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, Meng-Yuan Wei, Lijun Wang, Heng Feng, Xiang Gao, Ping Hu, Xianyou Zheng, Ling-Ling Chen, Guanghua Lei (), Youkui Huang () and Weiguo Zou ()
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Jinlong Suo: School of Medicine
Ling Li: ShanghaiTech University
Wuyuan Tan: Central South University
Xubin Yin: Chinese Academy of Sciences
Jinghui Wang: Chinese Academy of Sciences
Rui Shao: School of Medicine
Shaokun Sun: Chinese Academy of Sciences
Si-Kun Guo: Chinese Academy of Sciences
Jingyi Feng: Chinese Academy of Sciences
Bao-Qing Gao: Chinese Academy of Sciences
Ying Wang: Chinese Academy of Sciences
Meng-Yuan Wei: Chinese Academy of Sciences
Lijun Wang: Hainan Medical University
Heng Feng: Chinese Academy of Sciences
Xiang Gao: University of Chinese Academy of Sciences
Ping Hu: Guangzhou
Xianyou Zheng: School of Medicine
Ling-Ling Chen: ShanghaiTech University
Guanghua Lei: Central South University
Youkui Huang: Chinese Academy of Sciences
Weiguo Zou: School of Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-63343-z

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