ALC-0315 is a key component of the COVID‐19mRNA vaccine and a highly sought-after lipid for nucleic acid therapeutics research [1]. Ionizable cationic lipids are essential for efficient in vivo delivery of RNA by lipid nanoparticles (LNPs). DLin-MC3-DMA (MC3), ALC-0315, and SM-102 are the only ionizable cationic lipids currently clinically approved for RNA therapies. ALC-0315 and SM-102 are structurally similar lipids used in SARS-CoV-2 mRNA vaccines [2].
Cationic lipids (CLs) and ionizable lipids (ILs) initiate the first step of self-assembly via electrostatic interactions. because of toxicity issues and lack of in vivo efficacy, CLs have been replaced by pH-sensitive ILs. The overall architecture of CLs and ILs can be broken down into three parts: (1) the headgroup, (2) the linker, and (3) the tails. The headgroups of ALC-0315 contain a terminal hydroxyl group which could decrease the hydration of the headgroup and improve hydrogen-bonding interactions with the nucleic acid, potentially leading to improved transfection ability. The linker typically connects the headgroup with the tails, although the linkers may also be buried within the tails. DLin-MC3-DMA, ALC-0315, and SM-102 all have ester linkers. DLin-MC3-DMA has two linoleyl tails, while ALC-0315 and SM-102 contain two branched saturated tails that are postulated to endow a cone-shaped geometry, facilitating destabilization of the endosomal membrane and cytosolic release of the nucleic acid [3].
References:
[1]. Saadati F, Cammarone S, Ciufolini M A. A Route to Lipid ALC‐0315: a Key Component of a COVID‐19 mRNA Vaccine[J]. Chemistry–A European Journal, 2022, 28(48): e202200906.
[2]. Ferraresso F, Strilchuk A W, Juang L J, et al. Comparison of DLin-MC3-DMA and ALC-0315 for siRNA Delivery to Hepatocytes and Hepatic Stellate Cells[J]. Molecular Pharmaceutics, 2022.
[3]. Eygeris Y, Gupta M, Kim J, et al. Chemistry of lipid nanoparticles for RNA delivery[J]. Accounts of Chemical Research, 2021, 55(1): 2-12.