Polycation cytotoxicity: a delicate matter for nucleic acid therapy-focus on polyethylenimine

This article provides a critical assessment of the major challenges facing nucleic acid therapeutics, focusing on the safety and efficacy of delivery strategies using synthetic polycations and particularly polyethylenimines. Deficiencies in the field and avenues for further research are identified that could help with design and selection of an expanded and improved library of safer polycationic vectors for clinical gene therapy and RNA interference delivery. We critically assess and challenge some central orthodoxy, and notably the cytotoxicity issue, in the field of polycationic transfectants with particular reference to polyethylenimine and offer new avenues for further research.