Dynamic Covalent Prodrug Nanonetworks via Reaction-Induced Self-Assembly for Periodontitis Treatment.

Periodontitis is characterized by dysbiotic biofilms, gingival inflammation, and bone resorption, highlighting the urgent need for a comprehensive approach to drug combination therapy. In this study, we introduce dynamic covalent nanonetworks (dcNNWs) synthesized through a one-pot, four-component reaction-induced self-assembly method using polyamines, 2-formylphenylboronic acid, epigallocatechin gallate, and alendronate. The formation of iminoboronate bonds drives the creation of dcNNWs, allowing controlled release in the periodontitis microenvironment. The inclusion of catechol and bisphosphonate imparts exceptional bioadhesive properties to the dcNNWs, enhancing their efficacy in preventing pathogenic bacterial biofilm formation and eliminating mature biofilms. Moreover, the dcNNWs efficiently absorb pathogen-associated molecular patterns and scavenge excess reactive oxygen species, regulating the local immune response and demonstrating anti-inflammatory effects. Additionally, the released polyphenol and alendronate from the dcNNWs alleviated inflammation and enhanced osteogenesis significantly. The detailed synergistic effects of dcNNWs in biofilm eradication, anti-inflammation, and bone remodeling, with minimal impact on healthy tissues, are confirmed in a rat model of periodontitis. With a facile synthesis process, excellent synergistic effects in periodontitis treatment, and biocompatibility, our dcNNWs present a promising and translational solution for the effective management of periodontitis.