2025-08-04 北海道大学
代表的なイオン化脂質「ALC-0315」の構造とその生物学的影響
<関連情報>
- https://www.hokudai.ac.jp/news/2025/08/mrna-2.html
- https://www.hokudai.ac.jp/news/pdf/250804_pr2.pdf
- https://pubs.acs.org/doi/10.1021/jacs.5c08345
イオン化脂質 ALC0315 の立体異性体の合成と生物学的影響の評価 The Overlooked Stereoisomers of the Ionizable Lipid ALC315
Chandra Kanta De,Masumi Tsuda,Chendan Zhu,Stefanie Dehn,Heike Hinrichs,Nobuya Tsuji,Hui Jin,Hisashi Arase,Shinya Tanaka,and Benjamin List
Journal of the American Chemical Society Published: July 31, 2025
DOI:https://doi.org/10.1021/jacs.5c08345
Abstract
Lipid nanoparticles (LNPs) are a powerful delivery platform for nucleic acid therapeutics such as mRNA vaccines and gene therapies. Central to their success are ionizable lipids, which facilitate the cellular uptake and endosomal escape of nucleic acids. However, achieving a high delivery efficiency often comes with the drawback of increased cytotoxicity. Here, we report a chemical, biological, and toxicological investigation into the three stereoisomers of ALC315, a mixture of which constitutes one of the most successful marketed ionizable lipids for LNPs. We demonstrate that the individual stereoisomers of ALC315 can be accessed by either the asymmetric chemical synthesis or chromatography of an intermediate. An LNP formulation based on a single stereoisomer of ALC315 enhances mRNA transfer efficiency while reducing the associated cytotoxicity in human cell lines. Our results underscore the potential of stereochemically pure ionizable lipids as key components in the development of next-generation nucleic acid therapies, offering an enhanced delivery performance and better safety profiles.
