Mitochondria‐Targeted ROS Scavenging Natural Enzyme Cascade Nanogels for Periodontitis Treatment via Hypoxia Alleviation and Immunomodulation

Abstract Periodontitis is a chronic inflammatory disease characterized by hypoxia, excessive oxidative stress, and immune dysregulation, leading to tissue destruction and bone resorption. Although antioxidants can reduce ROS and inflammation, most lack specificity and have a short residence time, limiting their effectiveness. Since mitochondria are the primary source of ROS, targeting mitochondrial ROS is a promising strategy for periodontitis treatment. However, this alone cannot address the complex “ROS‐inflammation‐hypoxia” cycle in periodontitis, requiring a more comprehensive approach. Here, a natural enzyme cascade nanogel (TPP‐SAT) composed of triphenylphosphine (TPP), superoxide dismutase (SOD), and catalase (CAT) via in‐situ polymerization is developed. TPP‐SAT targets mitochondrial ROS, converting ROS (such as H 2 O 2 or ·O 2 − ) into O 2 through the enzyme cascade of SOD and CAT. This alleviates hypoxia, prevents oxidative damage, and restores the balance between pro‐inflammatory M1 and anti‐inflammatory M2 macrophages, reducing inflammation and immune dysfunction. TPP‐SAT breaks the “ROS‐inflammation‐hypoxia” cycle, inhibits alveolar bone resorption, and accelerates periodontal tissue regeneration. This approach offers a promising strategy for treating periodontitis and other chronic inflammatory diseases, with strong clinical potential.