SirT1, a NAD-dependent histone deacetylase, is an essential mediator of cellular longevity. Oct4, a POU-domain transcription factor, is highly expressed in maintaining pluri-potency and cellular reprogramming process in stem cells. Both Oct4 and SirT1 (Oct4/SirT1) expression was decreased in an age-dependent manner in retina and retinal pigment epithelium cells (RPEs). Cationic polyurethane, a biodegradable non-viral vector, protects DNA from nuclease degradation and helps to deliver genes efficiently. In this study, polyurethane-short branch polyethylenimine (PU-PEI) was used to deliver Oct4/SirT1 into aged RPEs (aRPEs) or light-injured rat retinas. Rats were anesthetized with intramuscular injections of an equal-volume mixture of 2% lidocaine (0.15 mL/kg) and ketamine (50 mg/mL). The light-injured retinas were confirmed with H&E staining and quantified with the changes in the outer nuclear layer (ONL) thickness. The results showed that Oct4/SirT1 overexpression increased the expression of several progenitor-related genes and the self-renewal ability of aRPEs. Moreover, Oct4/SirT1 overexpression resulted in the demethylation of the Oct4 promoter and enhanced the expression of antioxidant enzymes, which was accompanied by a decrease in intracellular ROS production and hydrogen peroxide-induced oxidative stress. Importantly, PU-PEI-mediated Oct4/SirT1 gene transfer rescued retinal cell loss and improved electroretinographic responses in light-injured rat retinas. These data suggest that PU-PEI-mediated delivery of Oct4/SirT1 reprograms aRPEs into a more primitive state and results in cytoprotection by regulating the antioxidative capabilities of these retinal cells. (Note: all experiments were performed in compliance with the Animal Care and Use Committee guidelines and in accordance with the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research)