Nature biotechnologySep 28, 2026

Improved lipid nanoparticles for delivering large RNA and targeting tissues to boost genome editing in living organisms

CRISPR Gene Editing Weekly Brief ↗PubMed ↗DOI ↗

Updated Sep 30, 2026

Abstract

LC-1 achieved up to 79% Cas9-mediated knockout in the liver with a 5.7-kb mRNA.

Large-cargo-optimized lipids were identified through a screening of 384 lipids.
LC-1 demonstrated significantly higher knockout efficiency compared to benchmarks LP-01 and ALC-0315.
In addition to liver, LC-1 also achieved 48% knockout in the brain and 27% in the lung.
Mechanistic studies indicated that LC-1 maintains stronger lipid-RNA interactions as mRNA size increases.
Unlike other lipids, LC-1 retains a stable structure that supports effective mRNA delivery.

Simplified

Although lipid nanoparticles are clinically validated for RNA delivery, their potency often declines as transcript size increases. Here we report a large-cargo-informed lipid discovery strategy that incorporates mRNA size into ionizable lipid screening. A combinatorial library of 384 lipids was screened using a 5.7-kb ABE-NanoLuc reporter mRNA, identifying large-cargo-optimized lipids led by LC-1. Following intravenous, intrathecal and intratracheal administration, LC-1 achieved up to 79% Cas9-mediated knockout in liver and 48% and 27% in brain and lung, up to fourfold higher than LP-01 and ALC-0315, and produced higher ABE-mediated reporter correction across all three routes. LC-1 supported base editing of PCSK9, CFTR^R55X and Ube3a-ATS. Mechanistic studies showed that, unlike the benchmarks, LC-1 forms stronger lipid-RNA interactions and retains an ordered, fusogenic inverted-hexagonal structure and pH-responsive membrane disruption as mRNA size increases, rather than becoming disordered. These findings establish cargo size as a key design parameter for ionizable lipid discovery.