Mini Review Open Access

Combinatorial Design and Synthesis of Novel Ionizable Lipids for mRNA Delivery with Efficient Chemical Reactions

Abstract

Lipid nanoparticles are the most clinically advanced mRNA delivery system. Ionizable lipid is the most important component of the four components comprising lipid nanoparticles. However, the structure-activity relationship of ionizable lipid is not clear. Traditional complicated design and synthesis procedures of ionizable lipids are time-consuming and laborious. Combinatorial design and synthesis of ionizable lipids with efficient chemical reaction can largely decrease the time of developing novel functional ionizable lipids. Michael addition and epoxy ring-opening reaction are the most used two-component reactions for developing novel lipids. Ugi reaction, A3-coupling, van Leusen imidazole synthesis reaction is efficient multi-component reaction used for ionizable lipid development. However, efficient chemical reactions used for combinatorial design and synthesis of ionizable lipids are still in lack. Therefore, utilizing more novel efficient chemical reactions for ionizable lipid development will certainly provide more novel functional ionizable lipids for efficient mRNA delivery.

Gang Zhang, Hongyi Cui, Xing-Jie Liang*