Manganese dioxide coupled metal-organic framework as mitophagy regulator alleviates periodontitis through SIRT1-FOXO3-BNIP3 signaling axis

Abstract

Periodontitis is a prevalent chronic inflammatory disease characterized by alveolar bone resorption. Its progression is closely linked to oxidative stress where reactive oxygen species (ROS) generated by mitochondria exacerbate inflammation in positive feedback loops. Strategies for mitochondrial regulation hold potential for therapeutic advances. Metal-organic frameworks (MOFs) have shown promise as nanozymes for ROS scavenging. However, inability to directly regulate cellular processes to prevent further ROS production from damaged mitochondria during persistent inflammation makes MOFs insufficient in treating periodontitis. This study synthesizes MnO₂@UiO-66(Ce) by introducing MnO₂ within nanoscale mesoporous UiO-66 type MOFs. MnO₂ coupled with Ce clusters in MOF channels, forms a superoxide dismutase/catalase cascade catalytic system. More importantnly, manganese endows the MOFs with bioactive effects which enhances mitophagy, facilitating the removal of damaged mitochondria, thereby restoring long-term cellular homeostasis. The results demonstrate that this synergistic antioxidant solution MnO₂@UiO-66 restores mitochondrial homeostasis and osteogenic activity of periodontal ligament cells in vitro and alleviates inflammatory bone resorption in a ligature-induced periodontitis model in vivo. The SIRT1-FOXO3-BNIP3 signaling axis plays a key role in this process. This study may provide a design strategy that combines a highly efficient cascade catalytic system with long-term regulation of cellular homeostasis to combat oxidative stress in chronic inflammation.

Keywords: Metal-organic frameworks; Mitophagy; Oxidative stress; Periodontitis.