Geometrically adaptive hydrogel attenuates osteoarthritis via metabolic reprogramming and defect sealing.
Effective treatment for osteoarthritis (OA) remains challenging because current therapies do not simultaneously restore biomechanical support and modulate the pathological intra-articular microenvironment. Here, we developed an injectable dual-network hydrogel that combines thermosensitive poly(N-isopropylacrylamide)-graft-gelatin (PNIPAAm-g-Gelatin) with a dynamic carboxymethyl chitosan/oxidized hyaluronic acid (CMCS/oxHA) network, enabling rapid in situ gelation, self-healing, and defect filling. Beyond providing structural support, the hydrogel created a biomimetic matrix environment that was associated with modulation of chondrocyte metabolism. Transcriptomic analysis and validation experiments indicated that hydrogel treatment attenuated IL-1β-induced catabolic responses and was accompanied by normalization of aberrantly activated PI3K/Akt signaling, thereby promoting a more anabolic chondrocyte phenotype in the absence of exogenous growth factors. In a rat OA model, a single intra-articular injection improved cartilage preservation, reduced subchondral bone deterioration, and was associated with better gait performance. Collectively, these findings suggest that the injectable hydrogel may serve as a disease-modifying biomaterial for OA by integrating in situ defect sealing with microenvironmental regulation and chondroprotective signaling modulation.