Engineered MSC‐sEVs as a Versatile Nanoplatform for Enhanced Osteoarthritis Treatment via Targeted Elimination of Senescent Chondrocytes and Maintenance of Cartilage Matrix Metabolic Homeostasis

Chondrocyte senescence is an important pathogenic factor causing osteoarthritis (OA) progression through persistently producing pro-inflammatory factors. Mesenchymal stem cells-derived small extracellular vesicles (MSC-sEVs) have shown anti-inflammatory effects in OA models, while persistent existence of senescent chondrocytes still promotes cartilage destruction. Therefore, improving the targeted elimination ability on senescent chondrocytes is required to facilitate the translation of MSC-sEVs in OA treatment. In this study, versatile engineered MSC-sEVs are developed to targetedly clear senescent chondrocytes and maintain cartilage metabolic homeostasis. Specifically, MSC-sEVs are loaded with siRNA mouse double minute 2 homologue (siMDM2) and modified with cartilage-targeting peptide WYRGRL-PEG_2K-DSPE (WPD), named WPD-sEVs^siMDM2. The results demonstrate versatile modification improves the cellular uptake of MSC-sEVs in chondrocytes, and thus improves the antiaging effects. Importantly, multifunctional modification enhances cartilage penetration ability and extends joint retention time of MSC-sEVs. In both post-traumatic OA mice and naturally aged mice, WPD-sEVs^siMDM2 more effectively eliminates senescent chondrocytes and maintained matrix metabolic homeostasis. By using the P53 phosphorylation inhibitor, the essential role MDM2-P53 pathway in the antiaging function of WPD-sEVs^siMDM2 on chondrocytes is verified. In ex vivo cultured human OA cartilage explants, it is confirmed that WPD-sEVs^siMDM2 alleviates senescent phenotype. Altogether, the findings suggest that WPD-sEVs^siMDM2 have promising translational potential for OA treatment.