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In addition to its complicated pathology, effective treatment of periodontitis is challenged by a dynamic oral microenvironment that prevents drug retention. To overcome these issues, an anti\u2010bacterial, ROS\u2010scavenging, and tissue\u2010regenerative hydrogel system (HQUP@TF127) is developed. In this triple\u2010functional HQUP@TF127, a ROS\u2010responsive gatekeeper on hollow mesoporous silica nanoparticles enabled the spatiotemporally controlled release of quercetin, a naturally occurring anti\u2010inflammatory and osteogenic ingredient. The covalent attachment of the antibacterial, 4\u2010terpineol with thermosensitive Pluronic F127 prolonged retention time, thereby ensuring deep penetration and eradication of subgingival pathogens. HQUP@TF127 restored endoplasmic reticulum homeostasis and, maximized the osteogenic potential of periodontal ligament stem cells. In a rat model of periodontitis, HQUP@TF127 effectively suppressed osteoclast activation by inhibiting inflammatory infiltration and collagen degradation. Micro\u2010computed tomography analysis confirmed an increase in bone mineral density and periodontal tissue regeneration. HQUP@TF127, addressed the multifactorial pathology and obstacles to local drug administration and, requires further translational research by virtue of its triple synergistic mechanisms of action and advantages in local drug delivery.<\/jats:p>","DOI":"10.1002\/advs.202508400","type":"journal-article","created":{"date-parts":[[2025,8,27]],"date-time":"2025-08-27T03:55:43Z","timestamp":1756266943000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Smart Gated Hollow Mesoporous Silica Hydrogel for Targeting Endoplasmic Reticulum Stress and Promoting Periodontal Tissue Regeneration"],"prefix":"10.1002","volume":"12","author":[{"given":"Guichun","family":"Wang","sequence":"first","affiliation":[{"name":"College of Pharmacy Anhui University of Chinese Medicine  Hefei 230012 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