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.
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Exosomes have been tested in preclinical models for delivering proteins and small RNA across the BBB.
“In addition, exosomes have also been tested in preclinical models for delivering proteins and small RNA across the BBB (16, 235, 323).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [16]
Alvarez-Erviti et al. pioneered exosomes as a delivery system for short-interfering RNA to the brain in mice.
“Alvarez-Erviti et al. at Oxford University have pioneered a novel approach employing exosomes as a delivery system for short-interfering RNA (siRNA) to the brain in mice [241].”
From Extracellular vesicles as nanotheranostic platforms for targeted neurological disorder interventions (2024) · cites this paper as [241]
Effective brain delivery of siRNA-loaded exosomes by systemic injection in mice has been demonstrated.
“The effective brain delivery of siRNA-loaded exosomes by systemic injection in mice has been successfully demonstrated by Alvarez-Erviti et al. [235].”
From Alzheimer's Disease: Treatment Strategies and Their Limitations. (2022) · cites this paper as [235]
Engineered targeted exosomes caused specific gene knockdown exclusively in the brain following delivery of GAPDH siRNA.
“These engineered targeted exosomes caused a specific gene knockdown exclusively in the brain following the delivery of GAPDH siRNA.”
From Alzheimer's Disease: Treatment Strategies and Their Limitations. (2022) · cites this paper as [235]
A microfluidic μNMR chip quantifies glioblastoma-specific EV proteins with sensitivity orders of magnitude above Western blotting and ELISA, and changes in EV protein profiles in serial serum samples appeared to track clinical response.
“In this study, Shao et al. report the fabrication of a microfluidic chip that quantifies presence of glioblastoma specific proteins, including EGFR, EGFRvIII, podoplanin (PDPN), and IDH1 R132H proteins by a micro-nuclear magnetic resonance (μNMR) [122].”
From Biogenesis of extracellular vesicles (EV): exosomes, microvesicles, retrovirus-like vesicles, and apoptotic bodies (2013) · cites this paper as [122]
There have been substantial advances in the small RNA delivery technology into the brain.
“there have been substantial advances in the small RNA delivery technology into the brain.”
From microRNA-33 Regulates ApoE Lipidation and Amyloid-β Metabolism in the Brain (2015) · cites this paper as Alvarez-Erviti et al., 2011
Intravenously injected RVG EVs delivered GAPDH siRNA specifically to neurons, microglia and oligodendrocytes in the brain, resulting in tissue-specific gene knockdown.
“It was reported that intravenously injected RVG EVs delivered GAPDH siRNA specifically to the neurons, microglia and oligodendrocytes in the brain, resulting in tissue-specific gene knockdown (Alvarez-Erviti et al., 2011).”
From Engineered Extracellular Vesicles Loaded With miR-124 Attenuate Cocaine-Mediated Activation of Microglia (2020) · cites this paper as Alvarez-Erviti et al., 2011
Alvarez-Erviti et al. successfully expressed Lamp2b fused to RVG peptide in dendritic cells, followed by loading EVs with exogenous siRNA of GAPDH.
“As a means to increase the specific delivery of EVs into the CNS, we followed the approach reported by Alvarez-Erviti et al. (2011) wherein the authors were able to successfully express Lamp2b, an EV membrane protein, fused to an rabies virus glycoprotein (RVG) peptide in dendritic cells, followed by loading the EVs isolated from these cells with exogenous siRNA of GAPDH.”
From Engineered Extracellular Vesicles Loaded With miR-124 Attenuate Cocaine-Mediated Activation of Microglia (2020) · cites this paper as Alvarez-Erviti et al. (2011)
RVG peptide targets the alpha-7-subunit of the nicotinic acetylcholine receptor and facilitates transcytosis of EVs across the blood-brain barrier, with specific targeting of neural cells in the brain.
“RVG peptide is known to target the alpha-7-subunit of the nicotinic acetylcholine receptor (Kim et al., 2010), and facilitates the transcytosis of the EVs across the blood-brain barrier, with specific targeting of neural cells in the brain (Loddo et al., 1966; Alvarez-Erviti et al., 2011).”
From Engineered Extracellular Vesicles Loaded With miR-124 Attenuate Cocaine-Mediated Activation of Microglia (2020) · cites this paper as Alvarez-Erviti et al., 2011
Engineered DC-derived exosomes with Lamp2b and RVG peptide loaded with exogenous siRNA specifically delivered cargo to neurons in the brain, downregulating the siRNA target gene and impacting Alzheimer's disease.
“Notably, exosomes specifically delivered loaded cargo to neurons in the brain, downregulating the siRNA target gene and impacted on Alzheimer’s disease (AD) [70].”
From The Therapeutic Potential and Clinical Significance of Exosomes as Carriers of Drug Delivery System (2022) · cites this paper as [70]
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- Authors
- Alvarez-Erviti, L., Seow, Y., Yin, H., Betts, C., Lakhal, S., & Wood, M. J. A.
- Affiliations
- University of Oxford (GB)
- Corresponding author
- Wood, Matthew J A
- Venue
- Nature Biotechnology
- Published
- 2011-03-20
- Volume
- 29
- Issue
- 4
- Pages
- 341-345
- ISSN
- 0733-222X (ISSN-L)
- 1087-0156
- 1546-1696
- OpenAlex
- W2066234893
- Cited by
- 4,930
- References
- 21
- Citations by year
- 2026: 387 · 2025: 433 · 2024: 486 · 2023: 436 · 2022: 477 · 2021: 493 · 2020: 410 · 2019: 362 · 2018: 300 · 2017: 228 · 2016: 228 · 2015: 197 · 2014: 178 · 2013: 155 · 2012: 112
- FWCI
- 63.16
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Nature Biotechnology (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- Parkinson's UK (J-0901, G-0904)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Keywords
- siRNA delivery, exosomes, brain targeting, dendritic cells, Lamp2b, BACE1, Alzheimer's disease, immunogenicity, microglia, oligodendrocytes, electroporation
- MeSH terms
- Alzheimer Disease, Animals, Brain, Cell Line, Dendritic Cells, Genetic Vectors, Male, Membrane Proteins, Mice, Inbred C57BL, Neurons, Peptides, Proteins, Rabies virus, RNA, Messenger, Aspartic Acid Endopeptidases, Microglia, Gene Transfer Techniques, RNA, Small Interfering, Mice, Lysosomal-Associated Membrane Protein 2, Amyloid Precursor Protein Secretases, Exosomes, Gene Knockdown Techniques
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