Nonviral delivery of chemically modified tRNA rescues nonsense mutations in cystic fibrosis
Suppressor transfer RNAs (sup-tRNAs) can rescue disease-causing nonsense mutations by promoting readthrough of premature termination codons (PTCs). Their clinical translation is limited by suboptimal activity and inefficient in vivo delivery. In this work, we combined site-specific chemical modification of sup-tRNAs with cargo-tailored pulmonary lipid nanoparticle (LNP) engineering to overcome these barriers. Incorporation of N 1 -methyladenosine in sup-tRNAs improved PTC readthrough, enhanced tRNA aminoacylation, prolonged functional persistence, and reduced innate immune activation. High-throughput ionizable lipid screening and formulation optimization identified a sup-tRNA–tailored LNP that efficiently delivered chemically modified sup-tRNAs to the lung. This approach restored cystic fibrosis transmembrane conductance regulator (CFTR) expression and function in bronchial epithelial cells, mouse models, and patient-derived organoids. Thus, LNP-delivered, chemically engineered sup-tRNAs represent a potential therapeutic platform for treating nonsense mutations.
Authors
- Tanja Gonska (ORCID: https://orcid.org/0000-0001-6786-4354)
- Zhichang Peter Zhou
- Sijin Luozhong (ORCID: https://orcid.org/0000-0001-8697-9480)
- Jingyi Pan (ORCID: https://orcid.org/0009-0003-4034-6719)
- Santiago Tijaro‐Bulla (ORCID: https://orcid.org/0009-0003-7408-7903)
- Rasangi Tennakoon
- Haissi Cui (ORCID: https://orcid.org/0000-0003-3358-8958)
- Jim Hu (ORCID: https://orcid.org/0000-0001-9134-7103)
- Muye Zhou
- Colette Maya Macarios (ORCID: https://orcid.org/0000-0002-1049-8581)
- Bowen Li (ORCID: https://orcid.org/0000-0001-5006-9143)
- Yue Xu (ORCID: https://orcid.org/0000-0001-7672-9170)
- Jingan Chen (ORCID: https://orcid.org/0009-0002-5105-102X)
- Songtao Dong (ORCID: https://orcid.org/0009-0000-6841-6924)
- Breanna Y. Seto (ORCID: https://orcid.org/0009-0006-6888-1811)
- Ziyan Rachel Chen
- Fanglin Gong (ORCID: https://orcid.org/0009-0003-4776-9351)
Institutions
- University Health Network (CA)
- University of Toronto (CA)
- Hospital for Sick Children (CA)
- Princess Margaret Cancer Centre (CA)
Publication Details
- Journal
- Science
- Published
- 2026-08-27
- DOI
- https://doi.org/10.1126/science.aeb0054
- Citations
- 1
- Primary Topic
- RNA Interference and Gene Delivery
- Type
- article
- Field-Weighted Citation Impact
- 3.03
Funders
- Cystic Fibrosis Foundation
- J.P. Bickell Foundation
- Cystic Fibrosis Canada
- Canada Research Chairs
- Connaught Fund
- National Institutes of Health
- Harrington Discovery Institute, University Hospitals
- Canadian Institutes of Health Research
- Natural Sciences and Engineering Research Council of Canada
- Leslie Dan Faculty of Pharmacy, University of Toronto