Nanozyme‐Integrated Hydrogel Targeting AGEs for Diabetic Osteoarthritis Therapy

Abstract Advanced glycation end‐products (AGEs) play a crucial role in the pathogenesis of diabetic osteoarthritis (DOA), contributing to cartilage degradation and impaired joint lubrication, which complicate clinical management. However, no therapeutics specifically targeting AGEs are developed for DOA treatment. Here, a composite hydrogel (PTC‐MP) incorporated with polydopamine‐coated tannic cerium (PTC) nanozymes and magnesium ions (Mg ²⁺ ), implementing a strategy of “restrain‐restore‐reinforce (3R)” for AGEs‐directed DOA therapy is reported. PTC‐MP hydrogel effectively restrains the formation of AGEs by scavenging free radicals, chelating ferrous ions, and competitive hydrophobic site binding. By leveraging mild photothermal therapy (mPTT), PTC‐MP hydrogel restores cartilage homeostasis by reducing AGEs‐induced reactive oxygen species (ROS) overproduction and mitochondrial dysfunction. Furthermore, Mg ²⁺ in PTC‐MP hydrogel reinforces joint repair by stimulating endogenous hyaluronic acid (HA) secretion to improve lubrication. In a rat DOA model, PTC‐MP hydrogel with mPTT significantly attenuated DOA progression, reduced osteophytes formation and synovial inflammation, and improved motor function. Therefore, the “3R” strategy targeting AGEs provides a promising therapeutic approach for recalcitrant DOA.