TH17–Associated Polyamine Metabolism‐Guided Nanozyme Promotes Alveolar Bone Repair in Periodontitis

Periodontitis is a chronic inflammatory disease characterized by persistent inflammation and limited repair at sites of alveolar bone loss. Although excessive reactive oxygen species (ROS) are recognized drivers of periodontal tissue damage, oxidative stress alone does not fully explain the persistence of inflammation and the failure of regeneration. The immune and metabolic processes that cooperate with oxidative stress in sustaining this disease‐supporting microenvironment remain incompletely defined. In this study, a pronounced T H 17‐skewed CD4 + T cell response is identified in experimental periodontitis, and enrichment of polyamine pathway activation is observed during T H 17 differentiation, suggesting a candidate immunometabolic axis for intervention. Guided by this observation, difluoromethylornithine‐loaded UiO‐66(Ce)‐Mn (DFMO@Ui‐Mn) is developed as a nanozyme platform that integrates the cascade ROS‐scavenging activity of UiO‐66(Ce)‐Mn with DFMO delivery for inhibition of polyamine metabolism. DFMO@Ui‐Mn reduces T H 17 polarization in vitro, alters polyamine‐related metabolic profiles, attenuates inflammatory responses in vivo, lowers the T H 17/Treg ratio, improves osteogenic readouts in a conditioned‐medium model, and promotes alveolar bone repair in ligature‐induced periodontitis. These findings support a therapeutic strategy that combines redox control with immunometabolic intervention to improve the periodontal microenvironment under inflammatory conditions. A pronounced T H 17‐skewed immune response is identified in experimental periodontitis, and enrichment of the polyamine pathway is observed during T H 17 differentiation, suggesting its potential as an immunometabolic target. Inspired by these findings, DFMO@Ui‐Mn is developed as a therapeutic platform combining cascade ROS scavenging with immunometabolic modulation to suppress T H 17 polarization, reduce inflammation, and promote alveolar bone repair in periodontitis.