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J Cell Sci. 2010 Apr 15;123(Pt 8):1183-9. doi: 10.1242/jcs.066399.

Breaking down the barriers: siRNA delivery and endosome escape.

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Dr John T Macdonald Foundation Department of Human Genetics, John P Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, 1501 NW 10 Ave, Miami, FL 33136, USA.


RNA interference (RNAi)-based technologies offer an attractive strategy for the sequence-specific silencing of disease-causing genes. The application of small interfering (si)RNAs as potential therapeutic agents requires safe and effective methods for their delivery to the cytoplasm of the target cells and tissues. Recent studies have shown significant progress in the development of targeting reagents that facilitate the recognition of and siRNA delivery to specific cell types. However, most of these delivery approaches are not optimized to enable the intracellular trafficking of the siRNAs into the cytoplasm where they must associate with the RNA-induced silencing complex (RISC) to direct the cleavage of mRNAs bearing complementary binding sites. In particular, the trafficking of siRNAs from endosomes into the cytoplasm represents a major rate-limiting step for many delivery approaches. This Commentary focuses on novel strategies designed to enhance endosomal escape and thereby increase the efficacy of siRNA-mediated gene silencing.

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