Polyphenol mediated zinc-oxygen synergistic hydrogel remodels senescent microenvironment for periodontal tissue regeneration

Senescent mesenchymal stem cells residing in an inflammatory, dysbiotic, and hypoxic microenvironment pose a barrier to periodontal regeneration. Here we introduce a hydrocaffeic acid (HCA)-mediated silk fibroin hydrogel incorporating Mn/HCA-modified calcium peroxide (Mn-hCaO₂) and HCA-modified zeolitic imidazolate framework-8 (hZIF8) to rejuvenate this environment. The strategy imbues the hydrogel with enhanced adhesion and adaptability in periodontal pockets. The Mn-HCA complex acts catalytically to reduce oxidative stress and correct hypoxia. Simultaneously, Zn²⁺ and HCA restore microbial balance and mitigate inflammation. This multifunctional hydrogel targets the senescent periodontal niche by normalizing microbiota homeostasis and promoting a regenerative immune profile. Concurrently, it directly alleviates telomere shortening, DNA damage and oxidative stress in stem cells, thereby rejuvenating cellular function. By specifically addressing hypoxia and zinc deficiency, this polyphenol-mediated synergistic strategy offers a pathway to rejuvenate the senescent periodontal microenvironment, thereby overcoming tissue regeneration barriers and offering a translatable pathway for treating periodontitis and other aging-associated inflammatory diseases. Periodontitis treatment is challenged by senescent stem cells in the periodontal niche. Here, authors develop a multifunctional hydrogel that alleviates hypoxia and stem cell aging, and restores microbial balance to accelerate regeneration.