Smart Gated Hollow Mesoporous Silica Hydrogel for Targeting Endoplasmic Reticulum Stress and Promoting Periodontal Tissue Regeneration

The hollow mesoporous silica loaded with quercetin (HM‐QU@PEG) is combined with a thermosensitive anti‐bacterial matrix (TF127) to prepare HQUP@TF127. HQUP@TF127 effectively eliminates excessive ROS, alleviates endoplasmic reticulum stress, relieves mitochondrial calcium overload, and blocks the p53‐dependent apoptotic cascade. Furthermore, it enhances the osteogenic differentiation capability of PDLSCs, thereby creating a favorable microenvironment for periodontal tissue regeneration. Abstract Periodontitis is a multifactorial inflammatory disease involving pathogenic biofilm formation, amplified oxidative stress, and impaired tissue regeneration. 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‐bacterial, ROS‐scavenging, and tissue‐regenerative hydrogel system (HQUP@TF127) is developed. In this triple‐functional HQUP@TF127, a ROS‐responsive gatekeeper on hollow mesoporous silica nanoparticles enabled the spatiotemporally controlled release of quercetin, a naturally occurring anti‐inflammatory and osteogenic ingredient. The covalent attachment of the antibacterial, 4‐terpineol 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‐computed 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. The hollow mesoporous silica loaded with quercetin (HM-QU@PEG) is combined with a thermosensitive anti-bacterial matrix (TF127) to prepare HQUP@TF127. HQUP@TF127 effectively eliminates excessive ROS, alleviates endoplasmic reticulum stress, relieves mitochondrial calcium overload, and blocks the p53-dependent apoptotic cascade. Furthermore, it enhances the osteogenic differentiation capability of PDLSCs, thereby creating a favorable microenvironment for periodontal tissue regeneration. Abstract Periodontitis is a multifactorial inflammatory disease involving pathogenic biofilm formation, amplified oxidative stress, and impaired tissue regeneration. 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-bacterial, ROS-scavenging, and tissue-regenerative hydrogel system (HQUP@TF127) is developed. In this triple-functional HQUP@TF127, a ROS-responsive gatekeeper on hollow mesoporous silica nanoparticles enabled the spatiotemporally controlled release of quercetin, a naturally occurring anti-inflammatory and osteogenic ingredient. The covalent attachment of the antibacterial, 4-terpineol 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-computed 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. Advanced Science, Volume 12, Issue 43, November 20, 2025.