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<p>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 <i>Musashi2 (Msi2)</i> 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.</p>

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Circular RNA-based protein replacement therapy mitigates osteoarthritis in male mice

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年9月26日

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  • 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,
  • Weiguo Zou

摘要

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.