Smart multifunctional Cu2O@RuO2 nanozyme for angiogenesis and osteogenesis in periodontitis

Nanozymes have emerged as promising nanomaterials for the treatment of inflammation-related diseases by eliminating excessive reactive oxide species (ROS) and immunoregulation. However, persistent inflammation invariably causes severe alveolar destruction in periodontitis; and the alleviation of inflammation alone by neglecting the impairment of vascular functions could not effectively realize periodontal regeneration. Herein, a multifunctional copper-ruthenium oxide-based yolk-shell nanozyme (Cu₂O@RuO₂, CRNC) is designed to promote effective periodontal regeneration. The ruthenium oxide (RuO₂) shell serves to alleviate inflammation by eliminating ROS and triggering macrophage polarization, whereas the cuprous oxide (Cu₂O) core acts as a responsive Cu^2 + nano-reservoir for promoting angiogenesis and osteogenesis. Results demonstrated that CRNC could activate transforming growth factor β/phosphatidylinositol 3-kinase (TGF-β/PI3K) and hypoxia-inducible factors (HIF-1α) signals, aiding angiogenesis in the human umbilical vein endothelial cells and osteogenesis in periodontal ligament stem cells, respectively. The multifunctional CRNC nanozyme successfully decreased periodontal inflammation and ameliorated alveolar regeneration in a periodontitis model. This study provides promising insights into periodontitis treatment by targeting both angiogenesis and osteogenesis.