Core–Shell Microspheres Enabling Sustained Hydrogen Release and Peroxidase‐Like Catalytic Activity for Periodontitis Therapy

ABSTRACT Periodontitis is among the most prevalent and challenging oral diseases worldwide. Effective intervention requires strategies that not only eliminate pathogens but also modulate the dysregulated oxidative microenvironment. Hydrogen (H 2 ) therapy holds promise in periodontitis immunotherapy due to its exceptional safety profile and unique selective antioxidant properties. Here, we present a tailored biomaterial platform—Magnesium hydride (MgH 2 )‐Poly(lactic‐co‐glycolic acid) (PLGA)@Oxygen‐deficient titanium dioxide (TiO 2‐x )‐Alginate core–shell microspheres (MTMs)—fabricated via coaxial electrostatic microdroplet technology for localized periodontitis therapy. This system provides rapid antibacterial activity together with sustained remodeling of the local tissue microenvironment. The MTMs achieve long‐term antioxidant and anti‐inflammatory effects through the synergistic sustained release of hydrogen molecules and Mg 2+ ions (up to 7 days). Concurrently, the surface‐etched TiO 2−x particles embedded in the shell layer, exhibiting peroxidase‐like catalytic activity, enable rapid antibacterial effects in the presence of low‐level exogenous hydrogen peroxide. In vitro, MTMs attenuated oxidative stress in periodontal ligament stem cells and promoted lipopolysaccharide‐stimulated macrophages to polarize from pro‐inflammatory M1 toward reparative M2 phenotypes. In a rat periodontitis model, short‐term treatment (1 week) reduced bacterial load, mitigated inflammation, and inhibited bone resorption, while long‐term application (1 month) promoted bone repair and remodeling. These findings demonstrate that MTMs represent a powerful therapeutic platform for periodontitis and hold potential for broader biomedical applications.