Ligand‐Modulated Manganese Ferrite Nanozyme Hydrogel with Balanced Antioxidant Activity and Biocompatibility for Periodontitis Treatment

ABSTRACT Nanozymes hold significant promise for periodontitis treatment, owing to their high catalytic efficiency, multi‐enzyme activity, robust stability, and low cost. However, the need for repeated administration and the complex oral environment present challenges in balancing biosafety and efficiency. Herein, we develop a ligand‐modulated manganese ferrite nanozyme hydrogel (MFZ@PG) with balanced antioxidant activity and biocompatibility for periodontitis treatment through ZBP1/β‐catenin signaling. MFZ@PG is synthesized by encapsulating zwitterionic dopamine sulfonate‐modified manganese ferrite nanoparticles within a gel matrix composed of polyvinyl alcohol, gelatin, and borax. The resulting hydrogel demonstrates potent antioxidant capacity, attributed to the innate nanozyme activity of manganese ferrite and the introduced catechol groups, as well as robust adhesiveness due to multiple chemical interactions between borax and polyvinyl alcohol. In vitro experiments demonstrate that MFZ@PG effectively protects MC3T3‐E1 cells from H 2 O 2 ‐induced impairment of proliferation, migration, and osteogenic differentiation. In vivo experiments demonstrate that MFZ@PG significantly promotes alveolar bone regeneration and suppresses bone resorption. Furthermore, transcriptomic analysis indicates that the therapeutic mechanism of MFZ@PG is achieved through the activation of the ZBP1/β‐catenin positive feedback loop. Histopathological and blood biochemical analyses demonstrate the good biocompatibility of MFZ@PG. This study presents a safe and efficient therapeutic strategy for periodontitis with high translational potential.