The Overlooked Stereoisomers of the Ionizable Lipid ALC315.

ABSTRACT: Lipid nanoparticles (LNPs) are a powerful delivery platform for nucleic acid therapeutics such as mRNA vaccines and gene therapies. Central to their success are ionizable lipids, which facilitate the cellular uptake and endosomal escape of nucleic acids. However, achieving a high delivery efficiency often comes with the drawback of increased cytotoxicity. Here, we report a chemical, biological, and toxicological investigation into the three stereoisomers of ALC315, a mixture of which constitutes one of the most successful marketed ionizable lipids for LNPs. We demonstrate that the individual stereoisomers of ALC315 can be accessed by either the asymmetric chemical synthesis or chromatography of an intermediate. An LNP formulation based on a single stereoisomer of ALC315 enhances mRNA trans

SUBMITTER: De CK 

PROVIDER: S-EPMC12356529 | biostudies-literature | 2025 Aug

REPOSITORIES: biostudies-literature