Multifunctional Small RNA Endogenous Modified Exosome‐Loaded Hydrogel Based on Photocrosslinking for Cartilage Repair

Abstract Exosomes derived from bone marrow mesenchymal stem cells (BMSCs) hold significant potential in the treatment of osteoarthritis (OA). However, simple exosomes therapy often proves insufficiently effective and challenging to achieve optimal therapeutic outcome. Herein, an innovative injectable multifunctional composite hydrogel (Exo shEZH2 @HG) is composed of photocrosslinking partially modified hyaluronic acid with o ‐nitrobenzyl alcohol (HA‐NB), gelatin, and shRNA‐EZH2 endogenously modified exosomes (Exo shEZH2 ), designed for cartilage defects, which are a primary cause of early OA. It exhibits rapid and controllable photo‐induced gelation characteristics, resembling human cancellous bone compressive strength, and boasting excellent biocompatibility. In vitro studies indicate that Exo shEZH2 @HG slowly releases Exo shEZH2 , promoting the migration and infiltration of BMSCs into surrounding tissues. By inhibiting the overexpression of EZH2, Exo shEZH2 suppresses histone hypermethylation and the nuclear factor kappa‐B (NF‐κB) signaling pathway, thereby inhibiting inflammation and apoptosis in chondrocytes. Simultaneously, it promotes the regeneration of the extracellular matrix and the chondrogenic differentiation of BMSCs. Within a rat cartilage defect model, Exo shEZH2 @HG significantly facilitates the regeneration of cartilage tissue resembling hyaline cartilage in the defect area, preventing the progression of OA. In summary, this multifunctional composite hydrogel offers a promising approach for the treatment of cartilage defects and the prevention of OA through multiple synergistic effects.