Triple-Combination Therapy with a Multifunctional Yolk-Shell Nanozyme Au@CeO₂ Loaded with Dimethyl Fumarate for Periodontitis

Periodontitis, a chronic inflammatory disease, is the leading cause of tooth loss in adults and is one of the most prevalent and complex oral conditions. Oxidative stress induced by the excessive generation of reactive oxygen species (ROS) leads to periodontitis, which is closely associated with pathological processes, including mitochondrial dysfunction of periodontal cells and local immune dysregulation. However, current treatment modalities that target single pathological processes have limited long-term therapeutic effects. Herein, a multifunctional Yolk-Shell nanozyme, Au@CeO₂-dimethyl fumarate (DMF), which comprehensively addresses the oxidative stress-induced pathophysiological processes of periodontitis through antioxidant activity, mitochondrial maintenance, and immune modulation mechanisms, is described. For material design logic, functionally complementary Au and CeO₂ formed an excellent photothermally regulated high-efficiency nanozyme, which also provided an ideal drug carrier for DMF. As for the therapeutic logic, Au@CeO₂-DMF restores mitochondrial dysfunction and immune dysregulation, which also contributes to endogenous ROS elimination, thereby achieving long-term stable therapeutic effects. In a rat model, local Au@CeO₂-DMF photothermal therapy effectively alleviated ROS-induced tissue damage and restored periodontal homeostasis. Altogether, this study presents a novel antioxidant nanozyme for managing alveolar bone loss under prolonged oxidative stress and demonstrates the importance of comprehensive intervention in key pathological processes in periodontitis treatment design.