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

Abstract 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.