<p>Radiation-induced brain injury (RIBI) represents a severe complication of cranial radiotherapy, substantially diminishing patients’ quality of life. Unlike conventional brain injuries, RIBI evokes a unique chronic neuroinflammatory response that notably aggravates neurodegenerative processes. Despite significant progress in understanding the molecular mechanisms related to neuroinflammation, the specific and precise mechanisms that regulate neuroinflammation in RIBI and its associated toxicological effects remain largely unclear. Additionally, targeted neuroprotective strategies for RIBI are currently lacking. In this study, we systematically characterized the pathophysiology of RIBI using zebrafish (larvae/adults) and murine models. We established direct associations between neuronal damage and cognitive-behavioral deficits. Mechanistically, we proposed a ROS-mitochondrial-immune axis. Specifically, radiation-induced ROS lead to mitochondrial dysfunction, resulting in the leakage of mitochondrial DNA into the cytosol. This, in turn, activated the cGAS-STING pathway, thereby driving persistent microglia-mediated neuroinflammation. Furthermore, we engineered a dual-function nanotherapeutic agent, Pep-Cu_5.4O@H151. This agent integrates ultrasmall copper-based nanozymes (Cu_5.4O) for ROS scavenging and H151 (a STING inhibitor) and is conjugated with peptides that can penetrate the blood-brain barrier and target microglia. This nanoplatform exhibited excellent synergistic therapeutic efficacy by simultaneously neutralizing oxidative stress and blocking inflammatory cascades. Our research provided an in-depth analysis of radiation-induced neurotoxicity, clarifying the crucial ROS-mitochondrial-immune axis. Moreover, we have developed a precise therapeutic strategy on the basis of this mechanism.</p>