Size-dependent ruthenium/ceria nanozymes synchronize catalytic ROS scavenging and electrostatic mtDNA sequestration...

Mitochondrial oxidative stress and release of mitochondrial DNA (mtDNA) are increasingly implicated in amplification of inflammatory responses in chronic diseases such as periodontitis. While cerium dioxide (CeO₂)-based nanozymes have been explored as antioxidants, their therapeutic efficacy remains limited by suboptimal catalytic performance and weak interactions with intracellular inflammatory mediators. Here, we report a structure-engineered ruthenium-sensitized ceria nanozyme platform designed to modulate mitochondrial redox imbalance and mtDNA-driven innate immune activation in periodontitis, in which the organization state of Ru species is precisely regulated to tune redox activity and surface electropositivity. Among the investigated configurations, Ru nanocluster-doped CeO₂ (Ru_NC-CeO₂) represents an optimal intermediate morphology that enhances electron density, increases accessible active sites, and strengthens metal-support interactions, leading to improved multi-enzyme-like activity for the efficient management of reactive oxygen species (ROS) scavenging. Concomitantly, Ru nanocluster sensitization increases the positive surface charge of CeO₂, enabling effective electrostatic sequestration with stress-released cytosolic mtDNA. This structure-enabled dual functionality facilitates mitochondrial protection and attenuates mtDNA-associated innate immune activation in macrophages under inflammatory conditions. Systematic size-dependent analyses reveal that Ru_NC-CeO₂ with a moderate oxidation state exhibits superior immunomodulatory performance compared with single-atom and nanoparticle counterparts, in both artificial and biological contexts. In a rat periodontitis model, local administration of Ru_NC-CeO₂ significantly alleviates gingival inflammation, suppresses inflammatory cytokine expression, and reduces periodontal tissue destruction. Collectively, this work establishes a structure-engineering strategy for nanozyme-based immunomodulation in periodontitis, demonstrating that dopant organization governs the coupling between mitochondrial redox homeostasis and mtDNA-mediated cGAS-STING signaling.