Rational design and combinatorial chemistry of ionizable lipids for RNA delivery
In 2018, LNPs enabled the first FDA approval of a siRNA drug (Onpattro); two years later, two SARS-CoV-2 vaccines (Comirnaty, Spikevax) based on LNPs containing mRNA also arrived at the clinic, saving millions of lives during the COVID-19 pandemic. Notably, each of the three FDA-approved LNP formulations uses a unique ionizable lipid while the other three components, i.e., cholesterol, helper lipid, and PEGylated lipid, are almost identical. Therefore, ionizable lipids are critical to the delivery efficiency of mRNA. This review covers recent advances in ionizable lipids used in RNA delivery over the past several decades. We will discuss chemical structures, synthetic routes, and structure–activity relationships of ionizable lipids.
- This article is part of the themed collections: Journal of Materials Chemistry B Recent Review Articles, Journal of Materials Chemistry B Emerging Investigators and mRNA vaccines against COVID-19: Celebrating the 2023 Nobel Prize in Physiology or Medicine