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Engineering of Amino Acid-Derived Ionizable Lipids Enables Inhaled Base Editing for Therapeutic Gene Correction in the Lung

ABSTRACT: CRISPR-based gene editing holds promise for treating genetic diseases, yet its application to lung disorders has been hindered by the challenges of pulmonary delivery. Inspired by the modularity and biocompatibility of amino acid-derived chemistries, we report the combinatorial synthesis of 960 ionizable lipids incorporating chemically diverse backbones from both proteinogenic and non-proteinogenic α-amino acids. Through high-throughput screening and structure-function analysis, we identify CHCha-10, a cyclohexyl amino acid-derived lipid that forms biodegradable nanoparticles capable of efficiently delivering mRNA-based gene editors to lung epithelial cells. Following intratracheal administration, CHCha-10 nanoparticles exhibit enhanced mucus penetration, and epithelial-specific transfection in both mice and ferrets. As a functional application, we demonstrate the first instance of in vivo base editing in the lung via inhalation. Delivery of adenine base editor mRNA and guide RNA targeting the CFTR G542X mutation restores CFTR expression and chloride channel function in G542X human airway epithelial cells, mouse-derived intestinal organoids, and the lungs of cystic fibrosis mice.

ORGANISM(S): Mus musculus

PROVIDER: GSE317845 | GEO | 2026/03/09

REPOSITORIES: GEO

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Amino acid supplementation enhances in vivo efficacy of lipid nanoparticle-mediated mRNA delivery in preclinical models

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