Multimodal Nanoregulator Rescues Impaired Neurovascular Units to Attenuate Secondary Injury Following Traumatic Brain Injury

Abstract Traumatic brain injury (TBI) triggers complex neurovascular unit (NVU) damage via ischemia, reactive oxygen species (ROS) accumulation, and persistent immune activation, contributing to long‐term neurological deficits. However, effective NVU repair remains challenging due to the multifactorial nature of secondary injury. Here, a novel multimodal nanotherapeutic platform designed to concurrently target multiple key pathological events underlying NVU disruption is presented. This nanodrug integrates ultrasmall cerium oxide nanoparticles and IRAK‐4 siRNA within a ROS‐responsive poly(1,4‐phenyleneacetone dimethylene thioketal) (PPADT) matrix, cloaked with neutrophil membranes for inflammation homing. At the injury lesion, the responsive nature enables on‐demand drug release, eliciting synergistic therapeutic actions. Specifically, the cerium nanodots catalyze ROS scavenging and oxygen generation, alleviating oxidative stress and hypoxia to facilitate blood–brain barrier restoration, pericyte repair, and improved cerebral perfusion. Simultaneously, IRAK‐4 siRNA downregulates pro‐inflammatory signaling and reprograms microglia toward an anti‐inflammatory phenotype. In a murine TBI model, the nanotherapy promotes vascular repair, reduces brain edema, attenuates neuroinflammation, and preserves neuronal integrity. Additionally, treatment ameliorates sleep spindle loss, reduces epileptiform activity, and significantly improves cognitive performance in learning and memory tasks. This work highlights a multipronged therapeutic strategy capable of restoring NVU homeostasis and mitigating secondary brain injury, offering great promise for advancing TBI treatment.