Glucose-Responsive Dual-Enzyme Mimetic Nanoreactor Remodels Diabetic Periodontitis Microenvironment for Augmented Alveolar Bone Regeneration

Background: Periodontitis in the context of diabetes severely disrupts bone metabolic homeostasis, leading to irreversible alveolar bone loss. The resulting alveolar bone defects face significant challenges in healing due to a pathological microenvironment characterized by the interplay of hyperglycemia, oxidative stress, infection, and inflammation. Existing therapeutic strategies often lack the capability to synchronously and intelligently regulate this complex milieu, resulting in delayed and inefficient bone repair. Methods: A composite material, termed MTS@QP-G@CO, was developed. Its core consists of manganese dioxide (MnO 2 ) nanoflowers loaded with a tannic acid (TA) -strontium metal (Sr)-phenolic network. These were conjugated with glucose oxidase via phenylboronic acid bonding and encapsulated within a pH-responsive Schiff base hydrogel. The structural characterization of the material, the performance of the cascade reaction, as well as its antioxidant and antibacterial properties have all been fully verified. A series of in vitro and in vivo experiments were conducted to evaluate the system’s efficacy in modulating the local metabolic and oxidative status, inducing macrophage polarization, promoting osteogenic differentiation, and restoring bone regeneration in diabetic alveolar bone defect models. Results: The MTS@QP-G@CO designed sequential action at the defect site involves triggering a “glucose starvation” effect via glucose oxidase, followed by hydrogen peroxide decomposition and oxygen generation catalyzed by the MnO 2 nanozyme. This achieves synchronized glucose reduction, hypoxia alleviation, reactive oxygen species (ROS) scavenging, and antibacterial activity. Subsequently, TA and Sr 2+ are programmable released. And the system effectively remodeled the local pathological microenvironment in diabetic bone defects. It successfully achieved synchronized precise glucose reduction, hypoxia alleviation, ROS scavenging, and bacterial inhibition. This was followed by the cooperative release of therapeutic ions, which modulated the immune microenvironment by suppressing inflammation and inducing macrophage polarization toward the pro-healing M2 phenotype. Consequently, the system accelerated early osteogenic differentiation and bone matrix maturation, transforming the disordered repair process into a coordinated and efficient regeneration, leading to high-quality bone repair. Conclusion: The MTS@QP-G@CO system effectively reverses the pathological microenvironment, coordinates immune modulation and osteogenesis, and transforms delayed healing into efficient, high-quality bone regeneration, offering a promising therapeutic approach for diabetes-related bone defects. The image illustrates a diabetic alveolar bone defect model. It begins with MTS@QP-G@CO applied to the bone defect, leading to a pH response release of MTS@QP-G. The process is divided into three main pathways: cascade reaction, antibacterial and anti-inflammatory. In the cascade reaction, glucose is converted to gluconic acid by glucose oxidase, producing hydrogen peroxide and oxygen, which reacts with manganese dioxide. The antibacterial pathway targets E. coli and S. aureus. The anti-inflammatory pathway involves macrophage transition from M0 to M1 and M2 states. Additionally, the diagram shows osteogenesis, where bone marrow stromal cells differentiate into osteoblasts.Diagram of MTS@QP-G@CO in treating diabetic bone defect model: pH response, cascade reaction, antibacterial, anti-inflammatory and osteogenesis.