Journal of the American Chemical SocietySep 3, 2026

Creating Light-Activated Ionizable Lipids for Delivering mRNA Nanoparticles in Living Organisms

mRNA Technology Weekly Brief ↗PubMed ↗DOI ↗

Updated Sep 4, 2026

Abstract

A library of 275 ionizable lipids was created using a photochemistry-based platform for mRNA delivery.

The photochemistry-based ionizable lipid library (PILL) platform facilitates the rapid discovery of new lipids.
A visible-light-driven reaction produced structurally diverse lipids from common chemical precursors in a single process.
A18B8C14 was identified as a promising candidate for mRNA delivery, showing improved in vivo gene expression compared to the existing MC3-based lipid formulation.
The A18B8C14-LNP formulation demonstrated a favorable safety profile while enabling organ-specific delivery through formulation adjustments.
The findings indicate that photochemistry could serve as an effective method for developing new lipid nanoparticles for nucleic acid therapies.

Simplified

Ionizable lipid is a key component of lipid nanoparticle (LNP) for mRNA delivery. However, the discovery of new lipid scaffolds remains constrained by the limited availability of efficient synthetic platforms capable of generating structurally diverse libraries. Here, we report a photochemistry-based ionizable lipid library (PILL) platform that enables the rapid discovery of ionizable lipids for mRNA delivery. Using a visible-light-driven multicomponent reaction under 427 nm irradiation, 275 α-branched amine-containing ionizable lipids were generated in a one-pot process from amines, aldehydes, and boronic acids under mild conditions. This modular photochemical strategy enabled the rapid construction of a structurally diverse lipid library that was directly integrated with purification-free in vitro screening and subsequent in vivo validation. A18B8C14 was identified as a lead ionizable lipid candidate for mRNA delivery, and the optimized A18B8C14-LNP formulation exhibited substantially higher in vivo gene expression than the benchmark MC3-based LNP while maintaining a favorable safety profile. In addition, organ-specific delivery could be achieved by adjusting the A18B8C14-LNP formulation according to the selective organ targeting (SORT) strategy. Together, these results establish photochemistry as a practical platform for ionizable lipid discovery and provide a versatile framework for the development of next-generation LNP systems for nucleic acid therapeutics.

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Creating Light-Activated Ionizable Lipids for Delivering mRNA Nanoparticles in Living Organisms

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