Circular RNA-based protein replacement therapy mitigates osteoarthritis in male mice
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.
Authors
- Jinlong Suo (ORCID: https://orcid.org/0000-0003-3389-3776)
- Xianyou Zheng (ORCID: https://orcid.org/0000-0002-9770-5394)
- Mengyuan Wei
- Weiguo Zou (ORCID: https://orcid.org/0000-0003-2516-0302)
- Heng Feng (ORCID: https://orcid.org/0000-0001-6830-4607)
- Wuyuan Tan (ORCID: https://orcid.org/0000-0001-8062-403X)
- Xiang Gao (ORCID: https://orcid.org/0000-0003-0699-0351)
- Si-Kun Guo (ORCID: https://orcid.org/0000-0003-1637-5299)
- Youkui Huang (ORCID: https://orcid.org/0000-0002-1233-7757)
- Xubin Yin
- Bao‐Qing Gao
- Guanghua Lei (ORCID: https://orcid.org/0000-0003-2987-138X)
- Ying Wang (ORCID: https://orcid.org/0000-0002-9659-977X)
- Jingyi Feng (ORCID: https://orcid.org/0000-0001-5064-7484)
- Lijun Wang (ORCID: https://orcid.org/0000-0002-3686-6098)
- Ling‐Ling Chen (ORCID: https://orcid.org/0000-0001-9501-0305)
- Ping Hu (ORCID: https://orcid.org/0000-0001-8832-1391)
- Rui Shao (ORCID: https://orcid.org/0000-0002-7388-851X)
- Shaokun Sun (ORCID: https://orcid.org/0000-0003-3896-6751)
- Ling Li (ORCID: https://orcid.org/0000-0001-7293-6228)
- Jinghui Wang (ORCID: https://orcid.org/0000-0002-4999-2106)
Institutions
- Central South University (CN)
- ShanghaiTech University (CN)
- Guangzhou Experimental Station (CN)
- Shanghai Institute of Nutrition and Health (CN)
- Hainan Provincial Academy of Agricultural Sciences (CN)
- Center for Excellence in Molecular Cell Science (CN)
- National Clinical Research (US)
- Shanghai Sixth People's Hospital (CN)
- Xiangya Hospital Central South University (CN)
- University of Chinese Academy of Sciences (CN)
- Hainan Medical University (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-09-26
- DOI
- https://doi.org/10.1038/s41467-025-63343-z
- Citations
- 6
- Primary Topic
- Circular RNAs in diseases
- Type
- article
- Field-Weighted Citation Impact
- 4.84
Funders
- National Natural Science Foundation of China
- Chinese Academy of Sciences
- Science and Technology Commission of Shanghai Municipality
- National Key Research and Development Program of China