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. Epub 2011 Mar 20.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / therapy
  • Amyloid Precursor Protein Secretases / genetics
  • Animals
  • Aspartic Acid Endopeptidases / genetics
  • Brain / metabolism*
  • Cell Line
  • Dendritic Cells / metabolism
  • Exosomes / metabolism*
  • Gene Knockdown Techniques
  • Gene Transfer Techniques*
  • Genetic Vectors
  • Lysosomal-Associated Membrane Protein 2 / genetics
  • Male
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Microglia / metabolism
  • Neurons / metabolism
  • Peptides / metabolism
  • Proteins / metabolism
  • RNA, Messenger / metabolism
  • RNA, Small Interfering / administration & dosage*
  • Rabies virus / metabolism


  • Lysosomal-Associated Membrane Protein 2
  • Membrane Proteins
  • Peptides
  • Proteins
  • RNA, Messenger
  • RNA, Small Interfering
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • Bace1 protein, mouse