The field of extracellular vesicle (EV) research has developed rapidly over the last decade from the study of fundamental biology to a subject of significant clinical relevance. The potential of harnessing EVs in the diagnosis and treatment of diseases — including cancer and neurological and cardiovascular disorders — is now being recognized. Accordingly, the applications of EVs as therapeutic targets, biomarkers, novel drug delivery agents and standalone therapeutics are being actively explored. This Review provides a brief overview of the characteristics and physiological functions of the various classes of EV, focusing on their association with disease and emerging strategies for their therapeutic exploitation.
This is a preview of subscription content, access via your institution
Open Access articles citing this article.
Immune checkpoint inhibition mediated with liposomal nanomedicine for cancer therapy
Military Medical Research Open Access 28 April 2023
The stromal-tumor amplifying STC1-Notch1 feedforward signal promotes the stemness of hepatocellular carcinoma
Journal of Translational Medicine Open Access 31 March 2023
MSCs-derived apoptotic extracellular vesicles promote muscle regeneration by inducing Pannexin 1 channel-dependent creatine release by myoblasts
International Journal of Oral Science Open Access 16 January 2023
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$189.00 per year
only $15.75 per issue
Rent or buy this article
Get just this article for as long as you need it
Prices may be subject to local taxes which are calculated during checkout
Valadi, H. et al. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat. Cell Biol. 9, 654–659 (2007). A hallmark study demonstrating the delivery of functional mRNA by EVs to recipient cells.
Skog, J. et al. Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nat. Cell Biol. 10, 1470–1476 (2008). One of the first studies to demonstrate the association of EV RNA cargo with disease.
Raposo, G. et al. B lymphocytes secrete antigen-presenting vesicles. J. Exp. Med. 183, 1161–1172 (1996).
Meckes, D. G. Jr et al. Human tumor virus utilizes exosomes for intercellular communication. Proc. Natl Acad. Sci. USA 107, 20370–20375 (2010).
Krejciova, Z. et al. Human stem cell-derived astrocytes replicate human prions in a PRNP genotype-dependent manner. J. Exp. Med. 214, 3481–3495 (2017).
Laulagnier, K. et al. Amyloid precursor protein products concentrate in a subset of exosomes specifically endocytosed by neurons. Cell. Mol. Life Sci. 75, 757–773 (2018).
Ngolab, J. et al. Brain-derived exosomes from dementia with Lewy bodies propagate α-synuclein pathology. Acta Neuropathol. Commun. 5, 46 (2017).
Jansen, F. et al. Endothelial microparticles reduce ICAM-1 expression in a microRNA-222-dependent mechanism. J. Cell. Mol. Med. 19, 2202–2214 (2015).
van Balkom, B. W. et al. Endothelial cells require miR-214 to secrete exosomes that suppress senescence and induce angiogenesis in human and mouse endothelial cells. Blood 121, 3997–4006 (2013).
Wang, X. et al. Cardiomyocytes mediate anti-angiogenesis in type 2 diabetic rats through the exosomal transfer of miR-320 into endothelial cells. J. Mol. Cell. Cardiol. 74, 139–150 (2014).
Qin, Y., Wang, L., Gao, Z., Chen, G. & Zhang, C. Bone marrow stromal/stem cell-derived extracellular vesicles regulate osteoblast activity and differentiation in vitro and promote bone regeneration in vivo. Sci. Rep. 6, 21961 (2016).
Zhu, F. et al. Adipose-derived mesenchymal stem cells employed exosomes to attenuate AKI-CKD transition through tubular epithelial cell dependent Sox9 activation. Oncotarget 8, 70707–70726 (2017).
Mao, J. et al. UBR2 enriched in p53 deficient mouse bone marrow mesenchymal stem cell-exosome promoted gastric cancer progression via Wnt/β-catenin pathway. Stem Cells 35, 2267–2279 (2017).
Wang, B., Wang, Y., Yan, Z., Sun, Y. & Su, C. Colorectal cancer cell-derived exosomes promote proliferation and decrease apoptosis by activating the ERK pathway. Int. J. Clin. Exp. Pathol. 12, 2485–2495 (2019).
Tauro, B. J. et al. Oncogenic H-Ras reprograms Madin-Darby canine kidney (MDCK) cell-derived exosomal proteins following epithelial-mesenchymal transition. Mol. Cell. Proteom. 12, 2148–2159 (2013).
Yang, T. T., Liu, C. G., Gao, S. C., Zhang, Y. & Wang, P. C. The serum exosome derived microRNA-135a, -193b, and -384 were potential Alzheimer’s disease biomarkers. Biomed. Environ. Sci. 31, 87–96 (2018).
Kapogiannis, D. et al. Dysfunctionally phosphorylated type 1 insulin receptor substrate in neural-derived blood exosomes of preclinical Alzheimer’s disease. FASEB J. 29, 589–596 (2015).
Foers, A. D. et al. Enrichment of extracellular vesicles from human synovial fluid using size exclusion chromatography. J. Extracell. Vesicles 7, 1490145 (2018).
Cheng, L., Sun, X., Scicluna, B. J., Coleman, B. M. & Hill, A. F. Characterization and deep sequencing analysis of exosomal and non-exosomal miRNA in human urine. Kidney Int. 86, 433–444 (2014).
Yap, T. et al. Predicting the presence of oral squamous cell carcinoma using commonly dysregulated microRNA in oral swirls. Cancer Prev. Res. 11, 491–502 (2018).
Thery, C. et al. Minimal Information for Studies of Extracellular Vesicles 2018 (MISEV2018): a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines. J. Extracell. Vesicles 7, 1535750 (2018). Recommended guidelines aimed at assisting researchers in the EV field to correctly isolate and characterize EVs in their studies.
van Niel, G., D’Angelo, G. & Raposo, G. Shedding light on the cell biology of extracellular vesicles. Nat. Rev. Mol. Cell Biol. 19, 213–228 (2018). Review detailing the biogenesis of EVs and their physiological and pathological functions.
Pegtel, D. M. et al. Functional delivery of viral miRNAs via exosomes. Proc. Natl Acad. Sci. USA 107, 6328–6333 (2010).
Quek, C. & Hill, A. F. The role of extracellular vesicles in neurodegenerative diseases. Biochem. Biophys. Res. Commun. 483, 1178–1186 (2017).
Guo, B. B., Bellingham, S. A. & Hill, A. F. Stimulating the release of exosomes increases the intercellular transfer of prions. J. Biol. Chem. 291, 5128–5137 (2016).
Asai, H. et al. Depletion of microglia and inhibition of exosome synthesis halt tau propagation. Nat. Neurosci. 18, 1584–1593 (2015).
Dinkins, M. B., Dasgupta, S., Wang, G., Zhu, G. & Bieberich, E. Exosome reduction in vivo is associated with lower amyloid plaque load in the 5XFAD mouse model of Alzheimer’s disease. Neurobiol. Aging 35, 1792–1800 (2014).
Nanbo, A., Kawanishi, E., Yoshida, R. & Yoshiyama, H. Exosomes derived from Epstein–Barr virus-infected cells are internalized via caveola-dependent endocytosis and promote phenotypic modulation in target cells. J. Virol. 87, 10334–10347 (2013).
Kawamoto, T. et al. Tumor-derived microvesicles induce proangiogenic phenotype in endothelial cells via endocytosis. PLoS ONE 7, e34045 (2012).
Lotvall, J. et al. Minimal experimental requirements for definition of extracellular vesicles and their functions: a position statement from the International Society for Extracellular Vesicles. J. Extracell. Vesicles 3, 26913 (2014).
Wollert, T. & Hurley, J. H. Molecular mechanism of multivesicular body biogenesis by ESCRT complexes. Nature 464, 864–869 (2010).
Verderio, C., Gabrielli, M. & Giussani, P. Role of sphingolipids in the biogenesis and biological activity of extracellular vesicles. J. Lipid Res. 59, 1325–1340 (2018).
Harding, C., Heuser, J. & Stahl, P. Endocytosis and intracellular processing of transferrin and colloidal gold-transferrin in rat reticulocytes: demonstration of a pathway for receptor shedding. Eur. J. Cell Biol. 35, 256–263 (1984).
Johnstone, R. M., Adam, M., Hammond, J. R., Orr, L. & Turbide, C. Vesicle formation during reticulocyte maturation. Association of plasma membrane activities with released vesicles (exosomes). J. Biol. Chem. 262, 9412–9420 (1987).
Andreu, Z. & Yáñez-Mó, M. Tetraspanins in extracellular vesicle formation and function. Front. Immunol. 5, 442 (2014).
Buschow, S. I. et al. MHC II in dendritic cells is targeted to lysosomes or T cell-induced exosomes via distinct multivesicular body pathways. Traffic 10, 1528–1542 (2009).
van Niel, G. et al. The tetraspanin CD63 regulates ESCRT-independent and -dependent endosomal sorting during melanogenesis. Dev. Cell 21, 708–721 (2011).
Coleman, B. M., Hanssen, E., Lawson, V. A. & Hill, A. F. Prion-infected cells regulate the release of exosomes with distinct ultrastructural features. FASEB J. 26, 4160–4173 (2012).
Jeppesen, D. K. et al. Reassessment of exosome composition. Cell 177, 428–445.e418 (2019).
Raiborg, C. & Stenmark, H. The ESCRT machinery in endosomal sorting of ubiquitylated membrane proteins. Nature 458, 445–452 (2009).
Zhang, H. et al. Identification of distinct nanoparticles and subsets of extracellular vesicles by asymmetric flow field-flow fractionation. Nat. Cell Biol. 20, 332–343 (2018).
Koifman, N., Biran, I., Aharon, A., Brenner, B. & Talmon, Y. A direct-imaging cryo-EM study of shedding extracellular vesicles from leukemic monocytes. J. Struct. Biol. 198, 177–185 (2017).
Mathieu, M., Martin-Jaular, L., Lavieu, G. & Théry, C. Specificities of secretion and uptake of exosomes and other extracellular vesicles for cell-to-cell communication. Nat. Cell Biol. 21, 9–17 (2019).
Piccin, A., Murphy, W. G. & Smith, O. P. Circulating microparticles: pathophysiology and clinical implications. Blood Rev. 21, 157–171 (2007).
Huttner, W. B. & Zimmerberg, J. Implications of lipid microdomains for membrane curvature, budding and fission. Curr. Opin. Cell Biol. 13, 478–484 (2001).
Crescitelli, R. et al. Distinct RNA profiles in subpopulations of extracellular vesicles: apoptotic bodies, microvesicles and exosomes. J. Extracell. Vesicles 2, 20677 (2013).
Lunavat, T. R. et al. Small RNA deep sequencing discriminates subsets of extracellular vesicles released by melanoma cells — evidence of unique microRNA cargos. RNA Biol. 12, 810–823 (2015).
Moss, D. K., Betin, V. M., Malesinski, S. D. & Lane, J. D. A novel role for microtubules in apoptotic chromatin dynamics and cellular fragmentation. J. Cell Sci. 119, 2362–2374 (2006).
Poon, I. K. et al. Unexpected link between an antibiotic, pannexin channels and apoptosis. Nature 507, 329–334 (2014).
Atkin-Smith, G. K. et al. A novel mechanism of generating extracellular vesicles during apoptosis via a beads-on-a-string membrane structure. Nat. Commun. 6, 7439 (2015). First study to show evidence that apoptotic bodies may be involved in intercellular communication.
Hayakawa, K. et al. Transfer of mitochondria from astrocytes to neurons after stroke. Nature 535, 551–555 (2016).
Bergsmedh, A. et al. Horizontal transfer of oncogenes by uptake of apoptotic bodies. Proc. Natl Acad. Sci. USA 98, 6407–6411 (2001).
Bergsmedh, A. et al. DNase II and the Chk2 DNA damage pathway form a genetic barrier blocking replication of horizontally transferred DNA. Mol. Cancer Res. 4, 187–195 (2006).
Lane, J. D., Allan, V. J. & Woodman, P. G. Active relocation of chromatin and endoplasmic reticulum into blebs in late apoptotic cells. J. Cell Sci. 118, 4059–4071 (2005).
Torr, E. E. et al. Apoptotic cell-derived ICAM-3 promotes both macrophage chemoattraction to and tethering of apoptotic cells. Cell Death Differ. 19, 671–679 (2012).
Truman, L. A. et al. CX3CL1/fractalkine is released from apoptotic lymphocytes to stimulate macrophage chemotaxis. Blood 112, 5026–5036 (2008).
Baxter, A. A. et al. Analysis of extracellular vesicles generated from monocytes under conditions of lytic cell death. Sci. Rep. 9, 7538 (2019).
Hakulinen, J., Sankkila, L., Sugiyama, N., Lehti, K. & Keski-Oja, J. Secretion of active membrane type 1 matrix metalloproteinase (MMP-14) into extracellular space in microvesicular exosomes. J. Cell. Biochem. 105, 1211–1218 (2008).
Laghezza Masci, V., Taddei, A. R., Gambellini, G., Giorgi, F. & Fausto, A. M. Microvesicles shed from fibroblasts act as metalloproteinase carriers in a 3-D collagen matrix. J. Circ. Biomark. 5, 1849454416663660 (2016).
Segura, E. et al. ICAM-1 on exosomes from mature dendritic cells is critical for efficient naive T-cell priming. Blood 106, 216–223 (2005).
Yáñez-Mó, M. et al. Biological properties of extracellular vesicles and their physiological functions. J. Extracell. Vesicles 4, 27066 (2015).
Iraci, N., Leonardi, T., Gessler, F., Vega, B. & Pluchino, S. Focus on extracellular vesicles: physiological role and signalling properties of extracellular membrane vesicles. Int. J. Mol. Sci. 17, 171 (2016).
Yuana, Y., Sturk, A. & Nieuwland, R. Extracellular vesicles in physiological and pathological conditions. Blood Rev. 27, 31–39 (2013).
Rackov, G. et al. Vesicle-mediated control of cell function: the role of extracellular matrix and microenvironment. Front. Physiol. 9, 651 (2018).
Prada, I. et al. A new approach to follow a single extracellular vesicle-cell interaction using optical tweezers. Biotechniques 60, 35–41 (2016).
Feng, D. et al. Cellular internalization of exosomes occurs through phagocytosis. Traffic 11, 675–687 (2010).
Shiratsuchi, A., Kaido, M., Takizawa, T. & Nakanishi, Y. Phosphatidylserine-mediated phagocytosis of influenza A virus-infected cells by mouse peritoneal macrophages. J. Virol. 74, 9240–9244 (2000).
Tian, T. et al. Exosome uptake through clathrin-mediated endocytosis and macropinocytosis and mediating miR-21 delivery. J. Biol. Chem. 289, 22258–22267 (2014).
Svensson, K. J. et al. Exosome uptake depends on ERK1/2-heat shock protein 27 signaling and lipid Raft-mediated endocytosis negatively regulated by caveolin-1. J. Biol. Chem. 288, 17713–17724 (2013).
Yokoi, A. et al. Malignant extracellular vesicles carrying MMP1 mRNA facilitate peritoneal dissemination in ovarian cancer. Nat. Commun. 8, 14470 (2017).
Somiya, M. Where does the cargo go?: solutions to provide experimental support for the “extracellular vesicle cargo transfer hypothesis”. J. Cell Commun. Signal. 14, 135–146 (2020).
Matsumoto, A. et al. Blood concentrations of small extracellular vesicles are determined by a balance between abundant secretion and rapid clearance. J. Extracell. Vesicles 9, 1696517 (2020).
Atay, S., Gercel-Taylor, C. & Taylor, D. D. Human trophoblast-derived exosomal fibronectin induces pro-inflammatory IL-1β production by macrophages. Am. J. Reprod. Immunol. 66, 259–269 (2011).
Cole, G. J. & Glaser, L. A heparin-binding domain from N-CAM is involved in neural cell-substratum adhesion. J. Cell Biol. 102, 403–412 (1986).
Purushothaman, A. et al. Fibronectin on the surface of myeloma cell-derived exosomes mediates exosome-cell interactions. J. Biol. Chem. 291, 1652–1663 (2016).
Gebraad, A. et al. Monocyte-derived extracellular vesicles stimulate cytokine secretion and gene expression of matrix metalloproteinases by mesenchymal stem/stromal cells. FEBS J. 285, 2337–2359 (2018).
Mathiesen, A. et al. Endothelial extracellular vesicles: from keepers of health to messengers of disease. Int. J. Mol. Sci. 22, 4640 (2021).
Gharbi, T., Zhang, Z. & Yang, G.-Y. The function of astrocyte mediated extracellular vesicles in central nervous system diseases. Front. Cell Dev. Biol. 8, 568889 (2020).
Takahashi, A. et al. Exosomes maintain cellular homeostasis by excreting harmful DNA from cells. Nat. Commun. 8, 4109 (2017).
Lan, Y. Y., Londoño, D., Bouley, R., Rooney, M. S. & Hacohen, N. Dnase2a deficiency uncovers lysosomal clearance of damaged nuclear DNA via autophagy. Cell Rep. 9, 180–192 (2014).
Villarroya-Beltri, C. et al. ISGylation controls exosome secretion by promoting lysosomal degradation of MVB proteins. Nat. Commun. 7, 13588 (2016).
Sivaganesh, S. et al. Copresentation of intact and processed MHC alloantigen by recipient dendritic cells enables delivery of linked help to alloreactive CD8 T cells by indirect-pathway CD4 T cells. J. Immunol. 190, 5829–5838 (2013).
Muntasell, A., Berger, A. C. & Roche, P. A. T cell-induced secretion of MHC class II-peptide complexes on B cell exosomes. EMBO J. 26, 4263–4272 (2007).
Leone, D. A., Rees, A. J. & Kain, R. Dendritic cells and routing cargo into exosomes. Immunol. Cell Biol. 96, 683–693 (2018).
Wang, R. et al. Role of gingival mesenchymal stem cell exosomes in macrophage polarization under inflammatory conditions. Int. Immunopharmacol. 81, 106030 (2020).
Mardpour, S. et al. Interaction between mesenchymal stromal cell-derived extracellular vesicles and immune cells by distinct protein content. J. Cell. Physiol. 234, 8249–8258 (2019).
Keerthikumar, S. et al. ExoCarta: a web-based compendium of exosomal cargo. J. Mol. Biol. 428, 688–692 (2016).
Jaworski, E. et al. Human T-lymphotropic virus type 1-infected cells secrete exosomes that contain Tax protein. J. Biol. Chem. 289, 22284–22305 (2014).
Canitano, A., Venturi, G., Borghi, M., Ammendolia, M. G. & Fais, S. Exosomes released in vitro from Epstein–Barr virus (EBV)-infected cells contain EBV-encoded latent phase mRNAs. Cancer Lett. 337, 193–199 (2013).
Ramachandra, L. et al. Mycobacterium tuberculosis synergizes with ATP to induce release of microvesicles and exosomes containing major histocompatibility complex class II molecules capable of antigen presentation. Infect. Immun. 78, 5116–5125 (2010).
Singh, P. P., Li, L. & Schorey, J. S. Exosomal RNA from Mycobacterium tuberculosis-infected cells is functional in recipient macrophages. Traffic 16, 555–571 (2015).
Kalluri, R. & LeBleu, V. S. The biology, function, and biomedical applications of exosomes. Science 367, eaau6977 (2020).
Pegtel, D. M. & Gould, S. J. Exosomes. Annu. Rev. Biochem. 88, 487–514 (2019).
Cho, J. A., Park, H., Lim, E. H. & Lee, K. W. Exosomes from breast cancer cells can convert adipose tissue-derived mesenchymal stem cells into myofibroblast-like cells. Int. J. Oncol. 40, 130–138 (2012).
Demory Beckler, M. et al. Proteomic analysis of exosomes from mutant KRAS colon cancer cells identifies intercellular transfer of mutant KRAS. Mol. Cell. Proteom. 12, 343–355 (2013).
Peinado, H. et al. Pre-metastatic niches: organ-specific homes for metastases. Nat. Rev. Cancer 17, 302–317 (2017).
Hoshino, A. et al. Tumour exosome integrins determine organotropic metastasis. Nature 527, 329–335 (2015).
Willms, E., Cabañas, C., Mäger, I., Wood, M. J. A. & Vader, P. Extracellular vesicle heterogeneity: subpopulations, isolation techniques, and diverse functions in cancer progression. Front. Immunol. 9, 738 (2018).
Willms, E. et al. Cells release subpopulations of exosomes with distinct molecular and biological properties. Sci. Rep. 6, 22519 (2016).
Chen, Y. et al. Aberrant low expression of p85α in stromal fibroblasts promotes breast cancer cell metastasis through exosome-mediated paracrine Wnt10b. Oncogene 36, 4692–4705 (2017).
Raulf, N. et al. Annexin A1 regulates EGFR activity and alters EGFR-containing tumour-derived exosomes in head and neck cancers. Eur. J. Cancer 102, 52–68 (2018).
Monypenny, J. et al. ALIX regulates tumor-mediated immunosuppression by controlling EGFR activity and PD-L1 presentation. Cell Rep. 24, 630–641 (2018).
Uribe, P. & Gonzalez, S. Epidermal growth factor receptor (EGFR) and squamous cell carcinoma of the skin: molecular bases for EGFR-targeted therapy. Pathol. Res. Pract. 207, 337–342 (2011).
Al-Nedawi, K., Meehan, B., Kerbel, R. S., Allison, A. C. & Rak, J. Endothelial expression of autocrine VEGF upon the uptake of tumor-derived microvesicles containing oncogenic EGFR. Proc. Natl Acad. Sci. USA 106, 3794–3799 (2009).
Costa-Silva, B. et al. Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver. Nat. Cell Biol. 17, 816–826 (2015).
Hikita, T., Kuwahara, A., Watanabe, R., Miyata, M. & Oneyama, C. Src in endosomal membranes promotes exosome secretion and tumor progression. Sci. Rep. 9, 3265 (2019).
Han, Q. et al. Vps4A mediates the localization and exosome release of β-catenin to inhibit epithelial-mesenchymal transition in hepatocellular carcinoma. Cancer Lett. 457, 47–59 (2019).
Xu, R. et al. Extracellular vesicles in cancer — implications for future improvements in cancer care. Nat. Rev. Clin. Oncol. 15, 617–638 (2018).
Möller, A. & Lobb, R. J. The evolving translational potential of small extracellular vesicles in cancer. Nat. Rev. Cancer 20, 697–709 (2020).
Cha, D. J. et al. KRAS-dependent sorting of miRNA to exosomes. eLife 4, e07197 (2015).
Sanchez, C. A. et al. Exosomes from bulk and stem cells from human prostate cancer have a differential microRNA content that contributes cooperatively over local and pre-metastatic niche. Oncotarget 7, 3993–4008 (2016).
Donnarumma, E. et al. Cancer-associated fibroblasts release exosomal microRNAs that dictate an aggressive phenotype in breast cancer. Oncotarget 8, 19592–19608 (2017).
Zomer, A. et al. In vivo imaging reveals extracellular vesicle-mediated phenocopying of metastatic behavior. Cell 161, 1046–1057 (2015).
Batagov, A. O. & Kurochkin, I. V. Exosomes secreted by human cells transport largely mRNA fragments that are enriched in the 3’-untranslated regions. Biol. Direct 8, 12 (2013).
de Jong, O. G. et al. A CRISPR-Cas9-based reporter system for single-cell detection of extracellular vesicle-mediated functional transfer of RNA. Nat. Commun. 11, 1113 (2020).
Placone, A. L., Quinones-Hinojosa, A. & Searson, P. C. The role of astrocytes in the progression of brain cancer: complicating the picture of the tumor microenvironment. Tumour Biol. 37, 61–69 (2016).
Janzer, R. C. & Raff, M. C. Astrocytes induce blood–brain barrier properties in endothelial cells. Nature 325, 253–257 (1987).
Abbott, N. J., Ronnback, L. & Hansson, E. Astrocyte-endothelial interactions at the blood–brain barrier. Nat. Rev. Neurosci. 7, 41–53 (2006).
Zhang, L. et al. Microenvironment-induced PTEN loss by exosomal microRNA primes brain metastasis outgrowth. Nature 527, 100–104 (2015).
Tominaga, N. et al. Brain metastatic cancer cells release microRNA-181c-containing extracellular vesicles capable of destructing blood–brain barrier. Nat. Commun. 6, 6716 (2015).
Zhou, W. et al. Cancer-secreted miR-105 destroys vascular endothelial barriers to promote metastasis. Cancer Cell 25, 501–515 (2014).
Faure, J. et al. Exosomes are released by cultured cortical neurones. Mol. Cell. Neurosci. 31, 642–648 (2006).
Pinto, S., Cunha, C., Barbosa, M., Vaz, A. R. & Brites, D. Exosomes from NSC-34 cells transfected with hSOD1-G93A are enriched in miR-124 and drive alterations in microglia phenotype. Front. Neurosci. 11, 273 (2017).
Rajendran, L. et al. Alzheimer’s disease β-amyloid peptides are released in association with exosomes. Proc. Natl Acad. Sci. USA 103, 11172–11177 (2006).
Rajendran, L. et al. Increased Aβ production leads to intracellular accumulation of Aβ in flotillin-1-positive endosomes. Neurodegener. Dis. 4, 164–170 (2007).
Vella, L. J. et al. Packaging of prions into exosomes is associated with a novel pathway of PrP processing. J. Pathol. 211, 582–590 (2007).
Grey, M. et al. Acceleration of α-synuclein aggregation by exosomes. J. Biol. Chem. 290, 2969–2982 (2015).
Basso, M. et al. Mutant copper-zinc superoxide dismutase (SOD1) induces protein secretion pathway alterations and exosome release in astrocytes: implications for disease spreading and motor neuron pathology in amyotrophic lateral sclerosis. J. Biol. Chem. 288, 15699–15711 (2013).
Prusiner, S. B. Novel proteinaceous infectious particles cause scrapie. Science 216, 136–144 (1982).
Fevrier, B. et al. Cells release prions in association with exosomes. Proc. Natl Acad. Sci. USA 101, 9683–9688 (2004).
Braak, H. & Braak, E. Staging of Alzheimer’s disease-related neurofibrillary changes. Neurobiol. Aging 16, 271–284 (1995).
Braak, H. et al. Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol. Aging 24, 197–211 (2003).
Baker, S., Polanco, J. C. & Götz, J. Extracellular vesicles containing P301L mutant tau accelerate pathological tau phosphorylation and oligomer formation but do not seed mature neurofibrillary tangles in ALZ17 mice. J. Alzheimers Dis. 54, 1207–1217 (2016).
Polanco, J. C., Scicluna, B. J., Hill, A. F. & Gotz, J. Extracellular vesicles isolated from the brains of rTg4510 mice seed tau protein aggregation in a threshold-dependent manner. J. Biol. Chem. 291, 12445–12466 (2016).
Bellingham, S. A., Coleman, B. M. & Hill, A. F. Small RNA deep sequencing reveals a distinct miRNA signature released in exosomes from prion-infected neuronal cells. Nucleic Acids Res. 40, 10937–10949 (2012).
Fernandes, A. et al. Secretome from SH-SY5Y APPSwe cells trigger time-dependent CHME3 microglia activation phenotypes, ultimately leading to miR-21 exosome shuttling. Biochimie 155, 67–82 (2018).
Vella, L. J. et al. A rigorous method to enrich for exosomes from brain tissue. J. Extracell. Vesicles 6, 1348885 (2017). One of the first studies to profile the proteome and genomic contents of EVs isolated from brain tissue.
Cheng, L. et al. Small RNA fingerprinting of Alzheimer’s disease frontal cortex extracellular vesicles and their comparison with peripheral extracellular vesicles. J. Extracell. Vesicles 9, 1766822 (2020).
Bobryshev, Y. V., Killingsworth, M. C. & Orekhov, A. N. Increased shedding of microvesicles from intimal smooth muscle cells in athero-prone areas of the human aorta: implications for understanding of the predisease stage. Pathobiology 80, 24–31 (2013).
Mesri, M. & Altieri, D. C. Endothelial cell activation by leukocyte microparticles. J. Immunol. 161, 4382–4387 (1998).
Mesri, M. & Altieri, D. C. Leukocyte microparticles stimulate endothelial cell cytokine release and tissue factor induction in a JNK1 signaling pathway. J. Biol. Chem. 274, 23111–23118 (1999).
Boulanger, C. M. et al. Circulating microparticles from patients with myocardial infarction cause endothelial dysfunction. Circulation 104, 2649–2652 (2001).
Yu, X. et al. Mechanism of TNF-α autocrine effects in hypoxic cardiomyocytes: initiated by hypoxia inducible factor 1α, presented by exosomes. J. Mol. Cell. Cardiol. 53, 848–857 (2012).
Gupta, S. & Knowlton, A. A. HSP60 trafficking in adult cardiac myocytes: role of the exosomal pathway. Am. J. Physiol. Heart Circ. Physiol. 292, H3052–H3056 (2007).
Yu, B. et al. Cardiomyocyte protection by GATA-4 gene engineered mesenchymal stem cells is partially mediated by translocation of miR-221 in microvesicles. PLoS ONE 8, e73304 (2013).
Feng, Y., Huang, W., Wani, M., Yu, X. & Ashraf, M. Ischemic preconditioning potentiates the protective effect of stem cells through secretion of exosomes by targeting Mecp2 via miR-22. PLoS ONE 9, e88685 (2014).
Luu, N. T. et al. Crosstalk between mesenchymal stem cells and endothelial cells leads to downregulation of cytokine-induced leukocyte recruitment. Stem Cell 31, 2690–2702 (2013).
Pulliam, L., Sun, B., Mustapic, M., Chawla, S. & Kapogiannis, D. Plasma neuronal exosomes serve as biomarkers of cognitive impairment in HIV infection and Alzheimer’s disease. J. Neurovirol 25, 702–709 (2019).
Logozzi, M. et al. High levels of exosomes expressing CD63 and caveolin-1 in plasma of melanoma patients. PLoS ONE 4, e5219 (2009).
Fiandaca, M. S. et al. Identification of preclinical Alzheimer’s disease by a profile of pathogenic proteins in neurally derived blood exosomes: a case-control study. Alzheimers Dement. 11, 600–607.e601 (2015).
Kapogiannis, D. et al. Association of extracellular vesicle biomarkers with Alzheimer disease in the Baltimore Longitudinal Study Of Aging. JAMA Neurol. 76, 1340–1351 (2019).
Rim, K. T. & Kim, S. J. Quantitative analysis of exosomes from murine lung cancer cells by flow cytometry. J. Cancer Prev. 21, 194–200 (2016).
Dinkins, M. B. et al. Neutral sphingomyelinase-2 deficiency ameliorates Alzheimer’s disease pathology and improves cognition in the 5XFAD mouse. J. Neurosci. 36, 8653–8667 (2016).
Hofmann, K., Tomiuk, S., Wolff, G. & Stoffel, W. Cloning and characterization of the mammalian brain-specific, Mg2+-dependent neutral sphingomyelinase. Proc. Natl Acad. Sci. USA 97, 5895–5900 (2000).
Tan, L. H. et al. Enriched expression of neutral sphingomyelinase 2 in the striatum is essential for regulation of lipid raft content and motor coordination. Mol. Neurobiol. 55, 5741–5756 (2018).
Kosgodage, U. S. et al. Cannabidiol (CBD) is a novel inhibitor for exosome and microvesicle (EMV) release in cancer. Front. Pharmacol. 9, 889 (2018).
Kosgodage, U. S., Trindade, R. P., Thompson, P. R., Inal, J. M. & Lange, S. Chloramidine/bisindolylmaleimide-I-mediated inhibition of exosome and microvesicle release and enhanced efficacy of cancer chemotherapy. Int. J. Mol. Sci. 18, 1007 (2017).
Kholia, S. et al. A novel role for peptidylarginine deiminases in microvesicle release reveals therapeutic potential of PAD inhibition in sensitizing prostate cancer cells to chemotherapy. J. Extracell. Vesicles 4, 26192 (2015).
Colombo, M. et al. Analysis of ESCRT functions in exosome biogenesis, composition and secretion highlights the heterogeneity of extracellular vesicles. J. Cell Sci. 126, 5553 (2013).
Vilette, D. et al. Efficient inhibition of infectious prions multiplication and release by targeting the exosomal pathway. Cell. Mol. Life Sci. 72, 4409–4427 (2015).
Li, W. et al. Rab27A regulates exosome secretion from lung adenocarcinoma cells A549: involvement of EPI64. APMIS 122, 1080–1087 (2014).
Sun, S., Zhou, X., Zhang, W., Gallick, G. E. & Kuang, J. Unravelling the pivotal role of Alix in MVB sorting and silencing of the activated EGFR. Biochem. J. 466, 475–487 (2015).
Datta, A. et al. High-throughput screening identified selective inhibitors of exosome biogenesis and secretion: a drug repurposing strategy for advanced cancer. Sci. Rep. 8, 8161 (2018).
Iguchi, Y. et al. Exosome secretion is a key pathway for clearance of pathological TDP-43. Brain 139, 3187–3201 (2016).
Gauthier, S. A. et al. Enhanced exosome secretion in Down syndrome brain — a protective mechanism to alleviate neuronal endosomal abnormalities. Acta Neuropathol. Commun. 5, 65 (2017).
Johnson, J. L. et al. Rab27a and Rab27b regulate neutrophil azurophilic granule exocytosis and NADPH oxidase activity by independent mechanisms. Traffic 11, 533–547 (2010).
Wang, J. S., Wang, F. B., Zhang, Q. G., Shen, Z. Z. & Shao, Z. M. Enhanced expression of Rab27A gene by breast cancer cells promoting invasiveness and the metastasis potential by secretion of insulin-like growth factor-II. Mol. Cancer Res. 6, 372–382 (2008).
Kalra, H. et al. Vesiclepedia: a compendium for extracellular vesicles with continuous community annotation. PLoS Biol. 10, e1001450 (2012).
Enderle, D. et al. Characterization of RNA from exosomes and other extracellular vesicles isolated by a novel spin column-based method. PLoS ONE 10, e0136133 (2015).
Castellanos-Rizaldos, E. et al. Exosome-based detection of EGFR T790M in plasma from non-small cell lung cancer patients. Clin. Cancer Res. 24, 2944–2950 (2018).
Castellanos-Rizaldos, E. et al. Exosome-based detection of activating and resistance EGFR mutations from plasma of non-small cell lung cancer patients. Oncotarget 10, 2911–2920 (2019).
Nawroz, H., Koch, W., Anker, P., Stroun, M. & Sidransky, D. Microsatellite alterations in serum DNA of head and neck cancer patients. Nat. Med. 2, 1035–1037 (1996).
McKiernan, J. et al. A novel urine exosome gene expression assay to predict high-grade prostate cancer at initial biopsy. JAMA Oncol. 2, 882–889 (2016).
McKiernan, J. et al. A prospective adaptive utility trial to validate performance of a novel urine exosome gene expression assay to predict high-grade prostate cancer in patients with prostate-specific antigen 2–10 ng/ml at initial biopsy. Eur. Urol. 74, 731–738 (2018).
Allenson, K. et al. High prevalence of mutant KRAS in circulating exosome-derived DNA from early-stage pancreatic cancer patients. Ann. Oncol. 28, 741–747 (2017).
Mohrmann, L. et al. Liquid biopsies using plasma exosomal nucleic acids and plasma cell-free DNA compared with clinical outcomes of patients with advanced cancers. Clin. Cancer Res. 24, 181–188 (2018).
Garcia-Silva, S. et al. Use of extracellular vesicles from lymphatic drainage as surrogate markers of melanoma progression and BRAF (V600E) mutation. J. Exp. Med. 216, 1061–1070 (2019).
Domenyuk, V. et al. Plasma exosome profiling of cancer patients by a next generation systems biology approach. Sci. Rep. 7, 42741 (2017).
Goetzl, E. J., Abner, E. L., Jicha, G. A., Kapogiannis, D. & Schwartz, J. B. Declining levels of functionally specialized synaptic proteins in plasma neuronal exosomes with progression of Alzheimer’s disease. FASEB J. 32, 888–893 (2018).
Wang, S. et al. Elevated LRRK2 autophosphorylation in brain-derived and peripheral exosomes in LRRK2 mutation carriers. Acta Neuropathol. Commun. 5, 86 (2017).
Stern, R. A. et al. Preliminary study of plasma exosomal tau as a potential biomarker for chronic traumatic encephalopathy. J. Alzheimers Dis. 51, 1099–1109 (2016).
Lugli, G. et al. Plasma exosomal miRNAs in persons with and without Alzheimer Disease: altered expression and prospects for biomarkers. PLoS ONE 10, e0139233 (2015).
Cheng, L. et al. Prognostic serum miRNA biomarkers associated with Alzheimer’s disease shows concordance with neuropsychological and neuroimaging assessment. Mol. Psychiatry 20, 1188–1196 (2015).
Cao, X. Y. et al. MicroRNA biomarkers of Parkinson’s disease in serum exosome-like microvesicles. Neurosci. Lett. 644, 94–99 (2017).
Lener, T. et al. Applying extracellular vesicles based therapeutics in clinical trials — an ISEV position paper. J. Extracell. Vesicles 4, 30087 (2015).
Ibrahim, A. G., Cheng, K. & Marban, E. Exosomes as critical agents of cardiac regeneration triggered by cell therapy. Stem Cell Rep. 2, 606–619 (2014).
Eleuteri, S. & Fierabracci, A. Insights into the secretome of mesenchymal stem cells and its potential applications. Int. J. Mol. Sci. 20, 4597 (2019).
Qian, X. et al. Immunosuppressive effects of mesenchymal stem cells-derived exosomes. Stem Cell Rev. Rep. 17, 411–427 (2020).
Lai, R. C. et al. Exosome secreted by MSC reduces myocardial ischemia/reperfusion injury. Stem Cell Res. 4, 214–222 (2010).
Doeppner, T. R. et al. Extracellular vesicles improve post-stroke neuroregeneration and prevent postischemic immunosuppression. Stem Cell Transl. Med. 4, 1131–1143 (2015).
Xin, H. et al. Systemic administration of exosomes released from mesenchymal stromal cells promote functional recovery and neurovascular plasticity after stroke in rats. J. Cereb. Blood Flow Metab. 33, 1711–1715 (2013).
Lee, J. K. et al. Exosomes derived from mesenchymal stem cells suppress angiogenesis by down-regulating VEGF expression in breast cancer cells. PLoS ONE 8, e84256 (2013).
Xin, H. et al. MiR-133b promotes neural plasticity and functional recovery after treatment of stroke with multipotent mesenchymal stromal cells in rats via transfer of exosome-enriched extracellular particles. Stem Cell 31, 2737–2746 (2013).
Kordelas, L. et al. MSC-derived exosomes: a novel tool to treat therapy-refractory graft-versus-host disease. Leukemia 28, 970–973 (2014).
Giebel, B., Kordelas, L. & Borger, V. Clinical potential of mesenchymal stem/stromal cell-derived extracellular vesicles. Stem Cell Investig. 4, 84 (2017).
Nassar, W. et al. Umbilical cord mesenchymal stem cells derived extracellular vesicles can safely ameliorate the progression of chronic kidney diseases. Biomater. Res. 20, 21 (2016).
Beauvillain, C., Ruiz, S., Guiton, R., Bout, D. & Dimier-Poisson, I. A vaccine based on exosomes secreted by a dendritic cell line confers protection against T. gondii infection in syngeneic and allogeneic mice. Microbes Infect. 9, 1614–1622 (2007).
Cheng, Y. & Schorey, J. S. Exosomes carrying mycobacterial antigens can protect mice against Mycobacterium tuberculosis infection. Eur. J. Immunol. 43, 3279–3290 (2013).
Sierra, G. V. et al. Vaccine against group B Neisseria meningitidis: protection trial and mass vaccination results in Cuba. NIPH Ann. 14, 195–210 (1991).
Rosenqvist, E. et al. Human antibody responses to meningococcal outer membrane antigens after three doses of the Norwegian group B meningococcal vaccine. Infect. Immun. 63, 4642–4652 (1995).
Arnold, R., Galloway, Y., McNicholas, A. & O’Hallahan, J. Effectiveness of a vaccination programme for an epidemic of meningococcal B in New Zealand. Vaccine 29, 7100–7106 (2011).
Bai, X., Findlow, J. & Borrow, R. Recombinant protein meningococcal serogroup B vaccine combined with outer membrane vesicles. Expert Opin. Biol. Ther. 11, 969–985 (2011).
Choi, S. J. et al. Active immunization with extracellular vesicles derived from Staphylococcus aureus effectively protects against staphylococcal lung infections, mainly via Th1 cell-mediated immunity. PLoS ONE 10, e0136021 (2015).
Martins, S. T., Kuczera, D., Lotvall, J., Bordignon, J. & Alves, L. R. Characterization of dendritic cell-derived extracellular vesicles during dengue virus infection. Front. Microbiol. 9, 1792 (2018).
Sprooten, J. et al. Trial watch: dendritic cell vaccination for cancer immunotherapy. Oncoimmunology 8, 1638212 (2019).
Escudier, B. et al. Vaccination of metastatic melanoma patients with autologous dendritic cell (DC) derived-exosomes: results of the first phase I clinical trial. J. Transl. Med. 3, 10 (2005).
Morse, M. A. et al. A phase I study of dexosome immunotherapy in patients with advanced non-small cell lung cancer. J. Transl. Med. 3, 9 (2005).
Jang, S. C. et al. ExoSTING, an extracellular vesicle loaded with STING agonists, promotes tumor immune surveillance. Commun. Biol. 4, 497 (2021).
Torreggiani, E. et al. Exosomes: novel effectors of human platelet lysate activity. Eur. Cell Mater. 28, 137–151 (2014).
Guo, S. C. et al. Exosomes derived from platelet-rich plasma promote the re-epithelization of chronic cutaneous wounds via activation of YAP in a diabetic rat model. Theranostics 7, 81–96 (2017).
Alvarez-Erviti, L. et al. Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nat. Biotechnol. 29, 341–345 (2011). Demonstration of delivery of functionalized EVs targeting the brain using modification of the surface of the injected EVs.
Banizs, A. B. et al. In vitro evaluation of endothelial exosomes as carriers for small interfering ribonucleic acid delivery. Int. J. Nanomed. 9, 4223–4230 (2014).
Pomatto, M. A. C. et al. Improved loading of plasma-derived extracellular vesicles to encapsulate antitumor miRNAs. Mol. Ther. Methods Clin. Dev. 13, 133–144 (2019).
Lamichhane, T. N., Raiker, R. S. & Jay, S. M. Exogenous DNA loading into extracellular vesicles via electroporation is size-dependent and enables limited gene delivery. Mol. Pharm. 12, 3650–3657 (2015).
Kooijmans, S. A. A. et al. Electroporation-induced siRNA precipitation obscures the efficiency of siRNA loading into extracellular vesicles. J. Control. Release 172, 229–238 (2013).
Johnsen, K. B. et al. Evaluation of electroporation-induced adverse effects on adipose-derived stem cell exosomes. Cytotechnology 68, 2125–2138 (2016).
Yin, W. et al. Immature exosomes derived from MicroRNA-146a overexpressing dendritic cells act as antigen-specific therapy for myasthenia gravis. Inflammation 40, 1460–1473 (2017).
Katakowski, M. et al. Exosomes from marrow stromal cells expressing miR-146b inhibit glioma growth. Cancer Lett. 335, 201–204 (2013).
Lee, H. K. et al. Mesenchymal stem cells deliver synthetic microRNA mimics to glioma cells and glioma stem cells and inhibit their cell migration and self-renewal. Oncotarget 4, 346–361 (2013).
Shao, N. et al. miR-454-3p is an exosomal biomarker and functions as a tumor suppressor in glioma. Mol. Cancer Ther. 18, 459–469 (2019).
Pi, F. et al. Nanoparticle orientation to control RNA loading and ligand display on extracellular vesicles for cancer regression. Nat. Nanotechnol. 13, 82–89 (2018).
Ruivo, C. F., Adem, B., Silva, M. & Melo, S. A. The biology of cancer exosomes: insights and new perspectives. Cancer Res. 77, 6480–6488 (2017).
Wang, J. H. et al. Anti-HER2 scFv-directed extracellular vesicle-mediated mRNA-based gene delivery inhibits growth of HER2-positive human breast tumor xenografts by prodrug activation. Mol. Cancer Ther. 17, 1133–1142 (2018).
Mendt, M. et al. Generation and testing of clinical-grade exosomes for pancreatic cancer. JCI Insight 3, e99263 (2018).
Gyorgy, B. et al. Rescue of hearing by gene delivery to inner-ear hair cells using exosome-associated AAV. Mol. Ther. 25, 379–391 (2017).
Putz, U. et al. Nedd4 family-interacting protein 1 (Ndfip1) is required for the exosomal secretion of Nedd4 family proteins. J. Biol. Chem. 283, 32621–32627 (2008).
Sterzenbach, U. et al. Engineered exosomes as vehicles for biologically active proteins. Mol. Ther. 25, 1269–1278 (2017).
Hartman, Z. C. et al. Increasing vaccine potency through exosome antigen targeting. Vaccine 29, 9361–9367 (2011).
Jang, S. C. et al. Bioinspired exosome-mimetic nanovesicles for targeted delivery of chemotherapeutics to malignant tumors. ACS Nano 7, 7698–7710 (2013).
Nasiri Kenari, A. et al. Proteomic and post-translational modification profiling of exosome-mimetic nanovesicles compared to exosomes. Proteomics 19, e1800161 (2019).
Zagar, T. M. et al. Two phase I dose-escalation/pharmacokinetics studies of low temperature liposomal doxorubicin (LTLD) and mild local hyperthermia in heavily pretreated patients with local regionally recurrent breast cancer. Int. J. Hyperth. 30, 285–294 (2014).
Gimona, M. et al. Critical considerations for the development of potency tests for therapeutic applications of mesenchymal stromal cell-derived small extracellular vesicles. Cytotherapy 23, 373–380 (2021).
Meyer, C. et al. Pseudotyping exosomes for enhanced protein delivery in mammalian cells. Int. J. Nanomed. 12, 3153–3170 (2017).
Webb, R. L. et al. Human neural stem cell extracellular vesicles improve recovery in a porcine model of ischemic stroke. Stroke 49, 1248–1256 (2018).
Sze, S. K. et al. Elucidating the secretion proteome of human embryonic stem cell-derived mesenchymal stem cells. Mol. Cell. Proteomics 6, 1680–1689 (2007).
Lian, Q. et al. Derivation of clinically compliant MSCs from CD105+ CD24− differentiated human ESCs. Stem Cells 25, 425–436 (2007).
Abels, E. R. & Breakefield, X. O. Introduction to extracellular vesicles: biogenesis, RNA cargo selection, content, release, and uptake. Cell. Mol. Neurobiol. 36, 301–312 (2016).
Van Deun, J. et al. EV-TRACK: transparent reporting and centralizing knowledge in extracellular vesicle research. Nat. Methods 14, 228–232 (2017).
Chevillet, J. R. et al. Quantitative and stoichiometric analysis of the microRNA content of exosomes. Proc. Natl Acad. Sci. USA 111, 14888–14893 (2014).
Willis, G. R., Kourembanas, S. & Mitsialis, S. A. Toward exosome-based therapeutics: isolation, heterogeneity, and fit-for-purpose potency. Front. Cardiovasc. Med. 4, 63 (2017).
Verweij, F. J. et al. Quantifying exosome secretion from single cells reveals a modulatory role for GPCR signaling. J. Cell Biol. 217, 1129–1142 (2018).
Turchinovich, A., Weiz, L., Langheinz, A. & Burwinkel, B. Characterization of extracellular circulating microRNA. Nucleic Acids Res. 39, 7223–7233 (2011).
Albanese, M et al. Micro RNAs are minor constituents of extracellular vesicles that are rarely delivered to target cells. PLoS Genet. 17, e1009951 (2021).
Mulligan, M. J. et al. Phase I/II study of COVID-19 RNA vaccine BNT162b1 in adults. Nature 586, 589–593 (2020).
Baden, L. R. et al. Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine. N. Engl. J. Med. 384, 403–416 (2021).
Nasiri Kenari, A., Cheng, L. & Hill, A. F. Methods for loading therapeutics into extracellular vesicles and generating extracellular vesicles mimetic-nanovesicles. Methods 177, 103–113 (2020).
Batista, B. S., Eng, W. S., Pilobello, K. T., Hendricks-Munoz, K. D. & Mahal, L. K. Identification of a conserved glycan signature for microvesicles. J. Proteome Res. 10, 4624–4633 (2011).
Williams, C. et al. Glycosylation of extracellular vesicles: current knowledge, tools and clinical perspectives. J. Extracell. Vesicles 7, 1442985 (2018).
Gerlach, J. Q. & Griffin, M. D. Getting to know the extracellular vesicle glycome. Mol. Biosyst. 12, 1071–1081 (2016).
Martins, A. M., Ramos, C. C., Freitas, D. & Reis, C. A. Glycosylation of cancer extracellular vesicles: capture strategies, functional roles and potential clinical applications. Cells 10, 109 (2021).
Lunavat, T. R. et al. RNAi delivery by exosome-mimetic nanovesicles — implications for targeting c-Myc in cancer. Biomaterials 102, 231–238 (2016).
Yang, Z. et al. Functional exosome-mimic for delivery of siRNA to cancer: in vitro and in vivo evaluation. J. Control. Release 243, 160–171 (2016).
Boing, A. N. et al. Single-step isolation of extracellular vesicles by size-exclusion chromatography. J. Extracell. Vesicles 3, 23430 (2014).
Liu, Y. S. et al. MiR-181b modulates EGFR-dependent VCAM-1 expression and monocyte adhesion in glioblastoma. Oncogene 36, 5006–5022 (2017).
Kanwar, S. S., Dunlay, C. J., Simeone, D. M. & Nagrath, S. Microfluidic device (ExoChip) for on-chip isolation, quantification and characterization of circulating exosomes. Lab Chip 14, 1891–1900 (2014).
Wu, M. et al. Isolation of exosomes from whole blood by integrating acoustics and microfluidics. Proc. Natl Acad. Sci. USA 114, 10584–10589 (2017).
Research in the Hill lab is supported by grants from the National Health and Medical Research Council of Australia (to A.F.H. GNT1041413; GNT1132604), and the Australian Research Council (to A.F.H. DP170102312; DP190101655).
The authors declare no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
- Extracellular vesicles
(EVs). Membranous particles secreted by mammalian and bacteria cells into the extracellular space.
- Endosomal pathways
The uptake or internalization of proteins through the endocytic pathway, which largely involves the early/sorting endosome, late endosomes and multivesicular bodies.
- Non-endosomal pathways
The uptake or internalization of proteins through the process of recruiting cargo into developing pits and subsequently forming vesicles.
- Apoptotic bodies
A type of extracellular vesicles formed by cells undergoing apoptosis.
Extracellular vesicles formed by outward blebbing of the plasma membrane of the cell.
A type of extracellular vesicles formed through an endocytic process and released through the multivesicular body.
- Neurodegenerative diseases
A collective term for neurological diseases normally associated with ageing.
- Endosomal sorting complex required for transport
(ESCRT). A family of proteins involved in the endocytic formation of small extracellular vesicles such as exosomes.
- Multivesicular body
A cellular structure in which endosomally derived extracellular vesicles are formed and from which they are released.
Rights and permissions
About this article
Cite this article
Cheng, L., Hill, A.F. Therapeutically harnessing extracellular vesicles. Nat Rev Drug Discov 21, 379–399 (2022). https://doi.org/10.1038/s41573-022-00410-w
This article is cited by
Immune checkpoint inhibition mediated with liposomal nanomedicine for cancer therapy
Military Medical Research (2023)
The stromal-tumor amplifying STC1-Notch1 feedforward signal promotes the stemness of hepatocellular carcinoma
Journal of Translational Medicine (2023)
NAMPT encapsulated by extracellular vesicles from young adipose-derived mesenchymal stem cells treated tendinopathy in a “One-Stone-Two-Birds” manner
Journal of Nanobiotechnology (2023)
MSCs-derived apoptotic extracellular vesicles promote muscle regeneration by inducing Pannexin 1 channel-dependent creatine release by myoblasts
International Journal of Oral Science (2023)
Mechanisms of axonal support by oligodendrocyte-derived extracellular vesicles
Nature Reviews Neuroscience (2023)