Ultra-small coordination dihydromyricetin nanodots attenuate alveolar bone resorption in periodontitis through inhibition of ITGB3-Driven osteoclast differentiation.

Irreversible alveolar bone resorption induced by periodontitis constitutes a major etiological factor in adult tooth loss, with its underlying pathological mechanism tightly linked to dysregulated osteoclast differentiation. Conventional clinical interventions for alveolar bone resorption, such as basic periodontal therapy and surgical procedures, are limited in their capacity to effectively inhibit osteoclast differentiation. Dihydromyricetin (DMY), a naturally derived flavonoid compound, exhibits promising inhibitory activity against osteoclast differentiation; however, its poor aqueous solubility and suboptimal bioavailability following localized administration hinder its therapeutic potential. To address these limitations, this study developed ultra-small coordination nanodots (DMY-NDs) with diameters under 10 nm through the coordination of DMY with copper ions and polyvinylpyrrolidone (PVP), thereby markedly improving its solubility and drug delivery efficiency. In vitro assessments confirmed that DMY-NDs possess excellent biocompatibility and robust osteoclast differentiation suppression capabilities. Moreover, these nanodots were innovatively self-assembled into carrier-free injectable hydrogel and evaluated in a murine model of periodontitis. The results demonstrated that the DMY-NDs based hydrogel significantly attenuated bone resorption and reduced osteoclast counts. RNA sequencing analysis indicated that DMY-NDs exert their therapeutic effects through inhibition of the integrin beta 3 (ITGB3)-mediated Focal Adhesion Kinase/Protein Kinase B (FAK/AKT) signaling pathway. Further validation via molecular docking assays confirmed the specific binding interaction between DMY, the active constituent of DMY-NDs, and ITGB3. This study introduces a novel ultra-small coordination nanodots platform for suppressing osteoclast differentiation and presents a carrier-free injectable hydrogel formulation based on ultra-small coordination nanodots, offering an innovative strategy for the clinical management of irreversible alveolar bone loss in periodontitis.