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-Cu5.4O@H151.　This　agent　integrates　ultrasmall　copper-based　nanozymes　(Cu5.4O)　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.