近日，中国科学院化学研究所董原辰团队研究了一种无副产物的计算优化核糖核酸环状化策略。2025年8月28日，《美国化学会志》发表了这一成果。

环状mRNA （mRNA）由于其增加的稳定性和延长的蛋白质翻译时间，在mRNA治疗中显示出广阔的潜力，这引发了对体外制备环状RNA的有效方法的迫切需求。

研究组提出了一种通用的自环化策略，采用简单的基序来合成环状RNA，实现了从几十个核苷酸到10个核苷酸序列的自动效率。通过利用自动化计算程序，研究组优化了高度特异性的锁键结构，以最大限度地提高循环效率，特别是对于长RNA底物。

此外，线性前体RNA和环状产物之间的共享序列和功能消除了去除多余核酸成分的额外纯化步骤的需要，简化了生产过程。这种方法还产生了具有优越稳定性和翻译效率的环状RNA，使体外和体内的蛋白质表达保持稳定。他们的计算优化，无需纯化的方法为可扩展的环状RNA生产和先进RNA治疗的发展提供了巨大的前景，显著推进了mRNA治疗。

附：英文原文

Title: A Computationally Optimized Ribonucleic Acid Circularization Strategy without Byproducts

Author: Ruofan Chen, Yuan Zhuang, Li Zhang, Yuanyuan Wu, Liangzhi Luo, Yufan Pan, Yujie Li, Chenyou Zhu, Rui Xu, Yifan Jiang, Ziyang Hao, Baolei Tian, Liang Zhang, Yuanchen Dong, Dongsheng Liu

Issue&Volume: August 28, 2025

Abstract: Circular mRNA (mRNA) exhibits promising potential in mRNA therapy due to its increased stability and extended duration of protein translation, which has sparked an urgent demand for efficient methods to prepare circular RNAs in vitro. Here, we present a versatile self-circularization strategy that employs simple motifs to synthesize circular RNAs, achieving robust efficiencies for sequences ranging from dozens to thousands of nucleotides. By leveraging an automated computational program, we optimized highly specific lock-key structures to maximize circularization efficiency, particularly for long RNA substrates. Furthermore, the shared sequence and functionality between linear precursor RNAs and circular products eliminate the need for additional purification steps to remove excess nucleic acid components, simplifying the production process. This approach also yields circular RNAs with superior stability and translation efficiency, enabling sustained protein expression in vitro and in vivo. Our computationally optimized, purification-free method holds immense promise for scalable circular RNA production and the development of advanced RNA therapeutics, significantly advancing mRNA therapy.

DOI: 10.1021/jacs.5c09798

Source: https://pubs.acs.org/doi/abs/10.1021/jacs.5c09798