Chaotropic ion-tuned protein/peptide hydrogel with enhanced trans-barrier delivery for effective periodontitis management via pathogen clearance, immunomodulation, and MSC preservation.

Periodontitis increases the risk of tooth loss and systemic comorbidities, with anatomical challenges, particularly in narrow periodontal pockets and furcation regions, necessitating advanced drug delivery systems. The keystone pathogen, Porphyromonas gingivalis, exacerbates disease progression by invading epithelial cells and evading intracellular immune responses. Current hydrogel delivery systems do not adequately address trans-barrier drug delivery and intracellular bacterial clearance. Leveraging the membrane-permeabilizing capacity of chaotropic anions, we engineered an iodide-functionalized gelatin/poly-L-lysine hydrogel (GPI). This system demonstrated enhanced injectability for sufficient pocket infiltration and robust mucosal adhesion. High-concentration iodide (5-10 mM) released at mucosal interfaces potentiates PLL trans-epithelial delivery via membrane fluidization, promoting intracellular P. gingivalis clearance. Diffused therapeutic iodide concentrations (0.5-1.0 mM) concurrently suppress proinflammatory cytokines and enhance osteogenesis. In rat periodontitis models, micro-CT confirms GPI30 reduces alveolar bone loss. A transgenic mouse model of Gli1-creERT2; tdTomato mice demonstrated sodium iodide-mediated preservation of Gli1+ mesenchymal stem cell reservoirs in periodontitis. This multifunctional platform leverages chaotropic ion effects to significantly enhance transmembrane delivery of antimicrobial peptides, enabling synergistic intracellular pathogen clearance while concurrently achieving immunomodulation, osteogenesis, and MSC preservation, thereby advancing precision hydrogel therapeutics for periodontitis management.