Mesenchymal Stem Cell Exosomes in Combination with Hydrogels for Osteoarthritis: From Exploratory Applications to Optimization and Translational Outlook.

Osteoarthritis (OA) is a chronic degenerative joint disorder characterized primarily by cartilage degradation and extensive inflammation. Its pathological progression is closely associated with the dysregulation of critical signaling pathways; consequently, the therapeutic targets of these pathways have become crucial for intervening underlying mechanisms of cartilage damage. Extensive laboratory studies have found that mesenchymal stem cell-derived exosomes (MSC-Exos) can deliver bioactive cargoes such as microRNAs (miRNAs) and antioxidant enzymes to modulate these targets, thereby exerting therapeutic effects that include mitigating inflammation, inhibiting chondrocyte apoptosis, maintaining extracellular matrix homeostasis, and promoting tissue repair. However, the clinical translation of MSC-Exos is significantly hampered by inherent limitations, including source variability, low stability, and rapid clearance from the joint cavity. Hydrogels, recognized for their excellent biocompatibility, three-dimensional biomimetic architecture, and controlled drug release capabilities, have been used for OA therapy. Therefore, this review summarizes current research on the combined application of exosomes and hydrogels for OA treatment, and proposes optimization strategies for exosome preconditioning, hydrogel material selection, and hydrogel functional design. These strategies aim to enhance exosome functionality as well as enable sustained responsive, and localized exosome release within the joint, thereby improving the therapeutic efficacy for OA.