Smart Gated Hollow Mesoporous Silica Hydrogel for Targeting Endoplasmic Reticulum Stress and Promoting 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.