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

• 成果类型: Article
• 署名作者: Chen, Jingan; Zhou, Muye; Dong, Songtao; Gong, Fanglin; Tennakoon, Rasangi; Seto, Breanna Y.; Chen, Ziyan Rachel; Zhou, Zhichang Peter; Pan, Jingyi; Xu, Yue; Luozhong, Sijin; Macarios, Colette Maya; Tijaro-Bulla, Santiago; Gonska, Tanja; Hu, Jim; Cui, Haissi; Li, Bowen
• 署名单位: University of Toronto; University of Toronto; University of Toronto; University of Toronto; Hospital for Sick Children (SickKids); University of Toronto; University of Toronto; University of Toronto; University Health Network Toronto; Princess Margaret Cancer Centre
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-8075; 1095-9203
• DOI: 10.1126/science.aeb0054
• 发表日期: 2026-08-27
• 页码: eaeb0054
• 关键词: aminoacyl-transfer-rna; in-vivo; lipid nanoparticles; gene-expression; messenger-rna; basal-cells; stem-cells; optimization; suppression; cftr

摘要

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.