A Smart Injectable Hydrogel with Dual Responsivity to Arginine Gingipain A and Reactive Oxygen Species for Multifunctional Therapy of Periodontitis

Abstract Distinct clinical phenotypes of periodontitis are associated with specific microbiome profiles and diverse inflammatory conditions. Current drug delivery systems face challenges in precisely modulating this dynamic microenvironment. Effective inhibition of bone resorption can only be achieved through a strategic response to bacterial infections and inflammation within the periodontal pocket, followed by prompt treatment tailored to disease severity. In this study, tannic acid (TA) is loaded into hollow mesoporous silica nanoparticles (HMSNs) that are functionalized with positively charged polyarginines (R8) and negatively charged human serum albumin (HSA). These HMSNs‐R8@TA‐HSA (HRT) nanoparticles are then encapsulated within an injectable Nap‐Gly‐Phe‐Phe‐Tyr‐OH (NapGFFY) hydrogel (NHRT). The intermediate linker R8 can interact with both arginine gingipain A (RgpA) and reactive oxygen species (ROS), which serve as markers of bacterial infections and inflammation, respectively. HSA, arginine, TA, and nitric oxide are differentially released from the hydrogel in response to varying concentrations of RgpA and ROS, demonstrating excellent antibacterial, antioxidant, and anti‐inflammatory properties. This smart RgpA/ROS dual‐responsive and injectable hydrogel with multifunctional therapy provides new prospects for the management of periodontitis.