Dual-engineered cartilage-targeting extracellular vesicles derived from mesenchymal stem cells enhance osteoarthritis treatment via miR-223/NLRP3/pyroptosis axis: Toward a precision therapy

Weixuan Liu; Anqi Liu; Xujun Li; Ziyang Sun; Zhenghua Sun; Yaru Liu; Gang Wang; Dan Huang; Hao Xiong; Shiyang Yu; Xintao Zhang; Cunyi Fan

doi:10.1016/j.bioactmat.2023.06.012

Dual-engineered cartilage-targeting extracellular vesicles derived from mesenchymal stem cells enhance osteoarthritis treatment via miR-223/NLRP3/pyroptosis axis: Toward a precision therapy

Bioact Mater. 2023 Aug 4:30:169-183. doi: 10.1016/j.bioactmat.2023.06.012. eCollection 2023 Dec.

Authors

Weixuan Liu^{1

2}, Anqi Liu^{3

4}, Xujun Li⁵, Ziyang Sun^{2

6}, Zhenghua Sun², Yaru Liu², Gang Wang², Dan Huang², Hao Xiong^{2

6}, Shiyang Yu^{2

6}, Xintao Zhang¹, Cunyi Fan^{2

6}

Affiliations

¹ Department of Sports Medicine, Peking University Shenzhen Hospital, Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center, Shenzhen, 518036, China.
² Shanghai Engineering Research Center for Orthopedic Material Innovation and Tissue Regeneration, Shanghai, 201306, China.
³ Department of Orthodontics, Shanghai Stomatological Hospital & School of Stomatology, Fudan University, Shanghai, 200001, China.
⁴ Shanghai Key Laboratory of Craniomaxillofacial Development and Diseases, Fudan University, Shanghai, 200001, China.
⁵ Minhang Hospital, Fudan University, Shanghai, 201199, China.
⁶ Department of Orthopedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China.

Abstract

Osteoarthritis (OA) is the most common disabling joint disease with no effective disease modifying drugs. Extracellular vesicles released by several types of mesenchymal stem cells could promote cartilage repair and ameliorate OA pathology in animal models, representing a novel therapeutic strategy. In this study, we demonstrated that extracellular vesicles derived from human umbilical cord mesenchymal stem cells (hUC-EVs) could maintain chondrocyte homeostasis and alleviate OA, and further revealed a novel molecular mechanism of this therapeutic effect. miR-223, which could directly bind with the 3'UTR of NLRP3 mRNA, was found to be a key miRNA for hUC-EVs to exert beneficial effects on inflammation inhibiting and cartilage protecting. For enhancing the effect on mitigating osteoarthritis, exogenous miR-223 was loaded into hUC-EVs by electroporation, and a collagen II-targeting peptide (WYRGRL) was modified onto the surface of hUC-EVs by genetic engineering to achieve a more targeted and efficient RNA delivery to the cartilage. The dual-engineered EVs showed a maximal effect on inhibiting the NLRP3 inflammasome activation and chondrocyte pyroptosis, and offered excellent results for the treatment of OA. This study provides a novel theoretical basis and a promising therapeutic strategy for the application of engineered extracellular vesicles in OA treatment.

Keywords: Cartilage-targeting; Extracellular vesicles; NLRP3 inflammasome; Osteoarthritis; Pyroptosis.