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The Transport Mechanism of Extracellular Vesicles at the Blood-Brain Barrier
Abstract
Recently, extracellular vesicles (EVs), like exosomes and microvesicles, have attracted attention as potent carriers of intercellular communication throughout the body, including the brain. They transmit biological signals from donor cells to recipient cells, and recent evidence suggests that they may even carry such signals to distant destinations through peripheral circulation. In the central nervous system (CNS), EVs contribute to maintaining normal neuronal function, as well as to the pathological development of neurodegenerative diseases. Although some evidence has suggested that EVs can cross the blood-brain barrier (BBB), moving from the peripheral circulation to the CNS, the mechanisms by which EVs facilitate communication between peripheral tissues and the CNS are not well understood. The BBB is a dynamic interface that regulates molecular trafficking between the peripheral circulation and the CNS. However, there is limited mechanistic understanding of how bloodborne EVs cross the BBB under physiological and pathological conditions. In this review, we focus on current knowledge of trafficking of EVs between the peripheral circulation and the brain. Moreover, we describe hypothetical transport routes by which EVs may cross the BBB based on previous reports. Further investigation is needed to understand the precise mechanisms by which EVs are transported across the BBB.
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“In addition, EVs have inherent targeting capabilities and can cross the BBB, facilitating efficient delivery of therapeutic cargo to the CNS [54–57].”
From Extracellular vesicles as nanotheranostic platforms for targeted neurological disorder interventions (2024) · cites this paper as [56]
In the citing paper
“Brain-derived EVs have been found to harbor the ability to penetrate the BBB. This breakdown is crucial as it potentially allows for releasing these EVs into peripheral circulation [54–57].”
From Extracellular vesicles as nanotheranostic platforms for targeted neurological disorder interventions (2024) · cites this paper as [56]
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“Moreover, EVs can cross the BBB, thus opening a new avenue for treatment of brain tumors or brain metastasis [95].”
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“Majority of hydrophilic compounds are unable to cross the BBB, owing to the presence of the efflux transporters like P-glycoprotein (P-gp) and other multi-drugrelated protein transporters (Matsumoto et al., 2017; Patel et al., 2018).”
BackgroundZika Virus Hijacks Extracellular Vesicle Tetraspanin Pathways for Cell-to-Cell Transmission
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“EVs arise from every cell type, are present in all bodily fluids (19, 20) and have even 75 been found to cross the blood brain barrier (21, 22) and the placenta (23, 24).”
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“However, the mechanisms are still not clear and multiple mechanisms may be involved.(44) MIC and MBC are generally used to evaluate the effects of antibacterial agents.”
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“EVs help in remote cell-to-cell signal transmission and cross the blood–brain barrier (BBB) without damaging the structure [16].”
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Exosome- and extracellular vesicle-based approaches for the treatment of lysosomal storage disorders
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Yang, J., Malone, F., Go, M., Kou, J., Lim, J.-E., Caughey, R. C., & Fukuchi, K.-I. (2020) · Journal of Molecular Neuroscience · doi:10.1007/s12031-020-01750-1 · Cited by 46
The emerging role of exosomes in communication between the periphery and the central nervous system
Han, W., Zhang, H., Feng, L., Dang, R., Wang, J., Cui, C., & Jiang, P. (2023) · MedComm · doi:10.1002/mco2.410 · Cited by 42
“103 Exosomes originating from leukemia could be of great value, as they can modify the integrity of the connection between endothelial cells in the body and even facilitate the passage into the brain.”
BackgroundLapchak, P. A., Boitano, P. D., de Couto, G., & Marbán, E. (2018) · Experimental Neurology · doi:10.1016/j.expneurol.2018.06.007 · Cited by 37
“Intravenous CDC-EVs have the ability to cross the BBB as shown in topographical distribution studies; we noted the presence of CDC-EVs in the ischemic zone, but not evident elsewhere.”
InfluentialWang, H., Atik, A., Stewart, T., Ginghină, C., Aro, P., Kerr, K. F., Seibyl, J. P., Jennings, D. L., Jensen, P. H., MAREK, K. L., et al. (2018) · Neurobiology of Disease · doi:10.1016/j.nbd.2018.04.015 · Cited by 41
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“Modifying exosomes with ligands that target these receptors offers a promising approach to further enhance delivery efficiency to the CNS [279].”
Exosomes-Based Nanomedicine for Neurodegenerative Diseases: Current Insights and Future Challenges
Cano, A. C., Muñoz-Morales, Á., Sánchez‐López, E., Ettcheto, M., Souto, E. B., Camins, A., Boada, M., & Ruiz, A. (2023) · Pharmaceutics · doi:10.3390/pharmaceutics15010298 · Cited by 48
“Because of these, crossing the BBB has gained much attention within the scientific and health communities.”
BackgroundInfluentialMicrobiota-Derived Extracellular Vesicle as Emerging Actors in Host Interactions
Margutti, P., D’Ambrosio, A., & Zamboni, S. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25168722 · Cited by 37
“It has also been hypothesized that [84] the most likely mechanisms of BEV distribution to the CNS are by crossing the BBB [246] and vagal nerve transport [247].”
BackgroundExosomes: current knowledge and future perspectives
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“10 There are two potential stops along the transcytosis pathway.”
BackgroundPhysiological and pathological consequences of exosomes at the blood–brain-barrier interface
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“Several mechanisms such as direct fusion, clathrin- and caveolin-mediated endocytosis, ligand-receptor interaction, macropinocytosis, and phagocytosis are involved in the entry of Exo into the brain parenchyma [58, 59].”
BackgroundMethodExosome-based approaches in the management of Alzheimer’s disease
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Exosome-based strategy for degenerative disease in orthopedics: Recent progress and perspectives
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“Given the endogenous sources of exosomes, it is also believed that the minimal tumorigenic risk will increase while using exosomes as the vehicle for delivering Small molecule drugs [25,26].”
BackgroundRole of Exosomes in Cancer-Related Cognitive Impairment
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“The results suggested that peripheral insults provoking systemic inflammation could induce exosomes from the peripheral circulation to cross the blood–brain barrier [50,51].”
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“Natural exosomes can additionally have nutritive effects on vascular regeneration [96,219].”
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Deciphering psychobiotics’ mechanism of action: bacterial extracellular vesicles in the spotlight
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“, 2018), the most likely mechanism of EVs distribution to the CNS is by (1) crossing the blood–brain barrier (BBB; Matsumoto et al., 2017).”
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“Further, given the important role of EVs in cell–cell communication [43,44], packaging of GFAP protein in EVs and their circulation via plasma serve multiple purposes [28].”
BackgroundCurrent Status of Mesenchymal Stem/Stromal Cells for Treatment of Neurological Diseases
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Quest for Quality in Translational Stroke Research—A New Dawn for Neuroprotection?
Haupt, M., Gerner, S., Bähr, M., & Doeppner, T. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23105381 · Cited by 28
“The fact that EVs are able to cross the intact blood–brain barrier after systemic delivery makes them attractive candidates for future stroke therapy [31].”
BackgroundDelivery of Functional Small RNAs via Extracellular Vesicles In Vitro and In Vivo
Zhang, D., Lee, H., & Jin, Y. (2020) · Methods in molecular biology · doi:10.1007/978-1-0716-0290-4_6 · Cited by 28
Zhang, M., Gong, W., Zhang, D., Ji, M. H., Chen, B., Chen, B., Li, X., Zhou, Y., Dong, C., Wen, G., et al. (2022) · Cell Death and Disease · doi:10.1038/s41419-022-04858-x · Cited by 35
“This transport, however, can be mediated by exosomes, which were reported to carry nucleic acid and proteins across BBB [13].”
Influential
Metadata
- Authors
- Matsumoto, J., Stewart, T., Banks, W. A., & Zhang, J.
- Affiliations
- University of Washington (US)
- VA Puget Sound Health Care System (US)
- Corresponding author
- Zhang, Jing
- Venue
- Current Pharmaceutical Design
- Publisher
- Bentham Science Publishers Ltd.
- Published
- 2018-02-15
- Volume
- 23
- Issue
- 40
- Pages
- 6206-6214
- ISSN
- 1381-6128 (ISSN-L)
- OpenAlex
- W2754129305
- Cited by
- 267
- References
- 0
- Citations by year
- 2026: 18 · 2025: 40 · 2024: 29 · 2023: 22 · 2022: 41 · 2021: 39 · 2020: 39 · 2019: 25 · 2018: 13
- FWCI
- 10.32
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Current Pharmaceutical Design (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (U01NS082137, U01NS091272)
- National Institute of Environmental Health Sciences (R01ES019277, P30ES007033)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Keywords
- extracellular vesicles, blood-brain barrier, exosomes, microvesicles, intercellular communication, neurodegenerative diseases, blood-brain barrier permeability, central nervous system
- MeSH terms
- Extracellular Vesicles, Animals, Biological Transport, Blood-Brain Barrier, Humans
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