Chemical Design Strategy of Ionizable Lipids for In Vivo mRNA Delivery

Abstract Lipid nanoparticles (LNPs) are the most clinically successful drug delivery systems that have accelerated the development of mRNA drugs and vaccines. Among various structural components of LNPs, more recent attention has been paid in ionizable lipids (ILs) that was supposed as the key component in determining the effectiveness of LNPs for in vivo mRNA delivery. ILs are typically comprised of three moieties including ionizable heads, linkers, and hydrophobic tails, which suggested that the combination of different functional groups in three moieties could produce ILs with diverse chemical structures and biological identities. In this concept article, we provide a summary of chemical design strategy for high‐performing IL candidates and discuss their structure‐activity relationships for shifting tissue‐selective mRNA delivery. We also propose an outlook for the development of next‐generation ILs, enabling the broader translation of mRNA formulated with LNPs.