Self-Delivering Supramolecular Hydrogel Ameliorates Periodontal Destruction Through Immunomodulation

Anti-inflammatory therapy targeting immune responses has emerged as an effective adjunctive treatment for periodontitis. However, few systems are available for topical application. This study investigates an injectable supramolecular hydrogel based on 8-aminoguanosine (8-AG) as a novel immunomodulatory agent to achieve anti-oxidative stress and immunomodulation via self-delivery of 8-AG for localized therapy in periodontitis. An 8-AG-PBA supramolecular hydrogel, based on dynamic phenylboronate esters, was constructed and characterized for its microstructure, injectability, and sustained 8-AG release. Its anti-oxidative stress and immunomodulatory effects were evaluated, with mechanisms explored via metabolomics and transcriptome sequencing. Finally, the therapeutic effect of periodontal injection in reducing alveolar bone resorption and tissue destruction was assessed in a mouse periodontitis model. The 8-AG-PBA hydrogel exhibited excellent stability, self-healing ability, biocompatibility, and degradability, with sustained release of 8-AG upon degradation. Through modulation of second messengers, 8-AG regulated MAPK and NF-κB signaling pathways, and together with the antioxidant properties of 1,4-phenylenebisboronic acid (PBA), inhibited oxidative damage, macrophage M1/M2 imbalance, and pro-inflammatory factor secretion in LPS-stimulated macrophages. In a mouse periodontitis model, periodontal injection of the hydrogel effectively suppressed inflammation, osteoclast differentiation, and alveolar bone loss. 8-AG demonstrates anti-inflammatory therapeutic potential as a novel anti-oxidative stress agent and immunomodulator. The injectable 8-AG-PBA supramolecular hydrogel, serving as a self-delivery platform for 8-AG, represents a promising new strategy for localized anti-inflammatory treatment of periodontitis.