Neuronal damage of the retina is a leading cause of visual impairment in patients with retinal ischemia-reperfusion injury (RIRI). Building on our clinical and experimental findings, the substantial decrease in catalase activity correlates with increased hydrogen peroxide (HO)-mediated oxidative stress that is primarily localized to the outer nuclear layer (ONL) situated in the posterior segment of the retina. Accordingly, we design a neural stem cell exosome with polylysine (K) decoration and catalase expression, named CataKNexo, which reaches the ONL and exerts synergistic antioxidant and neuroprotective therapy. Utilizing an in vitro retinal model recapitulating the layered architecture of the retina, we confirm that CataKNexo reaches the ONL through K-mediated transcytosis. In RIRI model mice, CataKNexo prevents the retina from HO-induced cell death, exerts neuroprotection, and restores vision function to near-normal levels. Moreover, CataKNexo shows promising antioxidative, neuroprotective, and safety profiles in RIRI model Bama miniature pigs, highlighting its potential for clinical translation.