Surface-Engineered Umbilical Cord Mesenchymal Stem Cell-Derived sEVs for Targeted Therapy of Osteoarthritis

Small extracellular vesicles (sEVs) from human umbilical-cord-derived mesenchymal stem cells (UCMSCs) hold promise for cartilage regeneration in osteoarthritis (OA). However, their therapeutic effectiveness is significantly limited by rapid clearance through blood and lymphatic vessels in the synovial tissue after intra-articular injection. This study aimed to enhance the chondrocyte-targeting ability and improve the cartilage repair potential of UCMSC-derived sEVs by conjugating them with a chondrocyte-affinity peptide (CAP) using copper-free click chemistry. The targeting ability and therapeutic effects of these CAP-modified sEVs (CAP-sEVs) were evaluated in vitro and in vivo. CAP-sEVs exhibited enhanced chondrocyte targeting and greater retention within the articular cavity compared to nonmodified sEVs. In IL-1β-stimulated chondrocytes, CAP-sEVs significantly reduced the expression of matrix-degrading enzymes while increasing collagen type II synthesis, demonstrating superior therapeutic effects. Animal experiments further confirmed that CAP-sEVs had good biocompatibility, delayed articular cartilage degradation, and reduced subchondral bone loss in early stage OA. These findings suggest that CAP-sEVs represent a novel and promising strategy for OA treatment and provide an innovative drug delivery system for targeted cartilage therapy.