Injectable Chondroitin Sulfate Methacrylate Hydrogel Microspheres Co-Loaded with GLPM Nanozyme, Dexamethasone, and Stem Cells for Synergistic Osteoarthritis Therapy

Osteoarthritis (OA) is a degenerative joint disease characterized by cartilage degradation, chronic inflammation, and subchondral bone remodeling. Conventional intra-articular therapies provide limited relief and fail to address its multifactorial pathogenesis. Here, we present an injectable hydrogel microsphere platform that integrates antioxidative, anti-inflammatory, and regenerative functions for localized OA management. Uniform (∼125 µm) chondroitin sulfate methacrylate (ChSMA)-based microspheres are fabricated via microfluidic photocross-linking. Manganese dioxide nanoparticles provided catalytic reactive oxygen species (ROS) scavenging, while dexamethasone sodium phosphate enabled sustained release, reducing TNF-α and IL-6 levels by ∼30%. Bone marrow mesenchymal stem cells (BMSCs) are co-delivered to promote cartilage repair. In vitro, the microspheres reduce intracellular ROS, induce M2 macrophage polarization, and suppress inflammatory cytokines by 60–70%, with IL-10 levels increased by ∼90%. 3D co-culture supports chondrocyte/BMSC viability and matrix production. In vivo, intra-articular injection in a rat OA model markedly reduces cartilage erosion, decreases osteophyte volume by 80%, and improves subchondral bone microarchitecture. Histological staining confirms matrix restoration and structural preservation, with Osteoarthritis Research Society International (OARSI) scores reduced by 88%. Collectively, this injectable hydrogel microsphere system offers a minimally invasive and integrated strategy, simultaneously delivering antioxidative, anti-inflammatory, and regenerative effects for comprehensive OA management.