Nature biomedical engineeringMar 18, 2026

'Tripod-shaped' lung-targeting fats for highly efficient and selective gene delivery and editing particles

mRNA Technology Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Jun 28, 2026

Abstract

Essence

Tripod-like lung-targeting lipids enabled highly selective lung LNP delivery of mRNA and CRISPR editors and improved an acute lung injury mRNA treatment model.

Evidence

This preclinical lipid-platform study synthesized and tested 444 LuT lipids, with lead 1A7B13 LNPs showing 25.5-fold higher mRNA delivery, 9.2-fold higher CRISPR-Cas9 editing, and over 90% lung selectivity versus DOTAP SORT LNPs.

Caveat

The evidence is preclinical carrier optimization and a therapeutic model, so it does not establish safety or efficacy in humans.

Simplified

Developing lung-targeting delivery systems is essential for treating pulmonary conditions such as genetic respiratory diseases, infections, fibrosis and cancer. We synthesized and evaluated 444 lung-targeting lipids (LuT lipids) that form lipid nanoparticles (LNPs) to efficiently deliver messenger RNA and CRISPR-Cas9 genome editors to lungs with minimal side effects. Empirical analyses revealed structure-activity relationships, with top-performing LuT lipids possessing a unique 'tripod-like' structure consisting of a quaternary amine head, three long alkyl chains as legs and a short chain as a handle. LuT lipids improved endosomal escape, cargo release and endogenous targeting via adsorption of plasma proteins. Lead 1A7B13 LNPs showed a 25.5-fold improvement in mRNA delivery and a 9.2-fold increase in CRISPR-Cas9 gene-editing efficiency compared to benchmark DOTAP SORT LNPs, achieving over 90% selectivity to the lungs. 1A7B13 LNPs effectively delivered IL-10 mRNA in a therapeutic model of acute lung injury. This study reveals the relationship between lipid structure and lung-targeting activity, enriching the toolkit for lung-specific carriers.