Abstract
While nanozymes effectively mitigate neuroinflammation by scavenging reactive oxygen species (ROS), they often fail to address the continuous ROS generation from dysfunctional cells within the spinal cord injury (SCI) microenvironment. Herein, we introduce a "root-cause" therapeutic strategy using a biomimetic nanoplatform (NMm-pPB-siRNATRAF6 that integrates Prussian blue (PB) nanozymes with TRAF6-silencing siRNA to synergistically scavenge ROS and restore cellular homeostasis. Mechanistically, by restoring the impaired autophagic flux, this system effectively inhibits neuronal pyroptosis and reprograms pro-inflammatory M1 macrophages into the reparative M2 phenotype, thereby eradicating ROS at their source. Notably, inspired by the sequential infiltration of immune cells following SCI, we propose the concept of "spatiotemporal delivery". Achieved through the camouflage of a hybrid neutrophil-macrophage membrane, this mechanism enables nanoparticles to continuously access at the lesion site throughout the critical window from Day 1 to Day 7 (temporal dimension) while precisely targeting the inflammatory microenvironment (spatial dimension). This biomimetic strategy significantly promoted functional recovery in SCI mice, providing a new paradigm for treating neuroinflammation-related diseases by simultaneously neutralizing oxidative stress and correcting upstream cellular dysfunction. The findings of this study not only deepen the understanding of disease-targeted delivery but also offer new insights for the construction and application of composite biomaterials.