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In vivo endosomal escape assay identifies mechanisms for efficient hepatic LNP delivery
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DOI：10.1038/s41587-026-03022-6.png)
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Abstract
En 中文
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. Endosomal escape of lipid nanoparticles is quantified and optimized in vivo.
Keywords:
Gene therapy
Nanoparticles
Proteomics
Life Sciences
general
Biotechnology
Biomedicine
Agriculture
Biomedical Engineering/Biotechnology
Bioinformatics
Journal
IF:
41.7
Papers:
1.2W
Citations:
10.1W
Organization
Cited Papers