ArticleJournal of the American Chemical Society2025
The Overlooked Stereoisomers of the Ionizable Lipid ALC315.
Article in Journal of the American Chemical Society, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
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Who cites it
4 citing papers in PubMed.
- Safe and sustainable by design (SSbD) for nanotechnology: scientific foundations, global policy perspectives, and industrial practice.Nano convergence · 2026Review
- Structural evolution of ionizable lipids for nucleic acid delivery.Nature reviews. Chemistry · 2026Review
- Epigenetic modifications in cancer drug resistance: molecular mechanisms and therapeutic interventions.Molecular biomedicine · 2026Review
- Engineering a spleen-selective mRNA-LNPs vaccine by decoupling the inflammation from cellular immunity-mediated cancer immunotherapy.Theranostics · 2025Article
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Authors and funding
10 authors.
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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.
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