Mitochondria-targeted nanozyme hydrogel remodels the microenvironment to enhance bone regeneration in diabetes-associated periodontitis

Diabetes-associated periodontitis is a multifactorial disease driven by metabolic disorders and chronic inflammation, featuring mitochondrial dysfunction, excessive reactive oxygen species (ROS), and impaired bone metabolism that collectively impair tissue regeneration. To modulate this pathological microenvironment, we developed an intelligent therapeutic system integrating antioxidation, mitochondrial targeting, and regeneration. The Mn-Zn-tannic acid@SS31 (MZT@S) nanozyme was encapsulated within a PLGA-PEG-PLGA (PPP) thermosensitive hydrogel to obtain MZT@S/PPP. MZT@S exhibits superoxide dismutase-like and catalase-like activities, which enable efficient elimination of ROS. In addition, the mitochondria targeting peptide SS31 enhances mitochondrial localization of the nanozyme and thereby promotes mitochondria-derived ROS scavenging and restores mitochondrial oxidative phosphorylation. The injectable hydrogel allows rapid in situ gelation and provides sustained local release. The MZT@S/PPP hydrogel restores mitochondrial function, promotes osteogenesis and angiogenesis, and induces macrophage M2 polarization, thereby re-establishing immune homeostasis. In vivo, the system suppresses alveolar bone loss and enhances new bone formation in diabetes-associated periodontitis, leading to a markedly improved inflammatory and regenerative microenvironment. This multifunctional hydrogel represents a promising strategy for precise treatment of diabetes-associated periodontitis.