Injectable hydrogel with synergistically accelerated degradation for synergistic antimicrobial and ER-stress-modulating therapy against diabetic periodontitis

Hydrogel matrix responds hierarchically to pathological periodontal milieu, including glucose and reactive oxygen species. • Activation energy for hydrogel degradation: 44.2 kJ/mol (glucose), 46.8 kJ/mol (H 2 O 2 ), and 22.3 kJ/mol under concurrent dual stimuli. • Dual stimuli accelerated matrix erosion and released MINO/GSK, achieving fastest, severity-scaled maximal release within 24 h. • GSK attenuated ER stress-driven inflammation, enhancing periodontal tissue tolerance to MINO. For antibiotic therapy of diabetic periodontitis, the central challenge is to anchor drugs deep inside the periodontal pocket and synchronise their release with pathological periodontal milieu, and to attain peak antimicrobial concentrations within the shortest possible time to rapidly suppress pathogens, avoiding the cytotoxicity or dysbiosis associated with prolonged tetracycline exposure. Existing stimuli-sensitive hydrogels were more focused on the responding independently to individual stimuli, while harnessing the synergistic effect of multiple concurrent stimuli to accelerate release in proportion to disease severity remains largely unexplored. Here, we reported an injectable hydrogel engineered from poly(vinyl alcohol) (PVA) and phenylboronic-acid-grafted hyaluronic acid (HA-APBA) that contains nano‑calcium carbonate (nCaCO₃) co-embedded with the antibiotic minocycline hydrochloride (MINO) and the selective PERK inhibitor GSK2606414 (GSK). Reversible boronate-ester cross-links enabled in-situ gelation within 30 s, meeting chair-side clinical requirements. The matrix responded to the diabetic periodontal milieu, including elevated glucose, ROS, and the acidic microenvironment. Each stimulus synergistically accelerated network erosion, delivering the fastest, severity-scaled maximal release within 24 h. Released MINO rapidly suppressed polymicrobial biofilms, and released GSK attenuated pathogen-induced endoplasmic reticulum (ER) stress-driven inflammation. Moreover, GSK-mediated cytoprotection enhances periodontal tissue tolerance to MINO. By integrating a pathological-milieu-responsive drug-release system with synergistic antimicrobial and ER-stress-modulating chemotherapies, the platform provides a multi-tiered, concerted intervention against diabetic periodontitis.