Thioamides Adjacent to the Ionizable Amine Headgroup in Ionizable Lipids Reduce the p K a of Lipid Nanoparticles and Enhance mRNA Transfection Efficiency in Vitro and in Vivo

in LNPs containing SAM lipids, compared with OAM lipids, is attributed to the increased hydrophobicity of the thioamide group. Furthermore, by synthesizing multiple libraries of SAM lipids and varying the ionizable head group, alkyl chains, and linker length, we discovered thioamide lipids with distinct tissue tropism, including lipids that mediate splenic targeting by LNPs.