Polymer-based siRNA delivery: Perspectives on the fundamental and phenomenological distinctions from polymer-based DNA delivery

Gene therapy holds tremendous promise in the treatment of many genetic and acquired diseases. The future of gene therapy in humans, however, is contingent upon the discovery of safe and effective carriers of genetic material. Polymers represent a class of materials that can be extensively modified to meet the needs of a particular gene delivery system. A variety of polymer formulations have been proposed in the literature as potential carriers, most of which facilitate gene delivery by encapsulating, and in some cases, condensing nucleic acids into nano-sized particles which can then be taken up by cells. Crucial to successful delivery of the gene to a cell is the polymer's ability to protect its contents from degradation in the extracellular environment. A well-designed carrier will also promote cellular uptake and intracellular release of the nucleic acid. In the past, a common approach to gene therapy has been to transfect cells with a polymer-encapsulated DNA plasmid designed to replace a defective gene in the target-cell genome. Within the last few years, however, RNA interference (RNAi) has emerged as a novel therapeutic pathway by which harmful genes can be "silenced" by delivering complementary short interfering RNA (siRNA) to target cells. siRNA delivery facilitated by polymers, although very promising, suffers from many of the same limitations as DNA delivery. This review will (1) highlight the similarities and differences between these two methods of gene therapy and (2) discuss how some of the remaining challenges in siRNA delivery facilitated by polymers can be addressed by applying knowledge from the longer-studied problem of DNA delivery. (C) 2007 Elsevier B.V. All rights reserved.