Amino acid-derived ionizable lipids enable inhaled base editing for therapeutic gene correction in the lung

Nature Materials (2026)Cite this article 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.This is a preview of subscription content, access via your institution Access Nature and 54 other Nature Portfolio journals Get Nature+, our best-value online-access subscription $32.99 / 30 days cancel any timeSubscribe to this journal Receive 12 print issues and online access $259.00 per yearonly $21.58 per issueBuy this articleUSD 39.95Prices may be subject to local taxes which are calculated during checkoutData supporting the findings of this study are available within the article and its Supplementary Information. 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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.These authors contributed equally: Fanglin Gong, Yue Xu.Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, CanadaFanglin Gong, Yue Xu, Jingan Chen, Songtao Dong, Muye Zhou, Rick Xing Ze Lu, Gen Li, Tyler Thomson, David X. W. Chen & Bowen LiInstitute of Biomedical Engineering, University of Toronto, Toronto, Ontario, CanadaFanglin Gong, Jingan Chen, Gen Li, Tyler Thomson & Bowen LiDepartment of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, CanadaShun Zhang & Basil P. HubbardDepartment of Chemistry, University of Toronto, Toronto, Ontario, CanadaLauren Healy, Breanna Seto & Bowen LiDepartment of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa, IA, USAYinghua Tang, John F. Engelhardt & Ziying YanDivision of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USAYinghua Tang, John F. Engelhardt & Ziying YanTranslational Medicine Program, Hospital for Sick Children Research Institute, Toronto, Ontario, CanadaZiyan Chen & Jim HuDepartment of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, CanadaZiyan Chen, Krista Antonio, Amy P. Wong & Jim HuProgram in Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, Ontario, CanadaKrista Antonio & Amy P. WongMichael Smith Laboratories, University of British Columbia, Vancouver, British Columbia, CanadaAndrew VarleyDepartment of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, OH, USACraig A. HodgesDepartment of Pediatrics, Case Western Reserve University School of Medicine, Cleveland, OH, USACraig A. HodgesPrincess Margaret Cancer Center, University Health Network, Toronto, Ontario, CanadaBowen LiSearch author on:PubMed Google ScholarSearch author on:PubMed Google ScholarSearch author on:PubMed Google ScholarSearch author on:PubMed Google ScholarSearch author on:PubMed Google ScholarSearch author on:PubMed Google ScholarSearch author on:PubMed Google ScholarSearch author on:PubMed Google ScholarSearch author on:PubMed Google ScholarSearch author on:PubMed Google ScholarSearch author on:PubMed Google ScholarSearch author on:PubMed Google ScholarSearch author on:PubMed Google ScholarSearch author on:PubMed Google ScholarSearch author on:PubMed Google ScholarSearch author on:PubMed Google ScholarSearch author on:PubMed Google ScholarSearch author on:PubMed Google ScholarSearch author on:PubMed Google ScholarSearch author on:PubMed Google ScholarSearch author on:PubMed Google ScholarSearch author on:PubMed Google ScholarSearch author on:PubMed Google ScholarF.G., Y.X. and B.L. conceived the study and designed the experiments. F.G., Y.X., J.C., S.Z., S.D., L.H., B.S., M.Z., R.X.Z.L., G.L., T.T., Y.T., Z.C. and K.A. performed the experiments and data analysis. F.G., Y.X. and B.L. wrote the study. F.G., A.V., D.X.W.C., J.H., Z.Y. and B.L. discussed the results and edited the paper. C.A.H., A.P.W., J.H., Z.Y., J.F.E., B.P.H. and B.L. acquired funding and supervised the project. All authors provided feedback and helped shape the research, data analysis and paper.Correspondence to Bowen Li.F.G., Y.X. J.C. and B.L. have filed an invention disclosure for ionizable lipids. The other authors declare no competing interests.Nature Materials thanks Yizhou Dong and Olivia Merkel for their contribution to the peer review of this work.Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.Supplementary Notes 1 and 2, Figs. 1–24 and Tables 1–6.Statistical source data.Statistical source data.Statistical source data.Statistical source data.Statistical source data.Unprocessed western blots.Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.Reprints and permissionsGong, F., Xu, Y., Chen, J. et al. Amino acid-derived ionizable lipids enable inhaled base editing for therapeutic gene correction in the lung. Nat. Mater. (2026). https://doi.org/10.1038/s41563-026-02555-0Download citationReceived: 19 May 2025Accepted: 20 February 2026Published: 01 April 2026Version of record: 01 April 2026DOI: https://doi.org/10.1038/s41563-026-02555-0Anyone you share the following link with will be able to read this content:Sorry, a shareable link is not currently available for this article. Provided by the Springer Nature SharedIt content-sharing initiative