Abstract

Osteoarthritis (OA) is a debilitating joint disorder characterized by synovial inflammation and cartilage degradation; however, current therapeutic options fail to simultaneously address these dual pathological progressions. Here, we present clinical evidence identifying synovial macrophage (Mφ) pyroptosis and chondrocyte senescence as pivotal features of OA, which amplify joint damage through sustained inflammatory cascades and metabolic dysfunction. To address this, we developed cuttlefish ink-derived melanin nanoparticle (CIMNP) hydrogels designed to target the ROS/HIF-1α/glycolysis axis, thereby concurrently mitigating synovial Mφ pyroptosis and chondrocyte senescence. The CIMNP hydrogels exhibit potent ROS-scavenging capacity and shear-thinning injectability, making them suitable for intra-articular delivery. In vitro, CIMNP/Alg hydrogels suppressed ROS-induced activation of the HIF-1α/glycolysis axis in Mφs, thereby attenuating inflammasome activation, reducing pore formation, and preventing pyroptotic cell death. Meanwhile, the hydrogels alleviated the ROS/HIF-1α/glycolysis-driven impairment of anabolic marker expression and counteracted the senescence phenotype in chondrocytes. In vivo, intra-articular delivery of CIMNP/Alg hydrogels synchronously suppressed ROS-driven HIF-1α/glycolytic signaling in both synovial and cartilage tissues, leading to inhibition of Mφ pyroptosis, alleviation of chondrocyte senescence, and mitigation of synovitis and cartilage erosion. This coordinated regulation of inflammation and senescence further improved subchondral bone microarchitecture and restored joint homeostasis in OA rats. In sum, this study demonstrates a simple yet effective metabolic reprogramming strategy against OA, with promising potential for treating other degenerative diseases, thereby paves the way for its broader clinical translation.