Abstract

Prolonged periodontal inflammation and progressive alveolar bone loss are typical manifestations of periodontitis. Antioxidative therapies targeting the central role of reactive oxygen species (ROS) have been explored, but lack of subcellular specificity limits efficacy. Mitochondria function as an upstream redox hub that drives oxidative stress, inflammatory responses, and alveolar bone resorption, making mitochondrial redox modulation a promising yet underexplored strategy for periodontitis therapy. Herein, we developed a mitochondria-targeted, redox-responsive nanocomposite (TC/pSeSe) that enables programmable redox modulation of the pathological periodontal microenvironment. The antioxidative core consists of a ROS-responsive diselenide-containing copolymer (pSeSe) capable of selenium release, while the triphenylphosphine/chitosan (TC) coating confers mitochondrial-targeted, controlled redox activity, mucosal retention and cationic antibacterial properties. With preferential mitochondrial localization, TC/pSeSe undergoes diselenide bond cleavage and selenium release under oxidative stress, thereby restoring mitochondrial redox homeostasis and attenuating downstream mitochondrial DNA (mtDNA)-cGAS-STING-mediated inflammatory signaling. Through combined ROS scavenging and selenium-mediated support, TC/pSeSe mitigates ferroptosis in a partially glutathione peroxidase 4 (GPX4)-dependent manner and restores osteogenic potential in bone marrow-derived stem cells. In parallel, TC/pSeSe exhibits antibacterial activity against periodontal pathogens through combined selenium and the cationic TC coating functionalities. In vivo , TC/pSeSe restored alveolar bone regeneration and attenuated periodontal inflammation. Collectively, this study proposes a mitochondria-centered redox modulation strategy, providing a comprehensive and promising therapeutic approach for periodontitis treatment.