Circular RNA-based protein replacement therapy mitigates osteoarthritis in male mice
Jinlong Suo, Ling Li, Wuyuan Tan, Xubin Yin, Jinghui Wang, Rui Shao, Shaokun Sun, Si-Kun Guo, Jingyi Feng, Bao‐Qing Gao, Ying Wang, Mengyuan Wei, Lijun Wang, Heng Feng, Xiang Gao, Ping Hu, Xianyou Zheng, Ling‐Ling Chen, Guanghua Lei, Youkui Huang, Weiguo Zou
Abstract
In vitro-transcribed and circularized RNAs (ivcRNAs) represent a robust platform for sustained protein translation, offering promising potential for localized therapeutic delivery in joint diseases. Osteoarthritis (OA), the most prevalent degenerative joint disorder, remains a major clinical challenge due to its progressive nature and the lack of disease-modifying treatments. In this study, we identify Musashi2 (Msi2) deficiency in articular chondrocytes as a key contributor to OA pathogenesis. To evaluate the efficacy of ivcRNA-mediated protein replacement therapy, we developed a localized delivery strategy that enables high-yield and prolonged protein expression in chondrocytes. Using a destabilization of the medial meniscus (DMM) mouse model, we demonstrate that intra-articular delivery of ivcRNA encoding MSI2 effectively mitigates OA progression in male mice. Furthermore, therapeutic supplementation of SOX5, a downstream effector of MSI2, via ivcRNA delivery further validates this approach. Our findings establish ivcRNA-based protein replacement as a potential RNA therapeutic strategy for osteoarthritis. In vitro transcribed circular RNAs (ivcRNAs) offer a stable and efficient platform for protein replacement therapy. Here, the authors show that localized ivcRNA delivery restores MSI2 and SOX5 expression in chondrocytes, mitigating osteoarthritis progression in mice.