Osteoarthritis Therapeutics: From Microenvironment Understanding to Regenerative Intervention—Current Advances and Future Perspectives

Osteoarthritis (OA) is a prevalent, chronic degenerative joint disease characterized by progressive cartilage degeneration and impaired joint function. Its rising global incidence poses a significant health and socioeconomic burden. Traditional therapies primarily offer symptomatic relief but fail to halt disease progression and are associated with notable limitations. The contemporary understanding of OA pathogenesis has evolved from a model of mechanical wear to one emphasizing systemic imbalance within the joint microenvironment, involving immune dysregulation, metabolic disturbances, cellular senescence, and the gut-joint axis. This paradigm shift supports the development of innovative, disease-modifying strategies. This review is structured around a unifying multi-axis microenvironmental imbalance model for osteoarthritis. It systematically integrates the crosstalk and cascade-amplifying mechanisms of immune dysregulation, cellular senescence, metabolic disturbances, and the gut-joint axis, clarifying that multi-dimensional microenvironmental disruption collectively forms the pathological core of OA. We focus on how renewable biomaterials, engineered exosomes, and their composite systems target and regulate the pathological network to restore joint homeostasis, enabling a paradigm shift from symptomatic management to root-cause intervention. This work provides an integrated theoretical and translational roadmap for next-generation disease-modifying OA therapies.