Injectable Schiff base-engineered hydrogel for spatiotemporal liraglutide delivery orchestrates diabetic periodontitis regression via multimodal microenvironment reprogramming.

The treatment of diabetic periodontitis is significantly challenged by a pathological microenvironment characterized by hyperglycemia, proinflammatory cytokine storm, and excessive reactive oxygen species (ROS), with current therapeutic strategies offering limited efficacy and susceptibility to antibiotic resistance. Although liraglutide (LIRA) possesses multifaceted therapeutic potential, including glycemic control, anti-inflammation, antioxidation, and osteoprotection, its systemic administration fails to achieve effective local concentrations within periodontal tissues. To address this, we engineered an injectable carboxymethyl chitosan-oxidized dextran hydrogel (LIRA@CMCS-OD) via dynamic Schiff base bonds for localized LIRA delivery. This hydrogel exhibited excellent injectability, tissue adhesion, biocompatibility, and pH-responsive drug release kinetics. In vitro studies demonstrated that LIRA@CMCS-OD inhibited Porphyromonas gingivalis growth, effectively scavenged intracellular ROS in human periodontal ligament cells (hPDLCs), and robustly promoted hPDLCs osteogenic differentiation. In a diabetic periodontitis rat model, local application of LIRA@CMCS-OD significantly ameliorated gingival inflammation and tooth mobility, enhanced alveolar bone regeneration, and demonstrated favorable biosafety. By enabling sustained local drug release and orchestrating a synergistic "antibacterial action-antioxidation- osteogenic protection" mechanism, this LIRA-loaded injectable hydrogel presents a potent and safe therapeutic strategy for diabetic periodontitis.