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A membrane receptor, Fas (CD95), and its ligand FasL have been considered as key players in diabetes pathogenesis. They are known to mediate interactions between β cells and cytotoxic T cells, which results in apoptotic cell death. We hypothesized that the interruption of Fas–FasL interactions by suppressing Fas expression in β cells would affect the development of diabetes. The effect of Fas-silencing siRNA (Fas siRNA) on diabetes development was evaluated in a cyclophosphamide (CY)-accelerated diabetes animal model after intravenous administration using a polymeric carrier, polyethylenimine (PEI). The systemic non-viral delivery of Fas siRNA showed significant delay in diabetes incidence up to 40 days, while the control mice treated with naked Fas siRNA, scrambled dsRNA, or PBS were afflicted with diabetes within 20 days. The retardation of diabetes incidence after the treatment of Fas siRNA may be due to the delayed progression of the pancreatic insulitis. In this study, the potential use of a non-viral carrier based siRNA gene therapy for the prevention of type-1 diabetes is demonstrated.Polyethylenimine(PEI)-mediated delivery of Fas siRNA protects NOD mice from cyclophosphamide-induced insulitis and diabetes.