A hierarchical, pH-responsive nanocomposite hydrogel platform for synergistic microenvironment reprogramming and...

Conventional periodontitis therapies are limited by their inability to concurrently address the interconnected challenges of persistent bacterial infection, excessive oxidative stress, and immune dysregulation. To overcome this, we developed an injectable, pH-responsive nanocomposite polypeptide hydrogel, PepGel@ZnO-PLP, through rational molecular interface engineering. The system is constructed by integrating poly-L-proline (PLP)-functionalized zinc oxide nanoparticles (ZnO-PLP) into a poly-L-glutamate containing polypeptide network (PepGel) via dynamic Zn²⁺-carboxylate coordination. This critical PLP interface ensures colloidal stability of ZnO nanoparticles and enables the formation of a homogeneous, pH-responsive release network. In the acidic periodontal microenvironment, the hydrogel exhibits potent antibacterial and reactive oxygen species (ROS)-scavenging activities. Furthermore, via PLP-enabled interfacial engineering, PepGel@ZnO-PLP reprograms inflammatory macrophage immunometabolism by driving a glycolytic-suppressed metabolic state that establishes metabolic homeostasis toward a reparative M2 phenotype, a process in which the PI3K-Akt pathway may be involved. In a murine periodontitis model, PepGel@ZnO-PLP adheres to periodontal defects, effectively disrupting the infection-inflammation cycle and leading to significant alveolar bone preservation. This work underscores the power of precise molecular-level design for holistically reprogramming the pathological microenvironment and offers a novel nanocomposite hydrogel for ameliorating inflammatory periodontal bone loss.