Exosomes are a heterogenous subpopulation of extracellular vesicles 30-150 nm in range and of endosome-derived origin. We explored the exosome formation through different systems, including the endosomal sorting complex required for transport (ESCRT) and ESCRT-independent system, looking at the mechanisms of release. Different isolation techniques and specificities of exosomes from different tissues and cells are also discussed. Despite more than 30 years of research that followed their definition and indicated their important role in cellular physiology, the exosome biology is still in its infancy with rapidly growing interest. The reasons for the rapid increase in interest with respect to exosome biology is because they provide means of intercellular communication and transmission of macromolecules between cells, with a potential role in the development of diseases. Moreover, they have been investigated as prognostic biomarkers, with a potential for further development as diagnostic tools for neurodegenerative diseases and cancer. The interest grows further with the fact that exosomes were reported as useful vectors for drugs.

Centre for Craniofacial and Regenerative Biology Faculty for Dentistry Oral and Craniofacial Sciences King's College University of London London SE1 9RT UK

Department of Anatomy Poznan University of Medical Sciences 60 781 Poznań Poland

Department of Biomaterials and Experimental Dentistry Poznan University of Medical Sciences 61 701 Poznan Poland

Department of Cancer Immunology Poznan University of Medical Sciences 61 866 Poznań Poland

Department of Diagnostics and Clinical Sciences Nicolaus Copernicus University in Torun 87 100 Toruń Poland

Department of Histology and Embryology Poznan University of Medical Sciences 60 781 Poznań Poland

Department of Obstetrics and Gynaecology University Hospital and Masaryk University 601 77 Brno Czech Republic

Department of Periodontology and Oral Implantology Dental Research Division University of Guarulhos Guarulhos 07030 010 Brazil

Department of Toxicology Poznan University of Medical Sciences 61 131 Poznań Poland

Department of Veterinary Surgery Nicolaus Copernicus University in Torun 87 100 Toruń Poland

Division of Reproduction Department of Obstetrics Gynecology and Gynecologic Oncology Poznan University of Medical Sciences 60 535 Poznan Poland

Institute of Veterinary Medicine Nicolaus Copernicus University in Toruń 87 100 Toruń Poland

Physiology Graduate Program North Carolina State University Raleigh NC 27695 USA

The School of Medicine Medical Sciences and Nutrition University of Aberdeen Aberdeen AB25 2ZD UK

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Gould S.J., Raposo G. As we wait: Coping with an imperfect nomenclature for extracellular vesicles. J. Extracell. Vesicles. 2013;2:3–5. doi: 10.3402/jev.v2i0.20389. PubMed DOI PMC

Lötvall J., Hill A.F., Hochberg F., Buzás E.I., Di Vizio D., Gardiner C., Gho Y.S., Kurochkin I.V., Mathivanan S., Quesenberry P., 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. 2014;3:1–6. doi: 10.3402/jev.v3.26913. PubMed DOI PMC

Shin S., Han D., Park M.C., Mun J.Y., Choi J., Chun H., Kim S., Hong J.W. Separation of extracellular nanovesicles and apoptotic bodies from cancer cell culture broth using tunable microfluidic systems. Sci. Rep. 2017;7 doi: 10.1038/s41598-017-08826-w. PubMed DOI PMC

Dignat-George F., Boulanger C.M. The many faces of endothelial microparticles. Arterioscler. Thromb. Vasc. Biol. 2011;31:27–33. doi: 10.1161/ATVBAHA.110.218123. PubMed DOI

Sturk A., Nieuwland R., van der Pol E., Boing A.N., Harrison P. Classification, functions, and clinical relevance of extracellular vesicles. Pharmacol. Rev. 2012;64:676–705. PubMed

Bobrie A., Colombo M., Krumeich S., Raposo G., Théry C. Diverse subpopulations of vesicles secreted by different intracellular mechanisms are present in exosome preparations obtained by differential ultracentrifugation. J. Extracell. Vesicles. 2012 doi: 10.3402/jev.v1i0.18397. PubMed DOI PMC

Baietti M.F., Zhang Z., Mortier E., Melchior A., Degeest G., Geeraerts A., Ivarsson Y., Depoortere F., Coomans C., Vermeiren E., et al. Syndecan-syntenin-ALIX regulates the biogenesis of exosomes. Nat. Cell Biol. 2012;14:677–685. doi: 10.1038/ncb2502. PubMed DOI

Bebelman M.P., Smit M.J., Pegtel D.M., Baglio S.R. Biogenesis and function of extracellular vesicles in cancer. Pharmacol. Ther.. 2018;188:1–11. doi: 10.1016/j.pharmthera.2018.02.013. PubMed DOI

Théry C., Zitvogel L., Amigorena S. Exosomes: Composition, biogenesis and function. Nat. Rev. Immunol. 2002;2:569–579. doi: 10.1038/nri855. PubMed DOI

Keller S., Ridinger J., Rupp A.K., Janssen J.W.G., Altevogt P. Body fluid derived exosomes as a novel template for clinical diagnostics. J. Transl. Med. 2011;9:1–9. doi: 10.1186/1479-5876-9-86. PubMed DOI PMC

Pan B.T., Johnstone R.M. Fate of the transferrin receptor during maturation of sheep reticulocytes in vitro: Selective externalization of the receptor. Cell. 1983;33:967–978. doi: 10.1016/0092-8674(83)90040-5. PubMed DOI

Harding C., Stahl P. Transferrin recycling in reticulocytes: pH and iron are important determinants of ligand binding and processing. Biochem. Biophys. Res. Commun. 1983;113:650–658. doi: 10.1016/0006-291X(83)91776-X. PubMed DOI

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. 1987;262:9412–9420. PubMed

Johnstone R.M. Maturation of reticulocytes: Formation of exosomes as a mechanism for shedding membrane proteins. The Jeanne Manery-Fisher Memorial Lecture 1991. Biochem. Cell Biol. 1992;70:179–190. doi: 10.1139/o92-028. PubMed DOI

Raposo G., Nijman H.W., Stoorvogel W., Liejendekker R., Harding C.V., Melief C.J.G.H. B Lymphocytes secrete antigen-Presentingvesicles. J. Exp. Med. 1996;183:1161–1172. doi: 10.1084/jem.183.3.1161. PubMed DOI PMC

Zitvogel L., Regnault A., Lozier A., Wolfers J., Flament C., Tenza D., Ricciardi-Castagnoli P., Raposo G., Amigorena S. Eradication of established murine tumors using a novel cell-free vaccine: Dendritic cell-derived exosomes. Nat. Med. 1998;4:594–600. doi: 10.1038/nm0598-594. PubMed DOI

Tkach M., Théry C. Communication by extracellular vesicles: Where we are and where we need to go. Cell. 2016;164:1226–1232. doi: 10.1016/j.cell.2016.01.043. PubMed DOI

Keerthikumar S., Chisanga D., Ariyaratne D., Al Saffar H., Anand S., Zhao K., Samuel M., Pathan M., Jois M., Chilamkurti N., et al. ExoCarta: A web-based compendium of exosomal cargo. J. Mol. Biol. 2015;428:688–692. doi: 10.1016/j.jmb.2015.09.019. PubMed DOI PMC

Gu Y., Li M., Wang T., Liang Y., Zhong Z., Wang X., Zhou Q., Chen L., Lang Q., He Z., et al. Lactation-Related microRNA expression profiles of porcine breast milk exosomes. PLoS ONE. 2012;7:e43691. doi: 10.1371/journal.pone.0043691. PubMed DOI PMC

Simhadri V.R., Reiners K.S., Hansen H.P., Topolar D., Simhadri V.L., Nohroudi K., Kufer T.A., Engert A., Pogge von Strandmann E. Dendritic cells release HLA-B-associated transcript-3 positive exosomes to regulate natural killer function. PLoS ONE. 2008;3:e3377. doi: 10.1371/journal.pone.0003377. PubMed DOI PMC

Zhang M., Jin K., Gao L., Zhang Z., Li F., Zhou F., Zhang L. Methods and technologies for exosome Isolation and characterization. Small Methods. 2018;2 doi: 10.1002/smtd.201800021. DOI

Hanson P.I., Cashikar A. Multivesicular body morphogenesis. Annu. Rev. Cell Dev. Biol. 2011;28:337–362. doi: 10.1146/annurev-cellbio-092910-154152. PubMed DOI

Futter C.E., Pearse A., Hewlett L.J., Hopkins C.R. Multivesicular endosomes containing internalized EGF-EGF receptor complexes mature and then fuse directly with lysosomes. J. Cell Biol. 1996;132:1011–1023. doi: 10.1083/jcb.132.6.1011. PubMed DOI PMC

Bebelman M., Bun P., Huveneers S., van Niel G., Pegtel D.M., Verweij F.J. Real-Time imaging of multivesicular body-plasma membrane fusion to quantify exosome release from single cells. Nat. Protoc. 2019;15:102–121. doi: 10.1038/s41596-019-0245-4. PubMed DOI

Doyle L.M., Wang M.Z. Overview of extracellular vesicles, their origin, composition, purpose, and methods for exosome isolation and analysis. Cells. 2019;8:727. doi: 10.3390/cells8070727. PubMed DOI PMC

Zhang Y., Liu Y., Liu H., Tang W.H. Exosomes: Biogenesis, biologic function and clinical potential. Cell Biosci. 2019;9 doi: 10.1186/s13578-019-0282-2. PubMed DOI PMC

Henne W.M., Buchkovich N.J., Emr S.D. The ESCRT pathway. Dev. Cell. 2011;21:77–91. doi: 10.1016/j.devcel.2011.05.015. PubMed DOI

Hessvik N.P., Llorente A. Current knowledge on exosome biogenesis and release. Cell Mol. Life Sci. 2018;75:193–208. doi: 10.1007/s00018-017-2595-9. PubMed DOI PMC

Babst M., Katzmann D.J., Snyder W.B., Wendland B., Emr S.D. Endosome-Associated complex, ESCRT-II, recruits transport machinery for protein sorting at the multivesicular body. Dev. Cell. 2002;3:283–289. doi: 10.1016/S1534-5807(02)00219-8. PubMed DOI

Progida C., Malerod L., Stuffers S., Brech A., Bucci C., Stenmark H. RILP is required for the proper morphology and function of late endosomes. J. Cell Sci. 2007;120:3729–3737. doi: 10.1242/jcs.017301. PubMed DOI

Colombo M., Raposo G., Théry C. Biogenesis, secretion, and intercellular interactions of exosomes and other extracellular vesicles. Annu Rev. Cell Dev. Biol. 2014;30:255–289. doi: 10.1146/annurev-cellbio-101512-122326. PubMed DOI

Trajkovic K., Hsu C., Chiantia S., Rajendran L., Wenzel D., Wieland F., Schwille P., Brügger B., Simons M. Ceramide triggers budding of exosome vesicles into multivesicular endosomes. Science. 2008;319:1244–1247. doi: 10.1126/science.1153124. PubMed DOI

Rana S., Zöller M. Exosome target cell selection and the importance of exosomal tetraspanins: A hypothesis. Biochem. Soc. Trans. 2011;39:559–562. doi: 10.1042/BST0390559. PubMed DOI

van Niel G., Charrin S., Simoes S., Romao M., Rochin L., Saftig P., Marks M.S., Rubinstein E., Raposo G. The tetraspanin CD63 regulates ESCRT-independent and-dependent endosomal sorting during melanogenesis. Dev. Cell. 2011;21:708–721. doi: 10.1016/j.devcel.2011.08.019. PubMed DOI PMC

Chairoungdua A., Smith D.L., Pochard P., Hull M., Caplan M.J. Exosome release of β-catenin: A novel mechanism that antagonizes Wnt signaling. J. Cell Biol. 2010;190:1079–1091. doi: 10.1083/jcb.201002049. PubMed DOI PMC

Nazarenko I., Rana S., Baumann A., McAlear J., Hellwig A., Trendelenburg M., Lochnit G., Preissner K.T., Zöller M. Cell surface tetraspanin Tspan8 contributes to molecular pathways of exosome-induced endothelial cell activation. Cancer Res. 2010;70:1668–1678. doi: 10.1158/0008-5472.CAN-09-2470. PubMed DOI

Perez-Hernandez D., Gutiérrez-Vázquez C., Jorge I., López-Martín S., Ursa A., Sánchez-Madrid F., Vázquez J., Yáñez-Mó M. The intracellular interactome of tetraspanin-enriched microdomains reveals their function as sorting machineries toward exosomes. J. Biol. Chem. 2013;288:11649–11661. doi: 10.1074/jbc.M112.445304. PubMed DOI PMC

De Gassart A., Geminard C., Fevrier B., Vidal M. Lipid raft–associated protein sorting in exosomes. Blood. 2015;102:4336–4345. doi: 10.1182/blood-2003-03-0871. PubMed DOI

Strauss K., Goebel C., Runz H., Möbius W., Weiss S., Feussner I., Simons M., Schneider A. Exosome secretion ameliorates lysosomal storage of cholesterol in Niemann-Pick type C disease. J. Biol. Chem. 2010;285:26279–26288. doi: 10.1074/jbc.M110.134775. PubMed DOI PMC

Laulagnier K., Grand D., Dujardin A., Hamdi S., Vincent-Schneider H., Lankar D., Salles J.-P., Bonnero C., Perreta B., Recorda M. PLD2 is enriched on exosomes and its activity is correlated to the release of exosomes. FEBS Lett. 2004;572:11–14. doi: 10.1016/j.febslet.2004.06.082. PubMed DOI

Ghossoub R., Lembo F., Rubio A., Gaillard C.B., Bouchet J., Vitale N., Slavík J., Machala M., Zimmermann P. Syntenin-ALIX exosome biogenesis and budding into multivesicular bodies are controlled by ARF6 and PLD2. Nat. Commun. 2014;5:3477. doi: 10.1038/ncomms4477. PubMed DOI

Sahu R., Kaushik S., Clement C.C., Cannizzo E.S., Scharf B., Follenzi A., Potolicchio I., Nieves E., Cuervo A.M., Santambrogio L. Microautophagy of cytosolic proteins by late endosomes. Dev. Cell. 2011;20:131–139. doi: 10.1016/j.devcel.2010.12.003. PubMed DOI PMC

Zhu H., Yu R.Y.L., Li W., Brancho D., Chow C.-W., Guariglia S., Peinado H., Lyden D., Salzer J., Bennett C. Mutation of SIMPLE in Charcot-Marie-Tooth 1C alters production of exosomes. Mol. Biol. Cell. 2013;24:1619–1637. doi: 10.1091/mbc.e12-07-0544. PubMed DOI PMC

Villarroya-Beltri C., Baixauli F., Mittelbrunn M., Fernández-Delgado I., Torralba D., Moreno-Gonzalo O., Baldanta S., Enrich C., Guerra S., Sánchez-Madrid F. ISGylation controls exosome secretion by promoting lysosomal degradation of MVB proteins. Nat. Commun. 2016;7:13588. doi: 10.1038/ncomms13588. PubMed DOI PMC

Hoshino D., Kirkbride K.C., Costello K., Clark E.S., Sinha S., Grega-Larson N., Tyska M.J., Weaver A.M. Exosome secretion is enhanced by invadopodia and drives invasive behavior. Cell Rep. 2013;5:1159–1168. doi: 10.1016/j.celrep.2013.10.050. PubMed DOI PMC

Villarroya-Beltri C., Gutiérrez-Vázquez C., Sánchez-Cabo F., Pérez-Hernández D., Vázquez J., Martin-Cofreces N., Martínez D.J., Pascual-Montano A., Mittelbrunn M., Sánchez-Madrid F. Sumoylated hnRNPA2B1 controls the sorting of miRNAs into exosomes through binding to specific motifs. Nat. Commun. 2013;4:2980. doi: 10.1038/ncomms3980. PubMed DOI PMC

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. 2019;21:9–17. doi: 10.1038/s41556-018-0250-9. PubMed DOI

Lane R.E., Korbie D., Anderson W., Vaidyanathan R., Trau M. Analysis of exosome purification methods using a model liposome system and tunable-resistive pulse sensing. Sci. Rep. 2015;5:7639. doi: 10.1038/srep07639. PubMed DOI PMC

Jung M.K., Mun J.Y. Sample preparation and imaging of exosomes by transmission electron microscopy. J. Vis. Exp. 2018;2018 doi: 10.3791/56482. PubMed DOI PMC

Rikkert L.G., Nieuwland R., Terstappen L.W.M.M., Coumans F.A.W. Quality of extracellular vesicle images by transmission electron microscopy is operator and protocol dependent. J. Extracell. Vesicles. 2019;8 doi: 10.1080/20013078.2018.1555419. PubMed DOI PMC

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. 2018;9:738. doi: 10.3389/fimmu.2018.00738. PubMed DOI PMC

Kalra H., Drummen G.P.C., Mathivanan S. Focus on extracellular vesicles: Introducing the next small big thing. Int. J. Mol. Sci. 2016;17:170. doi: 10.3390/ijms17020170. PubMed DOI PMC

Williams C., Palviainen M., Reichardt N.C., Siljander P.R.M., Falcón-Pérez J.M. Metabolomics applied to the study of extracellular vesicles. Metabolites. 2019;9:276. doi: 10.3390/metabo9110276. PubMed DOI PMC

Skotland T., Hessvik N.P., Sandvig K., Llorente A. Exosomal lipid composition and the role of ether lipids and phosphoinositides in exosome biology. J. Lipid Res. 2019;60:9–18. doi: 10.1194/jlr.R084343. PubMed DOI PMC

Skotland T., Sandvig K., Llorente A. Lipids in exosomes: Current knowledge and the way forward. Prog. Lipid Res. 2017;66:30–41. doi: 10.1016/j.plipres.2017.03.001. PubMed DOI

Moreau D., Vacca F., Vossio S., Scott C., Colaco A., Paz Montoya J., Ferguson C., Damme M., Moniatte M., Parton R.G., et al. Drug-Induced increase in lysobisphosphatidic acid reduces the cholesterol overload in Niemann-Pick type C cells and mice. EMBO Rep. 2019;20:e47055. doi: 10.15252/embr.201847055. PubMed DOI PMC

Turchinovich A., Drapkina O., Tonevitsky A. Transcriptome of extracellular vesicles: State-of-the-art. Front. Immunol. 2019;10:202. doi: 10.3389/fimmu.2019.00202. PubMed DOI PMC

Valadi H., Ekström K., Bossios A., Sjöstrand M., Lee J.J., Lötvall J.O. Exosome-Mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat. Cell Biol. 2007;9:654–659. doi: 10.1038/ncb1596. PubMed DOI

Luo S.-S., Ishibashi O., Ishikawa G., Ishikawa T., Katayama A., Mishima T., Takizawa T., Shigihara T., Goto T., Izumi A. Human villous trophoblasts express and secrete placenta-specific MicroRNAs into maternal circulation via exosomes1. Biol. Reprod. 2009;81:717–729. doi: 10.1095/biolreprod.108.075481. PubMed DOI

Gibbings D.J., Ciaudo C., Erhardt M., Voinnet O. Multivesicular bodies associate with components of miRNA effector complexes and modulate miRNA activity. Nat. Cell Biol. 2009;11:1143–1149. doi: 10.1038/ncb1929. PubMed DOI

Lässer C., Seyed Alikhani V., Ekström K., Eldh M., Torregrosa Paredes P., Bossios, Sjöstrand M., Gabrielsson S., Lötvall J., Valadi H. Human saliva, plasma and breast milk exosomes contain RNA: Uptake by macrophages. J. Transl. Med. 2011;14:9. PubMed PMC

Alvarez-Erviti L., Seow Y., Yin H., Betts C., Lakhal S., Wood M.J.A. Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nat. Biotechnol. 2011;29:341–345. doi: 10.1038/nbt.1807. PubMed DOI

Fatima F., Nawaz M. Vesiculated long non-coding RNAs: Offshore packages deciphering trans-regulation between cells, cancer progression and resistance to therapies. Non Coding RNA. 2017;3:10. doi: 10.3390/ncrna3010010. PubMed DOI PMC

Rahbarghazi R., Jabbari N., Sani N.A., Asghari R., Salimi L., Kalashani S.A., Feghhi M., Etemadi T., Akbariazar E., Mahmoudi M., et al. Tumor-Derived extracellular vesicles: Reliable tools for cancer diagnosis and clinical applications. Cell Commun. Signal. 2019;17:73. doi: 10.1186/s12964-019-0390-y. PubMed DOI PMC

Statello L., Maugeri M., Garre E., Nawaz M., Wahlgren J., Papadimitriou A., Lundqvist C., Lindfors L., Collén A., Sunnerhagen P., et al. Identification of RNA-binding proteins in exosomes capable of interacting with different types of RNA: RBP-facilitated transport of RNAs into exosomes. PLoS ONE. 2018;13:e0195969. doi: 10.1371/journal.pone.0195969. PubMed DOI PMC

Thakur B.K., Zhang H., Becker A., Matei I., Huang Y., Costa-Silva B., Zheng Y., Hoshino A., Brazier H., Xiang J., et al. Double-Stranded DNA in exosomes: A novel biomarker in cancer detection. Cell Res. 2014;24:766–769. doi: 10.1038/cr.2014.44. PubMed DOI PMC

Konečná B., Tóthová L., Repiská Exosomes-associated dna—New marker in pregnancy complications? Int. J. Mol. Sci. 2019;20:2890. doi: 10.3390/ijms20122890. PubMed DOI PMC

Jeppesen D.K., Fenix A.M., Franklin J.L., Higginbotham J.N., Zhang Q., Zimmerman L.J., Liebler D.C., Ping J., Liu Q., Evans R., et al. Reassessment of exosome composition. Cell. 2019;177:428–445. doi: 10.1016/j.cell.2019.02.029. PubMed DOI PMC

Klingeborn M., Dismuke W.M., Bowes Rickman C., Stamer W.D. Roles of exosomes in the normal and diseased eye. Prog. Retin. Eye Res. 2017;59:158–177. doi: 10.1016/j.preteyeres.2017.04.004. PubMed DOI PMC

Batrakova E.V., Kim M.S. Using exosomes, naturally-equipped nanocarriers, for drug delivery. J. Control Release. 2015;219:396–405. doi: 10.1016/j.jconrel.2015.07.030. PubMed DOI PMC

Théry C., Amigorena S., Raposo G., Clayton A. Isolation and characterization of exosomes from cell culture supernatants and biological fluids. Curr. Protoc. Cell Biol. 2006;3 doi: 10.1002/0471143030.cb0322s30. PubMed DOI

Yang X., Sun C., Wang L., Guo X. New insight into isolation, identification techniques and medical applications of exosomes. J. Control Release. 2019;308:119–129. doi: 10.1016/j.jconrel.2019.07.021. PubMed DOI

Cheruvanky A., Zhou H., Pisitkun T., Kopp J.B., Knepper M.A., Yuen P.S.T., Star R.A. Rapid isolation of urinary exosomal biomarkers using a nanomembrane ultrafiltration concentrator. Am. J. Physiol. Physiol. 2007;292:F1657–F1661. doi: 10.1152/ajprenal.00434.2006. PubMed DOI PMC

Zeringer E., Barta T., Li M., Vlassov A.V. Strategies for isolation of exosomes. Cold Spring Harb. Protoc. 2015;2015:319–323. doi: 10.1101/pdb.top074476. PubMed DOI

Lewis G.D., Metcalf T.G. Polyethylene glycol precipitation for recovery of pathogenic viruses, including hepatitis A virus and human rotavirus, from oyster, water, and sediment samples. Appl. Environ. Microbiol. 1988;54:1983–1988. doi: 10.1128/AEM.54.8.1983-1988.1988. PubMed DOI PMC

Yakimchuk K. Exosomes: Isolation methods and specific markers. Mater. Methods. 2015;5 doi: 10.13070/mm.en.5.1450. DOI

Li P., Kaslan M., Lee S.H., Yao J., Gao Z. Progress in exosome isolation techniques. Theranostics. 2017;7:789–804. doi: 10.7150/thno.18133. PubMed DOI PMC

Moser A.C., Hage D.S. Immunoaffinity chromatography: An introduction to applications and recent developments. Bioanalysis. 2010;2:769–790. doi: 10.4155/bio.10.31. PubMed DOI PMC

Liga A., Vliegenthart A.D.B., Oosthuyzen W., Dear J.W., Kersaudy-Kerhoas M. Exosome isolation: A microfluidic road-map. Lab Chip. 2015;15:2388–2394. doi: 10.1039/C5LC00240K. PubMed DOI

Nojima H., Freeman C.M., Schuster R.M., Japtok L., Kleuser B., Edwards M.J., Gulbins E., Lentsch A.B. Hepatocyte exosomes mediate liver repair and regeneration via sphingosine-1-phosphate. J. Hepatol. 2016;64:60–68. doi: 10.1016/j.jhep.2015.07.030. PubMed DOI PMC

Sung S., Kim J., Jung Y. Liver-Derived exosomes and their implications in liver. Pathobiology. 2018;19:3715. doi: 10.3390/ijms19123715. PubMed DOI PMC

Adamiak M., Sahoo S. Exosomes in myocardial repair: Advances and challenges in the development of next-generation therapeutics. Mol. Ther. 2018;26:1635–1643. doi: 10.1016/j.ymthe.2018.04.024. PubMed DOI PMC

Davidson S.M., Yellon D.M. Molecular aspects of medicine exosomes and cardioprotection e A critical analysis. Mol. Asp. Med. 2018;60:104–114. doi: 10.1016/j.mam.2017.11.004. PubMed DOI PMC

Gupta S., Knowlton A.A. HSP60 trafficking in adult cardiac myocytes: Role of the exosomal pathway. Am. J. Physiol. Circ. Physiol. 2007;292:H3052–H3056. doi: 10.1152/ajpheart.01355.2006. PubMed DOI

Liang Y., Sahoo S. Exosomes explosion for cardiac resuscitation. J. Am. Coll. Cardiol. 2015;66:612–615. doi: 10.1016/j.jacc.2015.06.1302. PubMed DOI PMC

Yang J., Yu X., Xue F., Li Y., Liu W., Zhang S. Exosomes derived from cardiomyocytes promote cardiac fibrosis via myocyte-fibroblast cross-talk. Am. J. Transl. Res. 2018;10:4350–4366. PubMed PMC

Vella L.J., Scicluna B.J., Cheng L., Bawden E.G., Masters C.L., Ang C.S., Willamson N., McLean C., Barnham K.J., Hill A.F. A rigorous method to enrich for exosomes from brain tissue. J. Extracell. Vesicles. 2017;6 doi: 10.1080/20013078.2017.1348885. PubMed DOI PMC

Pérez-González R., Gauthier S.A., Kumar A., Saito M., Saito M., Levy E. A Method for isolation of extracellular vesicles and characterization of exosomes from brain extracellular space. Methods Mol. Biol. 2017;1545:139–151. PubMed

Kapogiannis D., Boxer A., Schwartz J.B., Abner E.L., Biragyn A., Masharani U., Frassetto L., Petersen R.C., Miller B.L., Goetzl E.J. Dysfunctionally phosphorylated type 1 insulin receptor substrate in neural-derived blood exosomes of preclinical Alzheimer’s disease. FASEB J. 2015;29:589–596. doi: 10.1096/fj.14-262048. PubMed DOI PMC

Krämer-Albers E.M., Bretz N., Tenzer S., Winterstein C., Möbius W., Berger H., Nave K.A., Schild H., Trotter J. Oligodendrocytes secrete exosomes containing major myelin and stress-protective proteins: Trophic support for axons? Proteom. Clin. Appl. 2007;1:1446–1461. doi: 10.1002/prca.200700522. PubMed DOI

Potolicchio I., Carven G.J., Xu X., Stipp C., Riese R.J., Stern L.J., Santambrogio L. Proteomic analysis of microglia-derived exosomes: Metabolic role of the aminopeptidase CD13 in neuropeptide catabolism. J. Immunol. 2005;175:2237–2243. doi: 10.4049/jimmunol.175.4.2237. PubMed DOI

Gao M., Gao W., Papadimitriou J.M., Zhang C., Gao J., Zheng M. Exosomes—The enigmatic regulators of bone homeostasis. Bone Res. 2018;6 doi: 10.1038/s41413-018-0039-2. PubMed DOI PMC

Li D., Liu J., Guo B., Liang C., Dang L., Lu C., He X., Cheung H., Xu L., Lu C., et al. Osteoclast-Derived exosomal miR-214-3p inhibits osteoblastic bone formation. Nat. Commun. 2016;7:1–16. doi: 10.1038/ncomms10872. PubMed DOI PMC

Zhang Y., Yu M., Tian W. Physiological and pathological impact of exosomes of adipose tissue. Cell Prolif. 2016;49:3–13. doi: 10.1111/cpr.12233. PubMed DOI PMC

Boukouris S., Mathivanan S. Exosomes in bodily fluids are a highly stable resource of disease biomarkers. Proteom. Clin. Appl. 2015;9:358–367. doi: 10.1002/prca.201400114. PubMed DOI PMC

Tang X., Lu H., Dooner M., Chapman S., Quesenberry P.J., Ramratnam B. Exosomal Tat protein activates latent HIV-1 in primary, resting CD4+ T lymphocytes. JCI Insight. 2018;3 doi: 10.1172/jci.insight.95676. PubMed DOI PMC

Dias M.V.S., Costa C.S., Da Silva L.L.P. The ambiguous roles of extracellular vesicles in HIV replication and pathogenesis. Front. Microbiol. 2018;9:2411. doi: 10.3389/fmicb.2018.02411. PubMed DOI PMC

Patters B.J., Kumar S. The role of exosomal transport of viral agents in persistent HIV pathogenesis. Retrovirology. 2018;15:79. doi: 10.1186/s12977-018-0462-x. PubMed DOI PMC

Mukhamedova N., Hoang A., Dragoljevic D., Dubrovsky L., Pushkarsky T., Low H., Ditiatkovski M., Fu Y., Ohkawa R., Meikle P.J., et al. Exosomes containing HIV protein Nef reorganize lipid rafts potentiating inflammatory response in bystander cells. PLOS Pathog. 2019;15:e1007907. doi: 10.1371/journal.ppat.1007907. PubMed DOI PMC

Saeedi S., Israel S., Nagy C., Turecki G. The emerging role of exosomes in mental disorders. Transl. Psychiatry. 2019;9:122. doi: 10.1038/s41398-019-0459-9. PubMed DOI PMC

Zagrean A.M., Hermann D.M., Opris I., Zagrean L., Popa-Wagner A. Multicellular crosstalk between exosomes and the neurovascular unit after cerebral ischemia. therapeutic implications. Front. Neurosci. 2018;12:811. doi: 10.3389/fnins.2018.00811. PubMed DOI PMC

Rajendran L., Honsho M., Zahn T.R., Keller P., Geiger K.D., Verkade P., Simons K. Sciences of the USA 11172–11177. Proc. Natl. Acad. Sci. USA. 2006;103:11172–11177. doi: 10.1073/pnas.0603838103. PubMed DOI PMC

Saman S., Kim W.H., Raya M., Visnick Y., Miro S., Saman S., Jackson B., Mckee A., Alvarez V.E., Lee N.C.Y., et al. Exosome-Associated tau is secreted in tauopathy models and is selectively phosphorylated in cerebrospinal fluid in early Alzheimer disease. J. Biol. Chem. 2012;287:3842–3849. doi: 10.1074/jbc.M111.277061. PubMed DOI PMC

Goetzl E.J., Boxer A., Schwartz J.B., Abner E.L., Petersen R.C., Miller B.L., Kapogiannis D. Altered lysosomal proteins in neural-derived plasma exosomes in preclinical Alzheimer disease. Neurology. 2015;85:40–47. doi: 10.1212/WNL.0000000000001702. PubMed DOI PMC

Kanninen K.M., Bister N., Koistinaho J., Malm T. Biochimica et Biophysica Acta Exosomes as new diagnostic tools in CNS diseases. BBA Mol. Basis Dis. 2016;1862:403–410. doi: 10.1016/j.bbadis.2015.09.020. PubMed DOI

Benussi L., Ciani M., Tonoli E., Morbin M., Palamara L., Albani D., Fusco F., Forloni G., Glionna M., Baco M., et al. Loss of exosomes in progranulin-associated frontotemporal dementia. Neurobiol. Aging. 2016;40:41–49. doi: 10.1016/j.neurobiolaging.2016.01.001. PubMed DOI

Fraser K.B., Rawlins A.B., Clark R.G., Alcalay R.N., Standaert D.G., Liu N., Parkinson’s Disease Biomarker Program Consortium. West A.B. Ser(P)-1292 LRRK2 in urinary exosomes is elevated in idiopathic Parkinson’s disease. Mov. Disord. 2016;31:1543–1550. doi: 10.1002/mds.26686. PubMed DOI PMC

Westergard T., Jensen B.K., Wen X., Cai J., Kropf E., Iacovitti L., Pasinelli P., Trotti D. Cell-to-Cell transmission of dipeptide repeat proteins linked to C9orf72-ALS/FTD. Cell Rep. 2016;17:645–652. doi: 10.1016/j.celrep.2016.09.032. PubMed DOI PMC

Zhang W., Ou X., Wu X. Proteomics profiling of plasma exosomes in epithelial ovarian cancer: A potential role in the coagulation cascade, diagnosis and prognosis. Int. J. Oncol. 2019;54:1719–1733. doi: 10.3892/ijo.2019.4742. PubMed DOI PMC

Hartmann A., Muth C., Dabrowski O., Krasemann S., Glatzel M. Exosomes and the prion protein: More than one truth. Front. Neurosci. 2017;11:194. doi: 10.3389/fnins.2017.00194. PubMed DOI PMC

Kenney K., Motamedi V., Puccio A., Diaz-Arrastia R., Edwards K., Gill J. Exosomes in acquired neurological disorders: New insights into pathophysiology and treatment. Mol. Neurobiol. 2018;55:9280–9293. PubMed

Karttunen J., Heiskanen M., Lipponen A., Poulsen D., Pitkänen A. Extracellular vesicles as diagnostics and therapeutics for structural epilepsies. Int. J. Mol. Sci. 2019;20:259. doi: 10.3390/ijms20061259. PubMed DOI PMC

Costa-Silva B., Aiello N.M., Ocean A.J., Singh S., Zhang H., Thakur B.K., Becker A., Hoshino A., Mark M.T., Molina H., et al. Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver. Nat. Cell Biol. 2015;17:816–826. doi: 10.1038/ncb3169. PubMed DOI PMC

Skog J., Wurdinger T., Rijn SVan Meijer D., Gainche L., Sena-esteves M., Curry W.T., Jr., Carter R.S., Krichevsky A.M., Breakefield O.X. Glioblastoma microvesicles transport RNA and protein that promote promote tumor growth and provide diagnostic biomarkers Johan. Nat. Cell Biol. 2012;10:1470–1476. doi: 10.1038/ncb1800. PubMed DOI PMC

Luga V., Zhang L., Viloria-Petit A.M., Ogunjimi A.A., Inanlou M.R., Chiu E., Buchanan M., Hosein A.N., Basik M., Wrana J.L. Exosomes mediate stromal mobilization of autocrine Wnt-PCP signaling in breast cancer cell migration. Cell. 2012;151:1542–1556. doi: 10.1016/j.cell.2012.11.024. PubMed DOI

Kurywchak P., Tavormina J., Kalluri R. The emerging roles of exosomes in the modulation of immune responses in cancer. Genome Med. 2018;10:23. doi: 10.1186/s13073-018-0535-4. PubMed DOI PMC

O’Driscoll L. Expanding on exosomes and ectosomes in cancer. N. Engl. J. Med. 2015;372:2359–2362. doi: 10.1056/NEJMcibr1503100. PubMed DOI

Mao Y., Wang Y., Dong L., Zhang Y., Zhang Y., Wang C., Zhang Q., Yang S., Cao L., Zhang X., et al. Hypoxic exosomes facilitate angiogenesis and metastasis in esophageal squamous cell carcinoma through altering the phenotype and transcriptome of endothelial cells. J. Exp. Clin. Cancer Res. 2019;38:389. doi: 10.1186/s13046-019-1384-8. PubMed DOI PMC

Zhang Y.-F., Shi J.-B., Li C. Small extracellular vesicle loading systems in cancer therapy: Current status and the way forward. Cytotherapy. 2019;21:1122–1136. doi: 10.1016/j.jcyt.2019.10.002. PubMed DOI

Zhang K.L., Wang Y.J., Sun J., Zhou J., Xing C., Huang G., Li J., Yang H. Artificial chimeric exosomes for anti-phagocytosis and targeted cancer therapy. Chem. Sci. 2019;10:1555–1561. doi: 10.1039/C8SC03224F. PubMed DOI PMC

Chalmin F., Ladoire S., Mignot G., Vincent J., Bruchard M., Remy-Martin J.-P., Boireau W., Rouleau A., Simon B., Lanneau D., et al. Membrane-associated Hsp72 from tumor-derived exosomes mediates STAT3-dependent immunosuppressive function of mouse and human myeloid-derived suppressor cells. J. Clin. Investig. 2010;120:457–471. doi: 10.1172/JCI40483. PubMed DOI PMC

Yoshioka Y., Kosaka N., Konishi Y., Ohta H., Okamoto H., Sonoda H., Nonaka R., Yamamoto H., Ishii H., Mori M., et al. Ultra-sensitive liquid biopsy of circulating extracellular vesicles using ExoScreen. Nat. Commun. 2014;5:3591. doi: 10.1038/ncomms4591. PubMed DOI PMC

Melo S.A., Luecke L.B., Kahlert C., Fernandez A.F., Seth T., Kaye J., LeBleu V.S., Mittendorf E.A., Weitz J., Rahbari N., et al. Glypican-1 identiefies cancer exosomes and facilitates early detection of cancer. Nature. 2015;523:177–182. doi: 10.1038/nature14581. PubMed DOI PMC

Xu R., Rai A., Chen M., Suwakulsiri W., Greening D.W., Simpson R.J. Extracellular vesicles in cancer—Implications for future improvements in cancer care. Nat. Rev. Clin. Oncol. 2018;15:617–638. doi: 10.1038/s41571-018-0036-9. PubMed DOI

Sercombe L., Veerati T., Moheimani F., Wu S.Y., Sood A.K., Hua S. Advances and challenges of liposome assisted drug delivery. Front. Pharmacol. 2015;6:1–13. doi: 10.3389/fphar.2015.00286. PubMed DOI PMC

Agrawal U., Sharma R., Gupta M., Vyas S.P. Is nanotechnology a boon for oral drug delivery? Drug Discov. Today. 2014;19:1530–1546. doi: 10.1016/j.drudis.2014.04.011. PubMed DOI

Chai R., Wee R., Yeo Y., Hian K., Kiang S. Exosomes for drug deliver—A novel application for the mesenchymal stem cell. Biotechnol. Adv. 2013;31:543–551. PubMed

Ha D., Yang N., Nadithe V. Exosomes as therapeutic drug carriers and delivery vehicles across biological membranes: Current perspectives and future challenges. Acta Pharm. Sin. B. 2016;6:287–296. doi: 10.1016/j.apsb.2016.02.001. PubMed DOI PMC

Sun D., Zhuang X., Xiang X., Liu Y., Zhang S., Liu C., Barnes S., Grizzle W., Miller D., Zhang H. A novel nanoparticle drug delivery system: The anti-inflammatory activity of curcumin is enhanced when encapsulated in exosomes. Mol. Ther. 2010;18:1606–1614. doi: 10.1038/mt.2010.105. PubMed DOI PMC

Haney M.J., Klyachko N.L., Zhao Y., Gupta R., Plotnikova E.G., He Z., Patel T., Piroyan A., Sokolsky M., Kabanov A.V., et al. Exosomes as drug delivery vehicles for Parkinson’s disease therapy. J. Control Release. 2015;207:18–30. doi: 10.1016/j.jconrel.2015.03.033. PubMed DOI PMC

Srivastava A., Amreddy N., Babu A., Panneerselvam J., Mehta M., Muralidharan R., Chen A., Zhao Y.D., Razaq M., Riedinger N., et al. Nanosomes carrying doxorubicin exhibit potent anticancer activity against human lung cancer cells. Sci. Rep. 2016;6:38541. PubMed PMC

Lou G., Song X., Yang F., Wu S., Wang J., Chen Z., Liu Y. Exosomes derived from miR-122-modified adipose tissue-derived MSCs increase chemosensitivity of hepatocellular carcinoma. J. Hematol. Oncol. 2015;8:122. doi: 10.1186/s13045-015-0220-7. PubMed DOI PMC

The Role of Exosomes in Human Carcinogenesis and Cancer Therapy-Recent Findings from Molecular and Clinical Research