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Safe, Selective, & Specific siRNA

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Science  28 Feb 2014:
Vol. 343, Issue 6174, pp. 951
DOI: 10.1126/science.343.6174.951-b

RNA interference (RNAi) via small interfering (si) RNAs offers potential as a therapeutic tool for the specific knockdown of disease-associated genes. One limiting factor in the use of siRNAs as drugs involves delivering highly charged RNA molecules across cell membranes and into cells of the tissue of interest. Dong et al. used natural lipoprotein particles—which consist of apolipoprotein, phospholipid, cholesterol, and triglyceride and which have affinity for the liver—as a model for the design of an siRNA delivery system directed to the liver. They constructed lipopeptide nanoparticles (LPNs) by linking epoxide or aldehyde-derived lipid tails to amino acids or short peptides. Formulated with cholesterol, phospholipids, polyethylene glycol–lipid, and siRNA, the LPNs formed ∼70-nm spheres, suspensions of which could be administered by injection. Lysine-based lipopeptides with tail lengths of 12 to 14 carbons proved highly effective at gene silencing specifically in liver hepatocytes. Furthermore, LPNs showed low toxicity and high gene-silencing activity in mice and cynomolgus monkeys. Apolipoprotein E facilitated both cell uptake and the escape of specific chemical classes of LPN-complexed siRNAs from endosomes into the cytoplasm.

Proc. Natl. Acad. Sci. U.S.A. 10.1073/pnas.1322937111 (2014).

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