Reprogramming pathological secretory phenotype of chondrocytes inhibits neurovascular invasion for osteoarthritis treatment

Abstract

Pain severity in osteoarthritis (OA) often dissociates from the extent of cartilage structural damage, indicating that non-structural mechanisms contribute to symptom persistence. Here, we identify articular chondrocytes as active orchestrators of pathological neurovascular invasion through a pathogenic secretome, rather than merely passive victims of degeneration. Integrated human single-cell transcriptomic analysis reveals that OA chondrocytes undergo phenotypic reprogramming characterized by coordinated activation of angiogenic and neurotrophic programs. Functionally, inflammatory chondrocytes directly promote endothelial angiogenesis and sensory axon outgrowth, linking chondrocyte-derived signals to neurovascular invasion and sustained pain. To therapeutically target this upstream mechanism, we engineered MMP-13-responsive celecoxib-loaded hyaluronic acid methacrylate microspheres (HMPC) for disease-adaptive delivery to degenerative cartilage. HMPC suppresses chondrocyte COX-2 activity and remodels the pathological chondrocyte secretome through restoration of miR-339-5p_R-5 and miR-103-3p_R-2, thereby inhibiting angiopoietin-2 (Angpt2)-mediated angiogenesis and brain-derived neurotrophic factor (Bdnf)-driven sensory neurogenesis. In murine OA models, HMPC markedly alleviates pain-related behaviors, reduces neurovascular infiltration, and preserves joint structure. Collectively, this study supports a chondrocyte-centric framework in which reprogrammed chondrocytes govern neurovascular invasion through microRNA-dependent secretome regulation and introduces a smart biomaterial-enabled strategy with disease-modifying potential for OA pain intervention.