Zhang Yu, Liu Xiang, Shen Tingting, Wang Qiyan, Zhou Shurong, Yang Suling, Liao Shimiao, Su Ting, Mei Lei, Zhang Bei, Huynh Khoa, Xie Linying, Guo Youzhong, Guo Chunqing, Tyc Katarzyna M, Qu Xufeng, Wang Xiang-Yang, Liu Jinze, Zhu Guizhi
Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI, USA.
The Key Laboratory of Zhejiang Province for Aptamers and Theranostics, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, China.
Nat Biomed Eng. 2025 Feb;9(2):249-267. doi: 10.1038/s41551-025-01344-5. Epub 2025 Feb 7.
Messenger RNA vaccines have shown strong prophylactic efficacy against viral infections. Here we show that antigen-encoding small circular RNAs (circRNAs) loaded in lipid nanoparticles elicit potent and durable T cell responses for robust tumour immunotherapy after subcutaneous injection in mice, particularly when combined with immune checkpoint inhibition. The small circRNA vaccines are highly stable and show low levels of activation of protein kinase R as well as low cytotoxicity, enabling long-lasting antigen translation (longer than 1 week in cells). Relative to large protein-encoding unmodified or modified mRNAs and circRNAs, small circRNA vaccines elicited up to 10-fold antigen-specific T cells in mice and accounted for 30-75% of the total peripheral CD8 T cells over 6 months. Small circRNA vaccines encoding tumour-associated antigens, neoantigens and oncoviral or viral antigens elicited substantial CD8 and CD4 T cell responses in young adult mice and in immunosenescent aged mice. Combined with immune checkpoint inhibition, monovalent and multivalent circRNA vaccines reduced tumour-induced immunosuppression and inhibited poorly immunogenic mouse tumours, including melanoma resistant to immune checkpoint blockade.
信使核糖核酸疫苗已显示出对病毒感染具有强大的预防功效。在此，我们表明，负载于脂质纳米颗粒中的编码抗原的小环状核糖核酸（circRNA）在小鼠皮下注射后，可引发强效且持久的T细胞反应，用于强大的肿瘤免疫治疗，尤其是与免疫检查点抑制联合使用时。小环状核糖核酸疫苗高度稳定，蛋白激酶R的激活水平低且细胞毒性低，可实现持久的抗原翻译（在细胞中超过1周）。相对于编码蛋白质的未修饰或修饰的大信使核糖核酸和环状核糖核酸，小环状核糖核酸疫苗在小鼠体内引发的抗原特异性T细胞数量高达10倍，并在6个月内占外周CD8 T细胞总数的30%至75%。编码肿瘤相关抗原、新抗原以及肿瘤病毒或病毒抗原的小环状核糖核酸疫苗在年轻成年小鼠和免疫衰老的老年小鼠中引发了大量的CD8和CD4 T细胞反应。与免疫检查点抑制联合使用时，单价和多价环状核糖核酸疫苗可减少肿瘤诱导的免疫抑制，并抑制免疫原性较差的小鼠肿瘤，包括对免疫检查点阻断有抗性的黑色素瘤。
