title: Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes.
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.
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.
authors.forename: Lydia
authors.initials: L
authors.lastname: Alvarez-Erviti
authors.forename: Yiqi
authors.initials: Y
authors.lastname: Seow
authors.forename: Haifang
authors.initials: H
authors.lastname: Yin
authors.forename: Corinne
authors.initials: C
authors.lastname: Betts
authors.forename: Samira
authors.initials: S
authors.lastname: Lakhal
authors.forename: Matthew J A
authors.initials: MJ
authors.lastname: Wood
mesh_terms: D000544:Alzheimer Disease / Q000628:therapy; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics; D001921:Brain / Q000378:metabolism*; D002460:Cell Line; D003713:Dendritic Cells / Q000378:metabolism; D055354:Exosomes / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D052119:Lysosomal-Associated Membrane Protein 2 / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D010455:Peptides / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000008:administration & dosage*; D011820:Rabies virus / Q000378:metabolism
chemical_list: D052119:Lysosomal-Associated Membrane Protein 2; D008565:Membrane Proteins; D010455:Peptides; D011506:Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse