Proceedings of the National Academy of Sciences of the United States of AmericaMay 26, 2026

Easy-to-build biodegradable lipids for strong mRNA delivery and gene editing in living animals

mRNA Technology Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Jun 27, 2026

Abstract

Essence

A modular chemistry platform produced biodegradable lipids that may improve mRNA gene-editing delivery in mice.

Evidence

Preclinical platform experiments assembled and screened 500 ionizable lipids, modeled in vitro structure-activity patterns, and tested a lead LNP for delivery of gene-editing tools in wild-type and genetically modified mice against benchmark LNPs.

Caveat

The evidence is limited to delivery-platform performance in vitro and in mice, not disease correction or human clinical testing.

Simplified

mRNA-based gene editing therapeutics offer the potential to permanently cure diseases but are hindered by suboptimal delivery platforms. Here, we devise a robust combinatorial chemistry for the plug-and-play assembly of structurally diverse biodegradable ionizable lipids from amines/thiols and dialkyl maleates. After screening 500 ionizable lipids, we obtained structure-activity relationships essential for effective in vitro mRNA delivery with the help of machine learning. Furthermore, we identified a lead ionizable lipid candidate that produced potent lipid nanoparticles for the delivery of various gene editing tools in wild-type and genetically modified mice compared to literature and industry benchmark lipid nanoparticles. Mechanistically, our lipid nanoparticles show favorable physicochemical properties, which could synergistically contribute to the superior delivery performance. This study highlights the utility of this synthetic method as well as the generality of this platform for potent in vivo gene editing.