Scheme 1

Scheme 1

Schematic illustration of the investigation of the toxicological effects of radiation-induced neuroinflammation using cross-species models and engineered peptide nanodrugs for RIBI therapy. a Zebrafish (larvae/adults) and murine models were used to systematically examine the neurotoxic effects. b Subsequently, a novel peptide nanodrug system (Pep-Cu_5.4O@H151) was developed. It integrates ultrasmall Cu_5.4O nanozymes with broad-spectrum ROS scavenging capabilities and commercially available cGAS-STING axis inhibitors. This system, which includes BBB-penetrating peptides and microglial cell-targeting peptides, is designed to effectively cross the BBB and specifically target microglia for precise RIBI therapy. Mechanistically, mitochondrial dysfunction caused by radiation-induced ROS overproduction leads to cytosolic mtDNA leakage. This, in turn, excessively activates the cGAS-STING axis, resulting in a neuroinflammatory response. By leveraging the broad-spectrum ROS-scavenging properties of Cu_5.4O nanozymes and the inhibitory effects of H151 on overactivation of the cGAS-STING axis, precise RIBI therapy can be achieved. Images were created using BioRender. Shang, Y. (2025) https://BioRender.com/s5 nlayu (agreement number: KJ28IJ4ZXF)