An ionizable lipid toolbox for RNA delivery

Abstract

Recent years have witnessed incredible growth in RNA therapeutics, which has benefited significantly from decades of research on lipid nanoparticles, specifically its key component—the ionizable lipid. This comment discusses the major ionizable lipid types, and provides perspectives for future development.

Fig. 1. Mechanism for endosome disruption by ionizable lipids and five major structural classes of ionizable lipids.

The cone-shaped ion pairs formed by anionic endosomal phospholipids and protonated ionizable lipids can disrupt the bilayer structure to promote endosomal escape. Based on their structural properties, RNA-delivering ionizable lipids can be categorized into unsaturated (containing unsaturated bond), multi-tail (containing more than two tails), polymeric (containing polymer or dendrimer), biodegradable (containing biodegradable bond) and branched-tail (containing branched tail) ones.

Fig. 2. Selected ionizable lipids under clinical development for COVID-19 mRNA vaccines and other RNA therapeutics.

Ionizable lipids used in on-going clinical trials have not been publicly disclosed, so one of the possible structures (Acuitas A9, Arcturus Lipid 2,2 (8,8) 4C CH3, Genevant CL1 and LP01^,) is shown, respectively. i.v. intravenous, i.m. intramuscular.