An off‐the‐Shelf Injectable MSC Hydrogel with Microenvironment‐Driven Responsiveness for Precision Osteoarthritis Treatment

Abstract Osteoarthritis (OA) presents a heterogeneous and dynamic synovial microenvironment that limits the efficacy of conventional therapies. Here, a cryopreservable, microenvironment‐responsive mesenchymal stem cells (MSCs) hydrogel platform is reported for personalized OA therapy, addressing OA's heterogeneous synovial challenges. The system employs a glycerol/trehalose‐based cryoprotectant cocktail enabling direct thaw‐and‐inject application without cytotoxic residues. Using OA patient‐derived synovial fluid (SF), three in vitro models (SF exposure, SF‐chondrocyte, and SF‐macrophage co‐cultures) demonstrated MSC hydrogels’ adaptive plasticity, activating antioxidant, immunomodulatory, and matrix‐regenerative programs. MSCs engaged in bidirectional crosstalk with chondrocytes and macrophages, suppressing catabolism, enhancing cartilage repair, and polarizing macrophages toward anti‐inflammatory phenotypes. In OA rats, cryopreserved hydrogels reduced cartilage erosion, preserved proteoglycans, and inhibited matrix degradation. This scalable, off‐the‐shelf platform integrates engineered cryoprotection, injectability, and dynamic microenvironmental adaptation, offering a precision therapeutic strategy for degenerative and inflammatory joint diseases.