Journal article
Amino acid-derived ionizable lipids enable inhaled base editing for therapeutic gene correction in the lung
Nature materials
04/01/2026
DOI: 10.1038/s41563-026-02555-0
PMID: 41922838
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. Here, as a functional application, we demonstrate 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. This work establishes a chemically modular design framework for ionizable lipids and a translatable platform for RNA-based pulmonary gene correction.
Details
- Title: Subtitle
- Amino acid-derived ionizable lipids enable inhaled base editing for therapeutic gene correction in the lung
- Creators
- Fanglin Gong - University of TorontoYue Xu - University of TorontoJingan Chen - University of TorontoShun Zhang - University of TorontoSongtao Dong - University of TorontoLauren Healy - University of TorontoBreanna Seto - University of TorontoMuye Zhou - University of TorontoRick Xing Ze Lu - University of TorontoGen Li - University of TorontoTyler Thomson - University of TorontoYinghua Tang - University of IowaZiyan Chen - University of TorontoKrista Antonio - University of TorontoAndrew Varley - University of British ColumbiaDavid X W Chen - University of TorontoCraig A Hodges - Case Western Reserve UniversityAmy P Wong - University of TorontoJim Hu - University of TorontoBasil P Hubbard - University of TorontoJohn F Engelhardt - University of IowaZiying Yan - University of IowaBowen Li - University of Toronto
- Resource Type
- Journal article
- Publication Details
- Nature materials
- DOI
- 10.1038/s41563-026-02555-0
- PMID
- 41922838
- NLM abbreviation
- Nat Mater
- ISSN
- 1476-4660
- eISSN
- 1476-4660
- Publisher
- Nature Publishing Group
- Grant note
- J.C. acknowledges support from the PRiME Fellowship and the Nanomedicine Innovation Network Doctoral AwardR.L. acknowledges the Acceleration Consortium Postdoctoral Fellowship.Cystic Fibrosis Foundation grant (HODGES19R1)National Heart, Lung, and Blood Institute Federal Contract (75N92024C00008 to J.F.E.) and Cystic Fibrosis Foundation grant(ENGELH21XX0)D.C. acknowledges a CIHR Canada Graduate Research Scholarship (Master's)T.T. acknowledges the Cystic Fibrosis Foundation Student Traineeship (008475H224, Thomson) and the Ontario Graduate ScholarshipL.H. acknowledges the Queen Elizabeth II/F.E. Beamish Graduate Scholarships in Science and TechnologyThe authors acknowledge the funding support from the GSK Chair Professorship, the Leslie Dan Faculty of Pharmacy startup fund, the Princess Margaret Cancer Center operating fund, the Connaught Fund (514681, 523859), the J.P. Bickell Foundation (515159), thB.S. acknowledges the Ontario Graduate ScholarshipNational Institutes of Health grant (R01 HL174593) and Cystic Fibrosis Foundation grant (YAN23G0)
We acknowledge the funding support from the GSK Chair Professorship, the Leslie Dan Faculty of Pharmacy startup fund, the Princess Margaret Cancer Center operating fund, the Connaught Fund (grant nos. 514681 and 523859), the J.P. Bickell Foundation (grant no. 515159), the Canada Research Chairs Program (grant no. CRC-2022-00575), the Canadian Institutes of Health Research (CIHR) Project Grants (grant nos. PJH-185722, PJT-190109, PJT-192011, PJT-195669 and PJT-203954), Ontario Early Researcher Awards Program (grant no. ER24-18-177), Stem Cell Network (grant no. ECR-C5R1-5), National Sanitarium Association (grant no. 522574), Cystic Fibrosis Canada (grant no. 1188219), the New Frontiers in Research Fund (grant no. NFRFE-2023-00203), the Natural Sciences and Engineering Research Council of Canada (grant no. RGPIN-2023-05124), National Institutes of Health (NIH) grants (grant nos. 1R01HL174773 to B.L. and R01 HL174593 to Z.Y.), the National Heart, Lung, and Blood Institute Federal Contract (grant no. 75N92025C00007 to J.F.E.) and Cystic Fibrosis Foundation grants (grant nos. LI23G0 and LI23I0 to B.L., HODGES19R1 to C.A.H., ENGELH21XX0 to J.F.E. and YAN23G0 to Z.Y). J.C. acknowledges support from the PRiME Fellowship and the Nanomedicine Innovation Network Doctoral Award. L.H. acknowledges the Queen Elizabeth II/F.E. Beamish Graduate Scholarships in Science and Technology. B.S. acknowledges the Ontario Graduate Scholarship. R.X.Z.L. acknowledges the Acceleration Consortium Postdoctoral Fellowship. T.T. acknowledges the Cystic Fibrosis Foundation Student Traineeship (grant no. 008475H224, Thomson) and the Ontario Graduate Scholarship. D.X.W.C. acknowledges a CIHR Canada Graduate Research Scholarship (Master's). The authors acknowledge technical support from the Centre for Pharmaceutical Oncology Flow Cytometry and Imaging facilities and the Princess Margaret Cancer Centre for access to NMR and animal facilities. Figures 1d, 2a and 4c,f were generated via Bioinformatics at https://www.bioinformatics.com.cn, an online platform for data analysis and visualization.
- Language
- English
- Electronic publication date
- 04/01/2026
- Academic Unit
- Anatomy and Cell Biology
- Record Identifier
- 9985148849802771
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