Microenvironment-Adaptive Smart Hydrogel with 2D Vanadium Nitride MXenzyme Rescues Osteoarthritis via Coordinated ROS Scavenging and Hspa5/GPX4 Axis-Mediated Ferroptosis Suppression

Osteoarthritis (OA), a prevalent degenerative joint disorder characterized by articular cartilage deterioration, represents a major global health challenge. Recent studies highlight the pivotal role of reactive oxygen species (ROS)-mediated ferroptosis in OA pathogenesis. Here, we report a microenvironment-adaptive hydrogel system based on 2D vanadium nitride (V 2 N) MXene nanoenzyme (hereafter denoted as V 2 N MXenzyme@Gel). This system features a dual-crosslinked network that optimally balances between mechanical robustness and flexibility. Crucially, the V 2 N MXenzyme establishes a self-sustaining “capture-conversion-recycling” catalytic cycle, mimicking both superoxide dismutase (SOD) and catalase (CAT) activities. The cycle not only neutralizes detrimental ROS into water (H 2 O) and oxygen (O 2 ) but also generates nitric oxide (NO), collectively alleviating oxidative damage. Mechanistically, V 2 N MXenzyme@Gel effectively scavenges ROS, attenuates oxidative stress, and suppresses ferroptosis by regulating the Hspa5/GPX4 axis, while concurrently restoring the metabolic homeostasis of chondrocyte extracellular matrix (ECM). Meanwhile, intra-articular administration of V 2 N MXenzyme@Gel significantly attenuates cartilage degradation and inflammation levels in OA rats. Collectively, our work presents a V 2 N MXenzyme@Gel with dual capabilities for ROS elimination and ferroptosis blockade, demonstrating its efficacy in arresting OA progression and proposing a novel precision strategy for managing chronic joint diseases.