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

      Nature biotechnology
      Alzheimer Disease, therapy, Amyloid Precursor Protein Secretases, genetics, Animals, Aspartic Acid Endopeptidases, Brain, metabolism, Cell Line, Dendritic Cells, Exosomes, Gene Knockdown Techniques, Gene Transfer Techniques, Genetic Vectors, Lysosomal-Associated Membrane Protein 2, Male, Membrane Proteins, Mice, Mice, Inbred C57BL, Microglia, Neurons, Peptides, Proteins, RNA, Messenger, RNA, Small Interfering, administration & dosage, Rabies virus

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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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