Nonviral delivery of chemically modified tRNA rescues nonsense mutations in cystic fibrosis.

Authors

Jingan Chen, Muye Zhou, Songtao Dong, Fanglin Gong, Rasangi Tennakoon, Breanna Y Seto, Ziyan Rachel Chen, Zhichang Peter Zhou, Jingyi Pan, Yue Xu, Sijin Luozhong, Colette Maya Macarios, Santiago Tijaro-Bulla, Tanja Gonska, Jim Hu, Haissi Cui, Bowen Li

Published in

Science (New York, N.Y.). Volume 393. Issue 6814. Pages eaeb0054. Aug 27, 2026. Epub Aug 27, 2026.

Abstract

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 N¹-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.

PMID:
42658930
Bibliographic data and abstract were imported from PubMed on 28 Aug 2026.

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