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      Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes

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          Abstract

          To realize the therapeutic potential of RNA drugs, efficient, tissue-specific and nonimmunogenic delivery technologies must be developed. Here we show that exosomes-endogenous nano-vesicles that transport RNAs and proteins-can deliver short interfering (si)RNA to the brain in mice. To reduce immunogenicity, we used self-derived dendritic cells for exosome production. Targeting was achieved by engineering the dendritic cells to express Lamp2b, an exosomal membrane protein, fused to the neuron-specific RVG peptide. Purified exosomes were loaded with exogenous siRNA by electroporation. Intravenously injected RVG-targeted exosomes delivered GAPDH siRNA specifically to neurons, microglia, oligodendrocytes in the brain, resulting in a specific gene knockdown. Pre-exposure to RVG exosomes did not attenuate knockdown, and non-specific uptake in other tissues was not observed. The therapeutic potential of exosome-mediated siRNA delivery was demonstrated by the strong mRNA (60%) and protein (62%) knockdown of BACE1, a therapeutic target in Alzheimer's disease, in wild-type mice.

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          Author and article information

          Journal
          Nature Biotechnology
          Nat Biotechnol
          Springer Science and Business Media LLC
          1087-0156
          1546-1696
          April 2011
          March 20 2011
          April 2011
          : 29
          : 4
          : 341-345
          Article
          10.1038/nbt.1807
          21423189
          ddcbb5cd-bb43-43f2-9c0d-1e663f6ace68
          © 2011

          http://www.springer.com/tdm

          http://www.springer.com/tdm

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