H₂S-Scavenging Hydrogel Alleviating Mitochondria Damage to Control Periodontitis

H₂S, as a typical metabolite of periodontal pathogens, exhibits a clear positive correlation with the occurrence and development of periodontitis. H₂S at physiological concentrations can regulate many biological processes. However, excess H₂S in the periodontal pocket can trigger secretion of proinflammatory cytokines, cause oxidative stress, and result in mitochondrial damage and cell death in human gingival fibroblasts, exacerbating periodontitis development and periodontal tissue destruction. Worse, H₂S facilitates bacteria survival and proliferation by maintaining bacterial redox balance and enhancing antibiotic resistance. Unfortunately, scavenging H₂S during periodontitis treatment is usually ignored. Herein, a kind of hyaluronic acid methacryloyl/ZnO (HMZ) composite hydrogel with an H₂S-scavenging ability was prepared to enhance periodontitis treatment. The HMZ hydrogel possessed good injectability and cytocompatibility and was able to remove H₂S by a reaction with ZnO. As a result, the HMZ hydrogel was able to increase cell viability from 13% to 120% for human gingival fibroblasts and 22% to 94% for human periodontal ligament fibroblasts at 48 h, restore mitochondrial homeostasis, and alleviate cGAS-STING signaling pathway-mediated inflammation. Meanwhile, the HMZ hydrogel showed satisfactory antibacterial properties and efficiency of plaque biofilm removal. The in vivo results further confirmed that HMZ hydrogel decreased the concentration of H₂S within the periodontal pocket from 0.7 to 0.8 mM to the normal level (0.3 to 0.4 mM), killed the bacteria in the periodontal tissues, inhibited osteoclast activity, relieved excess inflammation, and decreased the vertical distance between the cementoenamel junction and the alveolar bone crest from 1,175 µm to 798 µm on the 7th day and from 1,075 µm to 693 µm on the 14th day, achieving efficient periodontal bone regeneration. In brief, an H₂S scavenging-based promising strategy was developed to enhance the therapeutic efficiency of periodontitis.