Berberine-Functionalized Bismuth-Doped Carbon Dots in a Pathogen-Responsive Hydrogel System: A Multifaceted Approach to Combating Periodontal Diseases

Periodontal disease, a global health burden linked to dysbiotic oral polymicrobial communities and disrupted immune-inflammatory responses, is critically mediated by<i>Porphyromonas gingivalis</i>(<i>Pg</i>)─the keystone pathogen that sabotages host immunity, triggers tissue inflammation and destruction, and disrupts microbiota balance. Effective therapies should combine antimicrobial action, immune modulation, virulence suppression, and microbiome restoration. Bismuth ions and berberine, which exhibit antimicrobial and epithelial barrier-protecting effects, show potential effectiveness in treating periodontal diseases but face practical limitations due to poor water solubility and bioavailability. To address this, we developed bismuth-doped carbon dots functionalized with structure-modified berberine (BiCD-Ber) as a multifunctional nanomedicine. BiCD-Ber eradicated <i>Pg</i> in various forms, restored <i>Pg</i>-perturbed immune responses in gingival fibroblasts, and preserved epithelial barrier integrity. The doped bismuth ions neutralized <i>Pg</i> virulence factors by blocking the catalytic sites of gingipains. To facilitate <i>in vivo</i> delivery, BiCD-Ber was encapsulated in a disulfide-modified hyaluronic acid hydrogel that degrades in response to <i>Pg</i> metabolites. This BiCD-Ber hydrogel system modulated subgingival microbiota, alleviated inflammation in gingiva, and thereby prevented alveolar bone loss. This approach to concurrently eliminating <i>Pg</i>, modulating inflammatory responses , suppressing virulence factors, and restoring microbiota showcases great potential in managing periodontitis effectively.