Ginsenoside Rd‐Loaded Antioxidant Polymersomes to Regulate Mitochondrial Homeostasis for Bone Defect Healing in Periodontitis

Abstract Periodontitis is the leading cause of tooth loss in adults. Initially triggered by bacterial infection, it is characterized by subsequent dysregulation of mitochondrial homeostasis, leading to ongoing loss of periodontal tissue. Mitophagic flux, a critical physiological mechanism for maintaining mitochondrial homeostasis, is compromised in periodontitis. Additionally, increased release of reactive oxygen species (ROS) exacerbates mitochondrial damage. In this study, a ginsenoside Rd (Rd)‐loaded antioxidative polymersome (RdAP) is designed, which is self‐assembled from a mitochondrial‐protective and ROS‐scavenging block copolymer, poly(ethylene oxide)‐block‐poly(phenylboronic acid pinacol ester‐conjugated polylysine) (PEO₁₁₃‐b‐P(Lys‐PAPE)₆₀). The phenylboronic acid pinacol ester (PAPE) segment exhibits excellent ROS‐responsive properties, enabling effective ROS scavenging through antioxidant production. Rd significantly enhances mitophagic flux by 2.5‐fold in periodontal ligament stem cells (PDLSCs) under oxidative stress. Together with the antioxidative polymersome, RdAPs restore mitochondrial homeostasis and enhance the osteogenic capacity of PDLSCs, bringing it closer to that of healthy controls. In a mouse model of periodontitis, the bone mass in the RdAP‐treated group is 1.37 times greater than that in the untreated periodontitis group. Overall, the findings propose a novel strategy for addressing refractory periodontitis, which may also be applicable to other diseases characterized by mitochondrial homeostasis imbalance.