Mechanism driven adaptation of smart hydrogels to the osteoarthritis pathological microenvironment.

Osteoarthritis (OA) arises from interconnected pathological processes, including persistent inflammation, mitochondrial dysfunction, cartilage matrix degeneration, and abnormal neurovascular remodeling. Current clinical care remains largely symptomatic and targets only a narrow set of mechanisms, which limits modification of the disease course. Smart hydrogels, owing to their injectability, biocompatibility, and responsiveness to intrinsic and extrinsic cues, offer notable advantages for OA therapy. By sensing changes in the joint microenvironment, they enable precise control of drug release in space and time and shift treatment from symptomatic control toward targeted repair. This review first synthesizes the roles and interactions of the principal mechanisms that shape the OA microenvironment. It then surveys recent advances in smart hydrogels for OA, with emphasis on applications that suppress inflammation, regulate mitochondrial function, promote cartilage repair, and modulate abnormal neurovascular remodeling. Design strategies for responsive crosslinking networks and their integration with delivery vehicles such as bioactive molecules, nanomaterials, and exosomes are also outlined. Remaining challenges are discussed, including harmonized efficacy endpoints, durability and safety