Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes
- Nat Biotechnol. 2011 Apr;29(4):341-5. doi: 10.1038/nbt.1807.
- 1. Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.
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.