Science (New York, N.Y.) · 2026
Nonviral delivery of chemically modified tRNA rescues nonsense mutations in cystic fibrosis.
СтатьяНазвание и аннотация: Перевод в очереди
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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
Аннотация
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.