Abstract
The efficient delivery of biologically functional short interfering RNA (siRNA) in vivo remains a widely unresolved technical problem in therapeutic drug development. The repertoire of concepts for the cellular uptake of oligonucleotide-based tools and drugs has been extended by the mechanistically novel finding that phosphorothioate (PS)- modified single-stranded oligodeoxyribonucleotides (ON) promote the intracellular accumulation of naked extra-cellular siRNA in a variety of cell types. This mode of delivery gives rise to substantial intracellular amounts of siRNA, up to 104 siRNA molecules per cell. Conversely, the moderate biological effectiveness strongly indicates that intracellular release of siRNA from sub-cellular compartments where it seems to be trapped is a necessary step towards efficient target suppression. Here, we summarize key characteristics of the PS-stimulated cellular uptake of siRNA and describe concepts for the increase of intracellular delivery of biologically functional siRNA.
Keywords: Delivery, oligonucleotide, RNAi, endoplasmatic reticulum, intracellular release
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