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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 \u201cROS\u2010inflammation\u2010hypoxia\u201d cycle in periodontitis, requiring a more comprehensive approach. Here, a natural enzyme cascade nanogel (TPP\u2010SAT) composed of triphenylphosphine (TPP), superoxide dismutase (SOD), and catalase (CAT) via in\u2010situ polymerization is developed. TPP\u2010SAT targets mitochondrial ROS, converting ROS (such as H\n                    <jats:sub>2<\/jats:sub>\n                    O\n                    <jats:sub>2<\/jats:sub>\n                    or \u00b7O\n                    <jats:sub>2<\/jats:sub>\n                    <jats:sup>\u2212<\/jats:sup>\n                    ) into O\n                    <jats:sub>2<\/jats:sub>\n                    through the enzyme cascade of SOD and CAT. This alleviates hypoxia, prevents oxidative damage, and restores the balance between pro\u2010inflammatory M1 and anti\u2010inflammatory M2 macrophages, reducing inflammation and immune dysfunction. TPP\u2010SAT breaks the \u201cROS\u2010inflammation\u2010hypoxia\u201d 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.\n                  <\/jats:p>","DOI":"10.1002\/advs.202507481","type":"journal-article","created":{"date-parts":[[2025,5,23]],"date-time":"2025-05-23T08:26:07Z","timestamp":1747988767000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":38,"title":["Mitochondria\u2010Targeted ROS Scavenging Natural Enzyme Cascade Nanogels for Periodontitis Treatment via Hypoxia Alleviation and Immunomodulation"],"prefix":"10.1002","volume":"12","author":[{"given":"Yanfen","family":"Zheng","sequence":"first","affiliation":[{"name":"Xiamen Key Laboratory of Stomatological Disease Diagnosis and Treatment Stomatological Hospital of Xiamen Medical College  Xiamen 361008 China"},{"name":"Engineering Research Center of Fujian University for Stomatological Biomaterials  Xiamen 361023 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