Covalent Organic Framework‐Based Artificial Antioxidases with π‐Electron Delocalization and Asymmetric Coordination Sites for Superior Inflammation Inhibition and Oral Bone Modulation

Periodontitis-induced alveolar bone loss represents a complex therapeutic challenge that demands simultaneous resolution of chronic inflammation and restoration of bone homeostasis. Drawing inspiration from natural antioxidases, the de novo design of an interlaminar ruthenium-coordinated covalent organic framework (COF) is reported that functions as an artificial antioxidase system. This fully condensed COF architecture (TTf-Ru) combines extended π-electron delocalization with precisely engineered asymmetric ruthenium coordination sites, thereby creating optimal electronic environments for scavenging reactive oxygen species (ROS). Spectroscopic and computational analyses reveal that TTf-Ru exhibits dual enzyme-mimetic activities, demonstrating both catalase- and superoxide dismutase-like functionality through tailored adsorption energetics for oxygen intermediates. At the cellular level, TTf-Ru effectively mitigates oxidative stress in mesenchymal stem cells, preserving their osteogenic differentiation capacity even under pro-inflammatory conditions. The artificial antioxidase simultaneously orchestrates an immunomodulatory response, suppressing pro-inflammatory macrophage polarization while promoting a tissue-reparative phenotype. In periodontitis models, this coordinated action translates to significant therapeutic outcomes, which reduce alveolar bone resorption and maintain periodontal tissue architecture. The findings establish a material design paradigm for COF-based enzyme mimics, highlighting how spatially organized biocatalytic centers can be engineered to address multifactorial diseases through integrated redox modulation and immune regulation, which provides new possibilities for treating ROS-mediated inflammatory disorders.