Dynamic Covalent Colloidal Gel via RISA for Treating Synergistic Progression of Periodontitis and Dental Demineralization

Abstract Severe periodontitis and tooth demineralization are two prevalent yet pathophysiologically distinct oral diseases that frequently coexist, forming a vicious cycle closely associated with pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). However, current therapeutic approaches typically target either inflammation or hard tissue loss in isolation, lacking adaptability and synergy for complex oral comorbidities. Here, we identified key therapeutic targets for the combined treatment of severe periodontitis with concomitant demineralization based on multidimensional clinical sample analysis. Subsequently, we present a multifunctional colloidal gel platform (PFE CGs) with a dynamic covalent colloidal network using the reaction-induced self-assembly (RISA) technique. Catechol groups in PFE CG ensure strong adhesion to tooth surfaces, creating a stable interface for remineralization. The positively charged three-dimensional (3D) network of PFE CGs enables efficient adsorption of PAMPs and DAMPs, suppressing toll-like receptor (TLR) 4/9-mediated inflammatory signaling and modulating macrophage’s inflammation. Under the acidic and oxidative stress conditions of periodontitis, dynamic covalent bonds are reversibly cleaved to release anti-inflammatory and antioxidant agents, and neutralize the acidic microenvironment that promotes demineralization. This RISA-based colloidal gel platform offers a comprehensive strategy for the synergistic treatment of inflammation and demineralization, and holds promise for managing complex oral comorbidities and guiding the design of next-generation bioactive materials.