We have previously demonstrated that adenoviral gene transfer of the NF-B inhibitor I B to human islets results in protection from interleukin (IL)-1-mediated dysfunction and apoptosis. Here we report that human and mouse islets can be efficiently transduced by a cationic peptide transduction domain (PTD-5) without impairment of islet function. PTD mediated delivery of a peptide inhibitor of the IL-1-induced I B kinase (IKK), derived from IKK (NBD; Nemo-binding domain), and completely blocked the detrimental effects of IL-1 on islet function and NF-B activity, in a similar manner to Ad-I B. We also demonstrate that mouse islets can be transduced in situ by infusion of the transduction peptide through the bile duct prior to isolation, resulting in 40% peptide transduction of the -cells. Delivery of the IKK inhibitor transduction fusion peptide (PTD-5-NBD) in situ to mouse islets resulted in improved islet function and viability after isolation. These results demonstrate the feasibility of using PTD-mediated delivery to transiently modify islets in situ to improve their viability and function during isolation, prior to transplantation.