An immunomodulatory hydrogel encapsulating dental follicle stem cell-derived small extracellular vesicles promotes neutrophil clearance and periodontal bone regeneration.

Abstract

Periodontitis, characterized by progressive alveolar bone resorption and periodontal defect formation, remains a major clinical challenge driven by bacterial infection and a dysregulated inflammatory immune microenvironment. Neutrophils, as the predominant innate immune cells, accumulate at infected sites to eliminate microbes but concurrently suppress osteoblast function, thereby impairing bone formation and accelerating alveolar bone loss. Lipopolysaccharide-preconditioned dental follicle stem cell-derived small extracellular vesicles (L-DFSC-sEV) exhibit potent immunomodulatory activity, facilitating the clearance of proinflammatory neutrophils and attenuating neutrophil hyperactivation, and reshaping the periodontal immunoregulatory microenvironment. However, the therapeutic efficacy of sEV is often hindered by the hostile infectious and inflammatory environment, as well as the lack of an appropriate delivery system tailored to periodontal conditions. To overcome these limitations, we developed a multifunctional, dynamically cross-linked hydrogel comprising gelatin, oxidized chondroitin sulfate, and epigallocatechin gallate at physiological pH, which encapsulates L-DFSC-sEV (L-DFSC-sEV@GCSE). This hydrogel exhibits excellent tissue adhesion, self-healing capability, antibacterial activity, and immunoregulatory properties, thereby creating a favorable microenvironment for sustained sEV release. In a rat periodontal defect model, L-DFSC-sEV@GCSE markedly enhanced sEV retention and delivery, effectively controlled infection and inflammation, modulated the osteoimmune microenvironment, and significantly promoted periodontal tissue regeneration.