2026年8月27日，加拿大多伦多大学药学院Bowen Li等科学家在《科学》发表研究，通过化学修饰tRNA结合肺靶向脂质纳米颗粒（LNP）递送，成功恢复了囊性纤维化中无义突变所致的CFTR蛋白表达与功能。

抑制型转移RNA（sup-tRNA）可通过促进提前终止密码子（PTC）的通读来挽救致病性无义突变。其临床转化受到活性欠佳和体内递送效率低下的限制。在这项工作中，研究人员将sup-tRNA的位点特异性化学修饰与货物特化的肺部脂质纳米颗粒（LNP）工程相结合，以克服这些障碍。在sup-tRNA中掺入N1-甲基腺苷可提高PTC通读效率，增强tRNA氨酰化，延长功能持续性，并减少先天免疫激活。通过高通量可电离脂质筛选和制剂优化，研究人员鉴定出一种适合sup-tRNA的LNP，能够高效地将化学修饰的sup-tRNA递送至肺部。该方法在支气管上皮细胞、小鼠模型和患者来源的类器官中恢复了囊性纤维化跨膜传导调节因子（CFTR）的表达和功能。因此，LNP递送的化学工程化sup-tRNA代表了治疗无义突变的一种潜在治疗平台。

附：英文原文

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

Author: 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

Issue&Volume: 2026-08-27

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.

DOI: 10.1126/science.aeb0054

Source: https://www.science.org/doi/10.1126/science.aeb0054