Self-Assembled Charge-Complementary Hydrogel with Sustained Release of Antimicrobial Peptides for Periodontitis Treatment.

Periodontitis is a pathogenic microbial-infected disease where immune dysregulation promotes chronic inflammation and excessive osteoclast activity, causing progressive tissue destruction. Current therapeutic approaches face challenges in achieving sustained drug release in periodontal pockets. In this study, we construct a self-assembled peptide hydrogel by combining negatively charged peptide amphiphile (PA) with positively charged antimicrobial peptide GL13K, namely PA/GL13K. GL13K electrostatically binds to self-assembled PA nanofibers, promoting PA self-assembly that yields a denser hydrogel network. This structural reinforcement enables sustained GL13K release. The PA/GL13K hydrogel demonstrates potent antibacterial effects and immunomodulatory properties, suppressing pro-inflammatory M1 macrophage polarization while promoting anti-inflammatory M2 macrophage activation. Moreover, the PA/GL13K hydrogel inhibits osteoclast differentiation in vitro. In an experimental periodontitis mouse model, local periodontal injection of the PA/GL13K hydrogel reduced inflammatory infiltration and osteoclast-mediated bone resorption, effectively mitigating periodontal tissue destruction. These findings suggest that the self-assembled peptide hydrogel system may represent a potential multifunctional therapeutic approach for periodontal treatment. STATEMENT OF SIGNIFICANCE: This study presents a peptide-based hydrogel system designed for the comprehensive treatment of periodontitis, addressing critical challenges in current therapeutic strategies. The self-assembled charge-complementary hydrogel is composed of negatively charged peptide amphiphile (PA) and positively charged antimicrobial peptide GL13K. GL13K electrostatically binds to self-assembled PA nanofibers, promoting PA self-assembly that yields a denser hydrogel network. This structural reinforcement enables sustained GL13K release. The system demonstrates synergistic effects, including antibacterial activity, immunomodulatory effects, and inhibition of osteoclastogenesis. Our findings highlight the hydrogel's potential as a promising platform for periodontitis management, combining structural optimization with multifunctional therapeutic outcomes.