This study aimed to verify the brain targeting and peripheral toxicity of Deltorphin A(1-8) [DYN-A(1-8)] nanoparticles in rats with cerebral ischemia-reperfusion injury. Methods: DYN-A(1-8) was encapsulated into poly (citric acid)-g-arginine (PCGA) based nanoparticles, and the characteristics of DYN-PCGA nanoparticles were evaluated. Fluorescent Cy5-labeled DYN-A(1-8) or DYN-PCGA was injected into middle cerebral artery occlusion (MCAO) rats via the tail vein, and an in vivo imaging system was used to validate the brain targeting ability of DYN-PCGA. The effects of DYN-A(1-8) nanoparticles on the histopathology of heart, liver, spleen, lung, and kidney tissues in MCAO rats were observed by HE staining to assess the in vivo toxicity of DYN-PCGA administered via the tail vein. Results: The characterization results showed that DYN-PCGA(1∶5) exhibited small particle size, high stability, and strong drug loading capacity. In vivo imaging results indicated that DYN-PCGA could effectively transport drugs across the blood-brain barrier to the brain after administration, demonstrating good brain targeting. HE staining results revealed that the tissue sections of heart, liver, spleen, lung, and kidney in MCAO rats showed normal cellular structure without edema or inflammatory cell infiltration, and no abnormal histopathological changes were found. Conclusion: DYN-PCGA nanoparticles extended the plasma half-life of DYN-A(1-8), exhibiting good brain targeting and certain safety.