Spatial Configuration-Guided Design of Covalent Organic Framework-Based Artificial Metalloantioxidases for Inhibiting Inflammatory Cascades and Regulating Bone Homeostasis

Intense oxidative stress in bone tissues can trigger the hyperactivation of neutrophils, thereby causing inflammatory cascades to deteriorate bone homeostasis. Here, inspired by the catalytic centers of natural antioxidases, we introduce the spatial configuration-guided design of covalent organic framework (COF)-based artificial metalloantioxidases for inhibiting inflammatory cascades and regulating bone homeostasis. Specifically, the hexaiminohexaazatrinaphthalene COF with ruthenium coordination (S-HACOF-Ru), featuring electron-rich centers with a spatial configuration, demonstrates exceptional antioxidase-like reactive oxygen species (ROS) scavenging capabilities for efficiently mitigating the oxidative stress. As a result, S-HACOF-Ru efficiently prevents the generation of neutrophil extracellular traps and inhibits the release of myeloperoxidase (MPO). By preventing MPO-induced activation of nuclear factor-kappa B and inhibiting proinflammatory macrophage polarization, S-HACOF-Ru successfully blocks the neutrophil-macrophage inflammatory cascades. This intervention promotes bone homeostasis by a shift from bone resorption to tissue regeneration, which can efficiently inhibit alveolar bone loss in periodontal tissues and reverse cartilage damage in ankle joint cavities. We propose that this design strategy provides an intriguing avenue for developing new artificial antioxidases and biocatalytic materials with potential applications in treating a wide range of chronic inflammatory diseases.