Nature biotechnologyMar 12, 2026

Live test finds how liver cells efficiently receive lipid nanoparticle delivery

CRISPR Gene Editing Weekly Brief ↗PubMed ↗DOI ↗

Updated Jun 28, 2026

Abstract

Essence

A branched ionizable phospholipid LNP improved liver RNA delivery, and an in vivo assay linked stronger performance to faster endosomal escape and altered endolysosomal trafficking.

Evidence

This preclinical liver-delivery study developed branched ionizable phospholipids and used LysoTag mice plus lysosomal barcoding to show that the lead BiP-20 LNP outperformed LP01 eightfold for low-dose TTR gene editing and that about 8% of BiP-20 LNPs reached the cytosol within 30 minutes, alongside proteomic and Rab7-loss mechanistic findings.

Caveat

The results come from mouse delivery and mechanistic endosomal-trafficking experiments, so the hepatic editing advantage and escape mechanisms remain preclinical.

Simplified

Endosomal escape is a central barrier to efficient nucleic acid delivery by lipid nanoparticles (LNPs) and remains challenging to quantify in vivo. We report a library of branched ionizable phospholipids that markedly enhance messenger RNA delivery to the liver. The lead candidate BiP-20 outperformed the clinical benchmark LP01 by eightfold for CRISPR-Cas9 editing of the TTR gene at low dose with rapid pharmacokinetics. To quantify the endosomal escape kinetics of BiP-20, we used LysoTag mice, which allow immunoisolation of liver lysosomes, and our Lysosomal Barcoding method, finding that ~8% of BiP-20 LNPs reach the cytosol within 30 min of administration. Lysosomal proteomics revealed mechanistic regulators of escape and BiP-20-induced alterations in endosomal maturation and recycling pathways. Loss of Rab7, a mediator of late endosomal maturation, increased LNP escape. These findings provide a potent class of ionizable lipids for RNA delivery, a method to quantify endosomal escape in vivo, and mechanistic insight into the endolysosomal determinants of LNP trafficking.