Journal
NATURE BIOTECHNOLOGY
Volume 29, Issue 4, Pages 341-U179Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nbt.1807
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Funding
- Muscular Dystrophy Ireland
- Muscular Dystrophy Campaign (UK)
- Agency for Science, Technology and Research (Singapore)
- MRC [G0900887] Funding Source: UKRI
- Medical Research Council [G0900887] Funding Source: researchfish
- Parkinson's UK [G-0904, J-0901] Funding Source: researchfish
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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(1,2)-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(3). 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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