A thermosensitive hydrogel encapsulating 2-DG alleviates periodontitis by inhibiting glycolysis and effector response of Th17 cells

Objective To investigate the mechanism of Th17 cells in immunomodulation during periodontitis and develop a localized drug delivery system based on glycolysis inhibition for safer and more effective therapeutic interventions. Methods Periodontitis models were established via the use of IL17A-KO mice to evaluate the impact of Th17-related cytokine deficiency on pathological progression. Using single-cell RNA sequencing (scRNA-seq), we investigated the metabolic profile of CD4 + T cells under periodontitis conditions. The glycolysis inhibitor 2-deoxy-D-glucose (2-DG) was used to assess its ability to suppress CD4 + T-cell proliferation and Th17 differentiation. A thermosensitive PLGA-PEG-PLGA hydrogel encapsulating 2-DG was synthesized and locally administered to a murine periodontitis model. Results IL17A-KO mice exhibited significantly attenuated alveolar bone resorption. Single-cell RNA sequencing revealed that, under periodontitis conditions, CD4 + T cells exhibited enhanced differentiation toward Th17 cells and increased glycolysis. The 2-DG hydrogel inhibited CD4 + T-cell expansion and Th17 polarization. Local application of the 2-DG hydrogel reduced periodontal inflammation, decreased bone destruction, and diminished granulocyte infiltration in gingival tissues. Conclusion Th17-cell differentiation exacerbates periodontitis progression, and glycolysis inhibition effectively modulates Th17-driven immunity. The localized 2-DG hydrogel delivery system presents a promising translational strategy for periodontitis management.