MSCs-derived ECM functionalized hydrogel regulates macrophage reprogramming for osteoarthritis treatment by improving mitochondrial function and energy metabolism.

Osteoarthritis (OA) is a degenerative disease that affects the entire joint, with synovial inflammation being a major pathological feature. Macrophages, as the most abundant immune cells in the synovium, have an M1/M2 imbalance that is closely related to the occurrence and development of OA. Mesenchymal stem cells (MSCs) have been shown to effectively suppress inflammation in the treatment of OA, but they still pose issues such as immune rejection and tumorigenicity. The extracellular matrix (ECM), as a major mediator of MSCs' immunoregulatory effects, offers a cell-free therapy to circumvent these risks. In this study, we developed an ECM-functionalized hydrogel by combining MSC-derived ECM with gelatin methacryloyl (GelMA). To enhance the immunomodulatory potential of MSCs, we pre-stimulated MSCs with the inflammatory factor interleukin-6 (IL-6) present in OA. In vitro results showed that the ECM-functionalized hydrogel promoted M2 macrophage polarization and inhibited the expression of various inflammatory genes, strongly indicating the hydrogel's powerful immunoregulatory capabilities. In an in vivo rat OA model, the ECM-functionalized hydrogel significantly reduced synovial inflammation and cartilage matrix degradation, alleviating the progression of OA. Furthermore, we utilized proteomics and transcriptomics analysis to reveal that the hydrogel accomplished macrophage metabolic reprogramming by regulating mitochondrial function and energy metabolism, thereby reducing inflammation. These findings suggest that the ECM-functionalized hydrogel is a promising biomaterial-based strategy for treating OA by targeting key pathological mechanisms.