Injectable Double-Cross-Linked Hydrogel Enhanced by Mg/Mn-Based Nanozymes for Photothermal Therapy and Immunomodulation in Periodontal Bone Resorption

The repair of irregular periodontal bone defects remains a formidable clinical challenge due to the complex oral microenvironment, which demands that therapeutic materials integrate early antibacterial and anti-inflammatory effects with sustained osteogenic support. Herein, we present an injectable multifunctional double-cross-linked hydrogel (GGCM) based on gelatin and chondroitin sulfate (CS), incorporating Mg/Mn-based nanozymes (MPM NZs) for photothermal therapy of periodontitis. MPM NZs were first synthesized via chemical deposition of nano-MnO2 onto mesoporous MgO nanoparticles and subsequently incorporated into a dual-cross-linked network formed by glycidyl methacrylate-modified gelatin and oxidized chondroitin sulfate (OCS) through sequential Schiff base and photopolymerization reactions. The resulting GGCM hydrogel exhibited a favorable microporous architecture, robust physicochemical properties, and excellent injectability to fill irregular periodontal pockets. Notably, MPM NZs endowed the hydrogel with potent photothermal antibacterial activity (>95%), superoxide dismutase (SOD)- and catalase (CAT)-mimetic activities for reactive oxygen species (ROS) scavenging, and the sustained release of bioactive Mg2+ and Mn2+ ions for immunomodulation and osteogenesis. Importantly, GGCM enables a time-sequential regenerative therapeutic cascade comprising rapid periodontal pathogen elimination upon NIR irradiation, subsequent anti-inflammatory immunomodulation via M2 macrophage polarization, and continuous osteogenic promotion and alveolar bone resorption reduction. Collectively, this multifunction-integrated MPM NZ-enhanced double-cross-linked hydrogel exhibits promising potential for periodontal bone regeneration, positioning it as a highly attractive photothermal therapeutic strategy for periodontitis and even other complex infectious bone defects.