaction under 427 nm irradiation, 275 α-branched amine-containing ionizable lipids were generated in a one-pot process from amines, aldehydes, and boronic acids under mild conditions. This modular photochemical strategy enabled the rapid construction of a structurally diverse lipid library that was directly integrated with purification-free in vitro screening and subsequent in vivo validation. A18B8C14 was identified as a lead ionizable lipid candidate for mRNA delivery, and the optimized A18B8C14-LNP formulation exhibited substantially higher in vivo gene expression than the benchmark MC3-based LNP while maintaining a favorable safety profile. In addition, organ-specific delivery could be achieved by adjusting the A18B8C14-LNP formulation according to the selective organ targeting (SORT) strategy. Together, these results establish photochemistry as a practical platform for ionizable lipid discovery and provide a versatile framework for the development of next-generation LNP systems for nucleic acid therapeutics.