Nanoparticle-integrated smart hydrogel with H2S-triggered antibacterial escalation and sustained oxygen release for periodontal regeneration

Periodontitis is a widespread chronic inflammatory disease characterized by pathogenic bacterial biofilms and a hypoxic microenvironment, which together impede effective treatment and tissue regeneration. To overcome these challenges, we developed an injectable, hydrogen sulfide (H2S)-responsive nanocomposite hydrogel, termed PDA@Hb/NOCG, for microenvironment-adaptive therapy. This hydrogel was formulated by incorporating hemoglobin-polydopamine nanoparticles (PDA@Hb NPs) as an oxygen-generating element and tetra-armed azide-terminated polyethylene glycol as an H2S-scavenging component into a dynamically cross-linked Schiff base network. The platform demonstrated satisfactory injectability, self-healing properties, and sustained oxygen release. Notably, upon encountering pathological levels of H2S, a key metabolite of anaerobic infection, the hydrogel underwent an azide-to-amine transformation, significantly enhancing its cationic antibacterial activity in situ. In vitro studies revealed that PDA@Hb/NOCG effectively reduced hypoxia, exhibited strong antibacterial and antibiofilm activities against Porphyromonas gingivalis, Escherichia coli, and Staphylococcus aureus, and possessed excellent cytocompatibility. Additionally, under inflammatory conditions, it promoted the osteogenic differentiation of human periodontal ligament stem cells (hPDLSCs) by activating the Wnt/β-catenin pathway. In a rat periodontitis model, PDA@Hb/NOCG significantly alleviated local bacterial burden, reduced inflammatory infiltration, and maintained alveolar bone structure, as confirmed by micro-CT and histological analyses, without inducing systemic toxicity. This study presents a novel nano-enabled, gas-responsive hydrogel that executes a sequential therapeutic strategy, from hypoxia alleviation and on-demand antibacterial enhancement to pro-osteogenic activation, offering a promising, minimally invasive approach for synergistic infection control and tissue regeneration in periodontitis.