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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.

Original publication




Journal article


Nat Biotechnol

Publication Date





341 - 345


Alzheimer Disease, Amyloid Precursor Protein Secretases, Animals, Aspartic Acid Endopeptidases, Brain, 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, Rabies virus