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

Journal article

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.

Authors: Alvarez-Erviti, L; Seow, Y; Yin, H; Betts, C; Lakhal, S

• Publication status: Published
• Journal: Nature biotechnology
• Volume: 29
• Issue: 4
• Pages: 341-345
• Publication date: 2011-04-01
• DOI: 10.1038/nbt.1807
• EISSN: 1546-1696
• ISSN: 1087-0156
• Language: English
• Keywords: Animals; Gene Knockdown Techniques; Brain; Male; Cell Line; Alzheimer Disease; RNA, Messenger; Aspartic Acid Endopeptidases; Exosomes; Peptides; Gene Transfer Techniques; Neurons; Microglia; RNA, Small Interfering; Lysosomal-Associated Membrane Protein 2; Genetic Vectors; Mice; Amyloid Precursor Protein Secretases; Rabies virus; Dendritic Cells; Membrane Proteins; Mice, Inbred C57BL; Proteins