Nitrogen-doped nano-mosaic with platelet membrane reversely targets neutrophils to break the ROS-NETs circuit in...

Efficient bio-targeting and potent ROS scavenging are required to alleviate neutrophil extracellular trap (NET)-mediated tissue destruction in diabetic periodontitis (DP); however, current pharmaceutical therapies are limited by insufficient catalytic activity and poor tissue specificity. Herein, by integrating guanidyl-rich metformin (Met) into the Fe-Curcumin (Cur) framework, we reconstruct the enzymatic center from a naive trivalent Fe-O motif into a saturated octahedral Fe-N/O configuration. This high-coordination environment facilitates the stabilization of high-valent iron intermediates, thereby significantly boosting catalytic performance. Inspired by the natural recruitment of neutrophils by activated platelets, encapsulation with a platelet membrane (PM) camouflage endows this nano-mosaic with a reverse-targeting capability. By leveraging the specific P-selectin/PSGL-1 interaction to anchor onto inflammation-homing neutrophils, the nanozymes effectively 'hitchhike' to the periodontal lesion. Synchrotron-based spectroscopy, theoretical simulations, and in vitro biochemical assays confirm that this transformation elicits a 2 to 4-fold increase in intrinsic antioxidant enzyme activities, thereby enabling highly efficient scavenging of reactive oxygen species (ROS). In vitro, platelet membrane camouflage increased neutrophil-associated uptake to 98.6%, while in vivo imaging demonstrated enhanced periodontal accumulation and prolonged retention. This targeted catalytic system effectively disrupts the ROS-neutrophil extracellular traps (NETs) amplification loop, suppresses inflammatory bone loss, and improves systemic metabolic parameters. This work demonstrates that a hetero-coordinated high-valence nano-mosaic, engineered through the rational repurposing of guanidine compounds and augmented by biomimetic targeting, offers a powerful therapeutic strategy for ameliorating diabetic periodontitis.