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Abstract

This review provides an updated perspective on rapidly proliferating efforts to harness extracellular vesicles (EVs) for therapeutic applications. We summarize current knowledge, emerging strategies, and open questions pertaining to clinical potential and translation. Potentially useful EVs comprise diverse products of various cell types and species. EV components may also be combined with liposomes and nanoparticles to facilitate manufacturing as well as product safety and evaluation. Potential therapeutic cargoes include RNA, proteins, and drugs. Strategic issues considered herein include choice of therapeutic agent, means of loading cargoes into EVs, promotion of EV stability, tissue targeting, and functional delivery of cargo to recipient cells. Some applications may harness natural EV properties, such as immune modulation, regeneration promotion, and pathogen suppression. These properties can be enhanced or customized to enable a wide range of therapeutic applications, including vaccination, improvement of pregnancy outcome, and treatment of autoimmune disease, cancer, and tissue injury.

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2015-01-06
2024-06-23
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Literature Cited

  1. Lee Y, El Andaloussi S, Wood MJA. 1.  2012. Exosomes and microvesicles: extracellular vesicles for genetic information transfer and gene therapy. Hum. Mol. Genet. 21:R125–34 [Google Scholar]
  2. El Andaloussi S, Mäger I, Breakefield XO, Wood MJA. 2.  2013. Extracellular vesicles: biology and emerging therapeutic opportunities. Nat. Rev. Drug Discov. 12:347–57 [Google Scholar]
  3. Marcus ME, Leonard JN. 3.  2013. FedExosomes: engineering therapeutic biological nanoparticles that truly deliver. Pharmaceuticals 6:659–80 [Google Scholar]
  4. Hagiwara K, Ochiya T, Kosaka N. 4.  2014. A paradigm shift for extracellular vesicles as small RNA carriers: from cellular waste elimination to therapeutic applications. Drug Deliv. Transl. Res. 4:31–37 [Google Scholar]
  5. Kittel A, Falus A, Buzás E. 5.  2013. Microencapsulation technology by nature: cell derived extracellular vesicles with therapeutic potential. Eur. J. Microbiol. Immunol. 3:91–96 [Google Scholar]
  6. Raposo G, Stoorvogel W. 6.  2013. Extracellular vesicles: exosomes, microvesicles, and friends. J. Cell Biol. 200:373–83 [Google Scholar]
  7. Manning AJ, Kuehn MJ. 7.  2013. Functional advantages conferred by extracellular prokaryotic membrane vesicles. J. Mol. Microbiol. Biotechnol. 23:131–41 [Google Scholar]
  8. Rodrigues ML, Nakayasu ES, Almeida IC, Nimrichter L. 8.  2014. The impact of proteomics on the understanding of functions and biogenesis of fungal extracellular vesicles. J. Proteomics 97:177–86 [Google Scholar]
  9. Oliveira DL, Nakayasu ES, Joffe LS, Guimarães AJ, Sobreira TJ. 9.  et al. 2010. Characterization of yeast extracellular vesicles: evidence for the participation of different pathways of cellular traffic in vesicle biogenesis. PLOS ONE 5:e11113 [Google Scholar]
  10. Mantel PY, Marti M. 10.  2014. The role of extracellular vesicles in Plasmodium and other protozoan parasites. Cell Microbiol. 16:344–54 [Google Scholar]
  11. Wang Q, Zhuang X, Mu J, Deng ZB, Jiang H. 11.  et al. 2013. Delivery of therapeutic agents by nanoparticles made of grapefruit-derived lipids. Nat. Commun. 4:1867 [Google Scholar]
  12. Ju S, Mu J, Dokland T, Zhuang X, Wang Q. 12.  et al. 2013. Grape exosome-like nanoparticles induce intestinal stem cells and protect mice from DSS-induced colitis. Mol. Ther. 21:1345–57 [Google Scholar]
  13. Wang J, Silva M, Haas LA, Morsci NS, Nguyen KC. 13.  et al. 2014. C. elegans ciliated sensory neurons release extracellular vesicles that function in animal communication. Curr. Biol. 24:519–25 [Google Scholar]
  14. Koles K, Budnik V. 14.  2012. Exosomes go with the Wnt. Cell. Logist. 2:169–73 [Google Scholar]
  15. Houseley J, LaCava J, Tollervey D. 15.  2006. RNA-quality control by the exosome. Nat. Rev. Mol. Cell Biol. 7:529–39 [Google Scholar]
  16. Théry C, Ostrowski M, Segura E. 16.  2009. Membrane vesicles as conveyors of immune responses. Nat. Rev. Immunol. 9:581–93 [Google Scholar]
  17. Morello M, Minciacchi VR, de Candia P, Yang J, Posadas E. 17.  et al. 2013. Large oncosomes mediate intercellular transfer of functional microRNA. Cell Cycle 12:3526–36 [Google Scholar]
  18. Contreras-Galindo R, Kaplan MH, Contreras-Galindo AC, Gonzalez-Hernandez MJ, Ferlenghi I. 18.  et al. 2012. Characterization of human endogenous retroviral elements in the blood of HIV-1-infected individuals. J. Virol. 86:262–76 [Google Scholar]
  19. Kalra H, Simpson RJ, Ji H, Aikawa E, Altevogt P. 19.  et al. 2012. Vesiclepedia: a compendium for extracellular vesicles with continuous community annotation. PLOS Biol. 10:e1001450 [Google Scholar]
  20. Prada I, Furlan R, Matteoli M, Verderio C. 20.  2013. Classical and unconventional pathways of vesicular release in microglia. Glia 61:1003–17 [Google Scholar]
  21. Pallet N, Sirois I, Bell C, Hanafi LA, Hamelin K. 21.  et al. 2013. A comprehensive characterization of membrane vesicles released by autophagic human endothelial cells. Proteomics 13:1108–20 [Google Scholar]
  22. Wurdinger T, Gatson NA, Balaj L, Kaur B, Breakefield XO, Pegtel DM. 22.  2012. Extracellular vesicles and their convergence with viral pathways. Adv. Virol. 2012:767694 [Google Scholar]
  23. Gould SJ, Booth AM, Hildreth JE. 23.  2003. The Trojan exosome hypothesis. Proc. Natl. Acad. Sci. USA 100:10592–97 [Google Scholar]
  24. Belting M, Wittrup A. 24.  2008. Nanotubes, exosomes, and nucleic acid-binding peptides provide novel mechanisms of intercellular communication in eukaryotic cells: implications in health and disease. J. Cell Biol. 183:1187–91 [Google Scholar]
  25. Wood CR, Huang K, Diener DR, Rosenbaum JL. 25.  2013. The cilium secretes bioactive ectosomes. Curr. Biol. 23:906–11 [Google Scholar]
  26. Llorente AS, Sylvänne T, Kauhanen D, Róg T, Orłowski A. 26.  et al. 2013. Molecular lipidomics of exosomes released by PC-3 prostate cancer cells. Biochim. Biophys. Acta 1831:1302–9 [Google Scholar]
  27. Morelli AE, Larregina AT, Shufesky WJ, Sullivan ML, Stolz DB. 27.  et al. 2004. Endocytosis, intracellular sorting, and processing of exosomes by dendritic cells. Blood 104:3257–66 [Google Scholar]
  28. Laulagnier K, Motta C, Hamdi S, Roy S, Fauvelle F. 28.  et al. 2004. Mast cell- and dendritic cell-derived exosomes display a specific lipid composition and an unusual membrane organization. Biochemistry 380:161–71 [Google Scholar]
  29. Vidal M, Sainte-Marie J, Philippot JR, Bienvenue A. 29.  1989. Asymmetric distribution of phospholipids in the membrane of vesicles released during in vitro maturation of guinea pig reticulocytes: evidence precluding a role for “aminophospholipid translocase.”. J. Cell. Physiol. 140:455–62 [Google Scholar]
  30. Choi DS, Kim DK, Kim YK, Gho YS. 30.  2013. Proteomics, transcriptomics and lipidomics of exosomes and ectosomes. Proteomics 13:1554–71 [Google Scholar]
  31. Simpson RJ, Lim JW, Moritz RL, Mathivanan S. 31.  2009. Exosomes: proteomic insights and diagnostic potential. Expert Rev. Proteomics 6:267–83 [Google Scholar]
  32. Mathivanan S, Fahner CJ, Reid GE, Simpson RJ. 32.  2012. ExoCarta 2012: database of exosomal proteins, RNA and lipids. Nucleic Acids Res. 40:D1241–44 [Google Scholar]
  33. de Curtis I, Meldolesi J. 33.  2012. Cell surface dynamics – how Rho GTPases orchestrate the interplay between the plasma membrane and the cortical cytoskeleton. J. Cell Sci. 125:4435–44 [Google Scholar]
  34. Mittelbrunn M, Sánchez-Madrid F. 34.  2010. Intercellular communication: diverse structures for exchange of genetic information. Nat. Rev. Mol. Cell Biol. 13:328–35 [Google Scholar]
  35. Tian T, Zhu YL, Hu FH, Wang YY, Huang NP, Xiao ZD. 35.  2013. Dynamics of exosome internalization and trafficking. J. Cell. Physiol. 228:1487–95 [Google Scholar]
  36. Bonnington KE, Kuehn MJ. 36.  2013. Protein selection and export via outer membrane vesicles. Biochim. Biophys. Acta 24:1843:1612–19 [Google Scholar]
  37. Keyel PA, Heid ME, Watkins SC, Salter RD. 37.  2012. Visualization of bacterial toxin induced responses using live cell fluorescence microscopy. J. Vis. Exp. 68:e4227 [Google Scholar]
  38. Mack M, Kleinschmidt A, Bruhl H, Klier C, Nelson PJ. 38.  et al. 2000. Transfer of the chemokine receptor CCR5 between cells by membrane-derived microparticles: a mechanism for cellular human immunodeficiency virus 1 infection. Nat. Med. 6:769–75 [Google Scholar]
  39. van der Vlist EJ, Arkesteijn GJA, van de Lest CHA, Stoorvogel W, Nolte-'t Hoen ENM, Wauben MHM. 39.  2012. CD4+ T cell activation promotes the differential release of distinct populations of nanosized vesicles. J. Extracell. Vesicles 1:18364 [Google Scholar]
  40. Al-Nedawi K, Meehan B, Micallef J, Lhotak V, May L. 40.  et al. 2008. Intercellular transfer of the oncogenic receptor EGFRvIII by microvesicles derived from tumour cells. Nat. Cell Biol. 10:619–24 [Google Scholar]
  41. Pegtel DM, Cosmopoulos K, Thorley-Lawson DA, van Eijndhoven MA, Hopmans E. 41.  et al. 2010. Functional delivery of viral miRNAs via exosomes. Proc. Natl. Acad. Sci. USA 107:6328–33 [Google Scholar]
  42. Lee C, Mitsialis SA, Aslam M, Vitali SH, Vergadi E. 42.  et al. 2012. Exosomes mediate the cytoprotective action of mesenchymal stromal cells on hypoxia-induced pulmonary hypertension. Circulation 126:2601–11 [Google Scholar]
  43. Arslan F, Lai RC, Smeets MB, Akeroyd L, Choo A. 43.  et al. 2013. Mesenchymal stem cell-derived exosomes increase ATP levels, decrease oxidative stress and activate PI3K/Akt pathway to enhance myocardial viability and prevent adverse remodeling after myocardial ischemia/reperfusion injury. Stem Cell Res. 10:301–12 [Google Scholar]
  44. Xin H, Li Y, Buller B, Katakowski M, Zhang Y. 44.  et al. 2012. Exosome-mediated transfer of miR-133b from multipotent mesenchymal stromal cells to neural cells contributes to neurite outgrowth. Stem Cells 30:1556–64 [Google Scholar]
  45. Pusic AD, Kraig RP. 45.  2014. Youth and environmental enrichment generate serum exosomes containing miR-219 that promote CNS myelination. Glia 62:284–99 [Google Scholar]
  46. Lee JK, Park SR, Jung BK, Jeon YK, Lee YS. 46.  et al. 2013. Exosomes derived from mesenchymal stem cells suppress angiogenesis by down-regulating VEGF expression in breast cancer cells. PLOS ONE 8:e84256 [Google Scholar]
  47. Bianco NR, Kim SH, Morelli AE, Robbins PD. 47.  2007. Modulation of the immune response using dendritic cell–derived exosomes. Methods Mol. Biol. 380:443–55 [Google Scholar]
  48. Robbins PD, Morelli AE. 48.  2014. Regulation of immune responses by extracellular vesicles. Nat. Rev. Immunol. 14:195–208 [Google Scholar]
  49. Taylor DD, Akyol S, Gercel-Taylor C. 49.  2006. Pregnancy-associated exosomes and their modulation of T cell signaling. J. Immunol. 176:1534–42 [Google Scholar]
  50. Stenqvist AC, Nagaeva O, Baranov V, Mincheva-Nilsson L. 50.  2013. Exosomes secreted by human placenta carry functional Fas ligand and TRAIL molecules and convey apoptosis in activated immune cells, suggesting exosome-mediated immune privilege of the fetus. J. Immunol. 191:5515–23 [Google Scholar]
  51. Bryniarski K, Ptak W, Jayakumar A, Pullmann K, Caplan MJ. 51.  et al. 2013. Antigen-specific, antibody-coated, exosome-like nanovesicles deliver suppressor T-cell microRNA-150 to effector T cells to inhibit contact sensitivity. J. Allergy Clin. Immunol. 132:170–81 [Google Scholar]
  52. Kim HD, Maxwell JA, Kong FK, Tang DCC, Fukuchi K. 52.  2005. Induction of anti-inflammatory immune response by an adenovirus vector encoding 11 tandem repeats of Aβ1–6: toward safer and effective vaccines against Alzheimer's disease. Biochem. Biophys. Res. Commun. 336:84–92 [Google Scholar]
  53. Kim SH, Bianco N, Menon R, Lechman ER, Shufesky WJ. 53.  et al. 2006. Exosomes derived from genetically modified DC expressing FasL are anti-inflammatory and immunosuppressive. Mol. Ther. 13:289–300 [Google Scholar]
  54. Kim SH, Bianco NR, Shufesky WJ, Morelli AE, Robbins PD. 54.  2007. Effective treatment of inflammatory disease models with exosomes derived from dendritic cells genetically modified to express IL-4. J. Immunol. 179:2242–49 [Google Scholar]
  55. Shen Y, Torchia MLG, Lawson GW, Karp CL, Ashwell JD, Mazmanian SK. 55.  2012. Outer membrane vesicles of a human commensal mediate immune regulation and disease protection. Cell Host Microbe 12:509–20 [Google Scholar]
  56. Delorme-Axford E, Donker RB, Mouillet JF, Chu T, Bayer A. 56.  et al. 2013. Human placental trophoblasts confer viral resistance to recipient cells. Proc. Natl. Acad. Sci. USA 110:12048–53 [Google Scholar]
  57. Li J, Liu K, Liu Y, Xu Y, Zhang F. 57.  et al. 2013. Exosomes mediate the cell-to-cell transmission of IFN-α-induced antiviral activity. Nat. Immunol. 14:793–803 [Google Scholar]
  58. Viaud S, Théry C, Ploix S, Tursz T, Lapierre V. 58.  et al. 2010. Dendritic cell-derived exosomes for cancer immunotherapy: What's next?. Cancer Res. 70:1281 [Google Scholar]
  59. Qu Y, Franchi L, Nunez G, Dubyak GR. 59.  2007. Nonclassical IL-1β secretion stimulated by P2X7 receptors is dependent on inflammasome activation and correlated with exosome release in murine macrophages. J. Immunol. 179:1913–25 [Google Scholar]
  60. Colino J, Snapper CM. 60.  2006. Exosomes from bone marrow dendritic cells pulsed with diphtheria toxoid preferentially induce type 1 antigen-specific IgG responses in naive recipients in the absence of free antigen. J. Immunol. 177:3757–62 [Google Scholar]
  61. Cheng Y, Schorey JS. 61.  2013. Exosomes carrying mycobacterial antigens can protect mice against Mycobacterium tuberculosis infection. Eur. J. Immunol. 43:3279–90 [Google Scholar]
  62. Del Cacho E, Gallego M, Lee SH, Lillehoj HS, Quilez J. 62.  et al. 2011. Induction of protective immunity against Eimeria tenella infection using antigen-loaded dendritic cells (DC) and DC-derived exosomes. Vaccine 29:3818–25 [Google Scholar]
  63. Beauvillain C, Juste MO, Dion S, Pierre J, Dimier-Poisson I. 63.  2009. Exosomes are an effective vaccine against congenital toxoplasmosis in mice. Vaccine 27:1750–57 [Google Scholar]
  64. Gaillard ME, Bottero D, Errea A, Ormazabal M, Zurita ME. 64.  et al. 2014. Acellular pertussis vaccine based on outer membrane vesicles capable of conferring both long-lasting immunity and protection against different strain genotypes. Vaccine 32:931–37 [Google Scholar]
  65. Sandbu S, Feiring B, Oster P, Helland OS, Bakke HS. 65.  et al. 2007. Immunogenicity and safety of a combination of two serogroup B meningococcal outer membrane vesicle vaccines. Clin. Vaccine Immunol. 14:1062–69 [Google Scholar]
  66. Keiser PB, Biggs-Cicatelli S, Moran EE, Schmiel DH, Pinto VB. 66.  et al. 2011. A phase 1 study of a meningococcal native outer membrane vesicle vaccine made from a group B strain with deleted lpxL1 and synX, over-expressed factor H binding protein, two PorAs and stabilized OpcA expression. Vaccine 29:1413–20 [Google Scholar]
  67. Gehrmann U, Hiltbrunner S, Georgoudaki AM, Karlsson MC, Näslund TI, Gabrielsson S. 67.  2013. Synergistic induction of adaptive antitumor immunity by codelivery of antigen with α-galactosylceramide on exosomes. Cancer Res. 73:3865–76 [Google Scholar]
  68. Lee EY, Park KS, Yoon YJ, Lee J, Moon HG. 68.  et al. 2012. Therapeutic effects of autologous tumor-derived nanovesicles on melanoma growth and metastasis. PLOS ONE 7:e33330 [Google Scholar]
  69. Clayton A, Harris CL, Court J, Mason MD, Morgan BP. 69.  2003. Antigen-presenting cell exosomes are protected from complement-mediated lysis by expression of CD55 and CD59. Eur. J. Immunol. 33:522–31 [Google Scholar]
  70. Kim HS, Choi DY, Yun SJ, Choi SM, Kang JW. 70.  et al. 2012. Proteomic analysis of microvesicles derived from human mesenchymal stem cells. J. Proteome Res. 11:839–49 [Google Scholar]
  71. Sun D, Zhuang X, Xiang X, Liu Y, Zhang S. 71.  et al. 2010. A novel nanoparticle drug delivery system: the anti-inflammatory activity of curcumin is enhanced when encapsulated in exosomes. Mol. Ther. 18:1606–14 [Google Scholar]
  72. Mizrak A, Bolukbasi MF, Ozdener GB, Brenner GJ, Madlener S. 72.  et al. 2013. Genetically engineered microvesicles carrying suicide mRNA/protein inhibit schwannoma tumor growth. Mol. Ther. 21:101–8 [Google Scholar]
  73. Ohno S, Takanashi M, Sudo K, Ueda S, Ishikawa A. 73.  et al. 2013. Systemically injected exosomes targeted to EGFR deliver antitumor microRNA to breast cancer cells. Mol. Ther. 21:185–91 [Google Scholar]
  74. Tian Y, Li S, Song J, Ji T, Zhu M. 74.  et al. 2014. A doxorubicin delivery platform using engineered natural membrane vesicle exosomes for targeted tumor therapy. Biomaterials 35:2383–90 [Google Scholar]
  75. Zhuang X, Xiang X, Grizzle W, Sun D, Zhang S. 75.  et al. 2011. Treatment of brain inflammatory diseases by delivering exosome encapsulated anti-inflammatory drugs from the nasal region to the brain. Mol. Ther. 19:1769–79 [Google Scholar]
  76. Alvarez-Erviti L, Seow Y, Yin H, Betts C, Lakhal S, Wood MJA. 76.  2011. Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nat. Biotechnol. 29:341–45 [Google Scholar]
  77. Théry C, Duban L, Segura E, Véron P, Lantz O, Amigorena S. 77.  2002. Indirect activation of naïve CD4+ T cells by dendritic cell–derived exosomes. Nat. Immunol. 3:1156–62 [Google Scholar]
  78. Montecalvo A, Shufesky WJ, Stolz DB, Sullivan MG, Wang Z. 78.  et al. 2008. Exosomes as a short-range mechanism to spread alloantigen between dendritic cells during T cell allorecognition. J. Immunol. 180:3081–90 [Google Scholar]
  79. Atay S, Banskota S, Crow J, Sethi G, Rink L, Godwin AK. 79.  2014. Oncogenic KIT-containing exosomes increase gastrointestinal stromal tumor cell invasion. Proc. Natl. Acad. Sci. USA 111:711–16 [Google Scholar]
  80. Bijnsdorp IV, Geldof AA, Lavaei M, Piersma SR, van Moorselaar RJA, Jimenez CR. 80.  2013. Exosomal ITGA3 interferes with non-cancerous prostate cell functions and is increased in urine exosomes of metastatic prostate cancer patients. J. Extracell. Vesicles 2:22097 [Google Scholar]
  81. Luga V, Zhang L, Viloria-Petit AM, Ogunjimi AA, Inanlou MR. 81.  et al. 2012. Exosomes mediate stromal mobilization of autocrine Wnt-PCP signaling in breast cancer cell migration. Cell 151:1542–56 [Google Scholar]
  82. Shin SJ, Smith JA, Rezniczek GA, Pan S, Chen R. 82.  et al. 2013. Unexpected gain of function for the scaffolding protein plectin due to mislocalization in pancreatic cancer. Proc. Natl. Acad. Sci. USA 110:19414–19 [Google Scholar]
  83. Tadokoro H, Umezu T, Ohyashiki K, Hirano T, Ohyashiki JH. 83.  2013. Exosomes derived from hypoxic leukemia cells enhance tube formation in endothelial cells. J. Biol. Chem. 288:34343–51 [Google Scholar]
  84. Kucharzewska P, Christianson HC, Welch JE, Svensson KJ, Fredlund E. 84.  et al. 2013. Exosomes reflect the hypoxic status of glioma cells and mediate hypoxia-dependent activation of vascular cells during tumor development. Proc. Natl. Acad. Sci. USA 110:7312–17 [Google Scholar]
  85. Grange C, Tapparo M, Collino F, Vitillo L, Damasco C. 85.  et al. 2011. Microvesicles released from human renal cancer stem cells stimulate angiogenesis and formation of lung premetastatic niche. Cancer Res. 71:5346–56 [Google Scholar]
  86. Clayton A, Mitchell JP, Court J, Linnane S, Mason MD, Tabi Z. 86.  2008. Human tumor-derived exosomes down-modulate NKG2D expression. J. Immunol. 180:7249–58 [Google Scholar]
  87. Clayton A, Mitchell JP, Court J, Mason MD, Tabi Z. 87.  2007. Human tumor-derived exosomes selectively impair lymphocyte responses to interleukin-2. Cancer Res. 67:7458–66 [Google Scholar]
  88. Balaj L, Lessard R, Dai L, Cho Y-J, Pomeroy SL. 88.  et al. 2011. Tumour microvesicles contain retrotransposon elements and amplified oncogene sequences. Nat. Commun. 2:180 [Google Scholar]
  89. Rak J, Guha A. 89.  2012. Extracellular vesicles–vehicles that spread cancer genes. Bioessays 34:489–97 [Google Scholar]
  90. Peinado H, Alečković M, Lavotshkin S, Matei I, Costa-Silva B. 90.  et al. 2012. Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. Nat. Med. 18:883–91 [Google Scholar]
  91. Yu S, Liu C, Su K, Wang J, Liu Y. 91.  et al. 2007. Tumor exosomes inhibit differentiation of bone marrow dendritic cells. J. Immunol. 178:6867–75 [Google Scholar]
  92. Kim OY, Hong BS, Park KS, Yoon YJ, Choi SJ. 92.  et al. 2013. Immunization with Escherichia coli outer membrane vesicles protects bacteria-induced lethality via Th1 and Th17 cell responses. J. Immunol. 190:4092–102 [Google Scholar]
  93. Jang SC, Kim OY, Yoon CM, Choi DS, Roh TY. 93.  et al. 2013. Bioinspired exosome-mimetic nanovesicles for targeted delivery of chemotherapeutics to malignant tumors. ACS Nano 7:7698–710 [Google Scholar]
  94. Wahlgren J, Karlson TDL, Brisslert M, Vaziri Sani F, Telemo E. 94.  et al. 2012. Plasma exosomes can deliver exogenous short interfering RNA to monocytes and lymphocytes. Nucleic Acids Res. 40:e130 [Google Scholar]
  95. Kooijmans SAA, Stremersch S, Braeckmans K, de Smedt SC, Hendrix A. 95.  et al. 2013. Electroporation-induced siRNA precipitation obscures the efficiency of siRNA loading into extracellular vesicles. J. Control. Release 172:229–38 [Google Scholar]
  96. Hood JL, Scott MJ, Wickline SA. 96.  2014. Maximizing exosome colloidal stability following electroporation. Anal. Biochem. 448:41–49 [Google Scholar]
  97. Raiborg C, Stenmark H. 97.  2009. The ESCRT machinery in endosomal sorting of ubiquitylated membrane proteins. Nature 458:445–52 [Google Scholar]
  98. Baietti MF, Zhang Z, Mortier E, Melchior A, Degeest G. 98.  et al. 2012. Syndecan–syntenin–ALIX regulates the biogenesis of exosomes. Nat. Cell Biol. 14:677–85 [Google Scholar]
  99. Nabhan JF, Hu R, Oh RS, Cohen SN, Lu Q. 99.  2012. Formation and release of arrestin domain-containing protein 1-mediated microvesicles (ARMMs) at plasma membrane by recruitment of TSG101 protein. Proc. Natl. Acad. Sci. USA 109:4146–51 [Google Scholar]
  100. Shen B, Wu N, Yang JM, Gould SJ. 100.  2011. Protein targeting to exosomes/microvesicles by plasma membrane anchors. J. Biol. Chem. 286:14383–95 [Google Scholar]
  101. Collino F, Deregibus MC, Bruno S, Sterpone L, Aghemo G. 101.  et al. 2010. Microvesicles derived from adult human bone marrow and tissue specific mesenchymal stem cells shuttle selected pattern of miRNAs. PLOS ONE 5:e11803 [Google Scholar]
  102. Gibbings DJ, Ciaudo C, Erhardt M, Voinnet O. 102.  2009. Multivesicular bodies associate with components of miRNA effector complexes and modulate miRNA activity. Nat. Cell Biol. 11:1143–49 [Google Scholar]
  103. Zhang Y, Liu D, Chen X, Li J, Li L. 103.  et al. 2010. Secreted monocytic miR-150 enhances targeted endothelial cell migration. Mol. Cell 39:133–44 [Google Scholar]
  104. Villarroya-Beltri C, Gutiérrez-Vázquez C, Sánchez-Madrid F, Mittelbrunn M. 104.  2013. Analysis of microRNA and protein transfer by exosomes during an immune synapse. Methods Mol. Biol. 1024:41–51 [Google Scholar]
  105. Bolukbasi MF, Mizrak A, Ozdener GB, Madlener S, Ströbel T. 105.  et al. 2012. miR-1289 and “zipcode”-like sequence enrich mRNAs in microvesicles. Mol. Ther. Nucleic Acids 1:e10 [Google Scholar]
  106. Koppers-Lalic D, Hackenberg M, van Eijndhoven ME, Sabogal Pineros Y, Sie D. 106.  et al. 2013. Comprehensive deep-sequencing analysis reveals non-random small RNA incorporation into tumour exosomes and biomarker potential. Proc. Int. Soc. Extracell. Vesicles, 2nd, Boston, Apr. 17–20 [Google Scholar]
  107. Rechavi O, Erlich Y, Amram H, Flomenblit L, Karginov FV. 107.  et al. 2009. Cell contact-dependent acquisition of cellular and viral nonautonomously encoded small RNAs. Genes Dev. 23:1971–79 [Google Scholar]
  108. Kosaka N, Iguchi H, Yoshioka Y, Hagiwara K, Takeshita F, Ochiya T. 108.  2012. Competitive interactions of cancer cells and normal cells via secretory microRNAs. J. Biol. Chem. 287:1397–405 [Google Scholar]
  109. Akao Y, Iio A, Itoh T, Noguchi S, Itoh Y. 109.  et al. 2011. Microvesicle-mediated RNA molecule delivery system using monocytes/macrophages. Mol. Ther. 19:395–99 [Google Scholar]
  110. Hergenreider E, Heydt S, Tréguer K, Boettger T, Horrevoets AJG. 110.  et al. 2012. Atheroprotective communication between endothelial cells and smooth muscle cells through miRNAs. Nat. Cell Biol. 14:249–56 [Google Scholar]
  111. Hartman ZC, Wei J, Glass OK, Guo H, Lei G. 111.  et al. 2011. Increasing vaccine potency through exosome antigen targeting. Vaccine 29:9361–67 [Google Scholar]
  112. Zeelenberg IS, Ostrowski M, Krumeich S, Bobrie A, Jancic C. 112.  et al. 2008. Targeting tumor antigens to secreted membrane vesicles in vivo induces efficient antitumor immune responses. Cancer Res. 68:1228–35 [Google Scholar]
  113. Lai CP, Mardini O, Ericsson M, Prabhakar S, Maguire CA. 113.  et al. 2014. Dynamic biodistribution of extracellular vesicles in vivo using a multimodal imaging reporter. ACS Nano 8:483–94 [Google Scholar]
  114. Maguire CA, Balaj L, Sivaraman S, Crommentuijn M, Ericsson M. 114.  et al. 2012. Microvesicle-associated AAV vector as a novel gene delivery system. Mol. Ther. 20:960–71 [Google Scholar]
  115. Feng Z, Hensley L, McKnight KL, Hu F, Madden V. 115.  et al. 2013. A pathogenic picornavirus acquires an envelope by hijacking cellular membranes. Nature 496:367–71 [Google Scholar]
  116. Lai CP, Tannous BA, Breakefield XO. 116.  2014. Noninvasive in vivo monitoring of extracellular vesicles. Methods Mol. Biol. 1098:249–58 [Google Scholar]
  117. Saunderson SC, Dunn AC, Crocker PR, McLellan AD. 117.  2014. CD169 mediates the capture of exosomes in spleen and lymph node. Blood 123:208–16 [Google Scholar]
  118. Thorne RG, Pronk GJ, Padmanabhan V, Frey WH II. 118.  2004. Delivery of insulin-like growth factor-I to the rat brain and spinal cord along olfactory and trigeminal pathways following intranasal administration. Neuroscience 127:481–96 [Google Scholar]
  119. Nolte-'t Hoen ENM, Buschow SI, Anderton SM, Stoorvogel W, Wauben MHM. 119.  2009. Activated T cells recruit exosomes secreted by dendritic cells via LFA-1. Blood 113:1977–81 [Google Scholar]
  120. Vallhov H, Gutzeit C, Johansson SM, Nagy N, Paul M. 120.  et al. 2011. Exosomes containing glycoprotein 350 released by EBV-transformed B cells selectively target B cells through CD21 and block EBV infection in vitro. J. Immunol. 186:73–82 [Google Scholar]
  121. Ruiss R, Jochum S, Mocikat R, Hammerschmidt W, Zeidler R. 121.  2011. EBV-gp350 confers B-cell tropism to tailored exosomes and is a neo-antigen in normal and malignant B cells—a new option for the treatment of B-CLL. PLOS ONE 6:e25294 [Google Scholar]
  122. Atai NA, Balaj L, van Veen H, Breakefield XO, Jarzyna PA. 122.  et al. 2013. Heparin blocks transfer of extracellular vesicles between donor and recipient cells. J. Neuro-Oncology 115:343–51 [Google Scholar]
  123. Christianson HC, Svensson KJ, van Kuppevelt TH, Li JP, Belting M. 123.  2013. Cancer cell exosomes depend on cell-surface heparan sulfate proteoglycans for their internalization and functional activity. Proc. Natl. Acad. Sci. USA 110:17380–85 [Google Scholar]
  124. Record M, Subra C, Silvente-Poirot S, Poirot M. 124.  2011. Exosomes as intercellular signalosomes and pharmacological effectors. Biochem. Pharmacol. 81:1171–82 [Google Scholar]
  125. Parolini I, Federici C, Raggi C, Lugini L, Palleschi S. 125.  et al. 2009. Microenvironmental pH is a key factor for exosome traffic in tumor cells. J. Biol. Chem. 284:34211–22 [Google Scholar]
  126. Bartlett JS, Wilcher R, Samulski RJ. 126.  2000. Infectious entry pathway of adeno-associated virus and adeno-associated virus vectors. J. Virol. 74:2777–85 [Google Scholar]
  127. Temchura VV, Tenbusch M, Nchinda G, Nabi G, Tippler B. 127.  et al. 2008. Enhancement of immunostimulatory properties of exosomal vaccines by incorporation of fusion-competent G protein of vesicular stomatitis virus. Vaccine 26:3662–72 [Google Scholar]
  128. Shtam TA, Kovalev RA, Varfolomeeva EY, Makarov EM, Kil YV, Filatov MV. 128.  2013. Exosomes are natural carriers of exogenous siRNA to human cells in vitro. Cell Commun. Signal 11:88 [Google Scholar]
  129. Jo W, Jeong D, Kim J, Cho S, Jang SC. 129.  et al. 2014. Microfluidic fabrication of cell-derived nanovesicles as endogenous RNA carriers. Lab Chip 14:1261–69 [Google Scholar]
  130. Qu Y, Ramachandra L, Mohr S, Franchi L, Harding CV. 130.  et al. 2009. P2X7 receptor-stimulated secretion of MHC class II-containing exosomes requires the ASC/NLRP3 inflammasome but is independent of caspase-1. J. Immunol. 182:5052–62 [Google Scholar]
  131. Constantinescu P, Wang B, Kovacevic K, Jalilian I, Bosman GJCGM. 131.  et al. 2010. P2X7 receptor activation induces cell death and microparticle release in murine erythroleukemia cells. Biochim. Biophys. Acta 1798:1797–804 [Google Scholar]
  132. Aharon A, Tamari T, Brenner B. 132.  2008. Monocyte-derived microparticles and exosomes induce procoagulant and apoptotic effects on endothelial cells. Thromb. Haemost. 100:878–85 [Google Scholar]
  133. van der Pol E, Böing AN, Harrison P, Sturk A, Nieuwland R. 133.  2012. Classification, functions, and clinical relevance of extracellular vesicles. Pharmacol. Rev. 64:676–705 [Google Scholar]
  134. György B, Pálóczi K, Kovács A, Barabás E, Bekő G. 134.  et al. 2014. Improved circulating microparticle analysis in acid-citrate dextrose (ACD) anticoagulant tube. Thromb. Res. 133:285–92 [Google Scholar]
  135. Kim SH, Lechman ER, Bianco N, Menon R, Keravala A. 135.  et al. 2005. Exosomes derived from IL-10-treated dendritic cells can suppress inflammation and collagen-induced arthritis. J. Immunol. 174:6440–48 [Google Scholar]
  136. Shavnin SA, Pedroso de Lima MC, Fedor J, Wood P, Bentz J, Düzgüneş N. 136.  1988. Cholesterol affects divalent cation-induced fusion and isothermal phase transitions of phospholipid membranes. Biochim. Biophys. Acta 946:405–16 [Google Scholar]
  137. van Lummel M, van Blitterswijk WJ, Vink SR, Veldman RJ, van der Valk MA. 137.  et al. 2011. Enriching lipid nanovesicles with short-chain glucosylceramide improves doxorubicin delivery and efficacy in solid tumors. FASEB J. 25:280–89 [Google Scholar]
  138. Yotsumoto S, Kakiuchi T, Aramaki Y. 138.  2007. Enhancement of IFN-γ production for Th1-cell therapy using negatively charged liposomes containing phosphatidylserine. Vaccine 25:5256–62 [Google Scholar]
  139. Chen X, Doffek K, Sugg SL, Shilyansky J. 139.  2004. Phosphatidylserine regulates the maturation of human dendritic cells. J. Immunol. 173:2985–94 [Google Scholar]
  140. Deng ZB, Zhuang X, Ju S, Xiang X, Mu J. 140.  et al. 2013. Exosome-like nanoparticles from intestinal mucosal cells carry prostaglandin E2 and suppress activation of liver NKT cells. J. Immunol. 190:3579–89 [Google Scholar]
  141. De La Peña H, Madrigal JA, Rusakiewicz S, Bencsik M, Cave GWV. 141.  et al. 2009. Artificial exosomes as tools for basic and clinical immunology. J. Immunol. Methods 344:121–32 [Google Scholar]
  142. Crescitelli R, Lässer C, Szabó TG, Kittel A, Eldh M. 142.  et al. 2013. Distinct RNA profiles in subpopulations of extracellular vesicles: apoptotic bodies, microvesicles and exosomes. J. Extracell. Vesicles 2:20677 [Google Scholar]
  143. Hwang KJ, Padki MM, Chow DD, Essien HE, Lai JY, Beaumier PL. 143.  1987. Uptake of small liposomes by non-reticuloendothelial tissues. Biochim. Biophys. Acta 901:88–96 [Google Scholar]
  144. Mignot G, Roux S, Thery C, Ségura E, Zitvogel L. 144.  2006. Prospects for exosomes in immunotherapy of cancer. J. Cell Mol. Med. 10:376–88 [Google Scholar]
  145. Escudier B, Dorval T, Chaput N, Andre F, Caby MP. 145.  et al. 2005. 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 [Google Scholar]
  146. Morse MA, Garst J, Osada T, Khan S, Hobeika A. 146.  et al. 2005. A phase I study of dexosome immunotherapy in patients with advanced non-small cell lung cancer. J. Transl. Med. 3:9 [Google Scholar]
  147. Dai S, Wei D, Wu Z, Zhou X, Wei X. 147.  et al. 2008. Phase I clinical trial of autologous ascites-derived exosomes combined with GM-CSF for colorectal cancer. Mol. Ther. 16:782–90 [Google Scholar]
  148. Nienhuis AW. 148.  2013. Development of gene therapy for blood disorders: an update. Blood 122:1556–64 [Google Scholar]
  149. Miller JL, Petteway SR Jr, Lee DC. 149.  2001. Ensuring the pathogen safety of intravenous immunoglobulin and other human plasma-derived therapeutic proteins. J. Allergy Clin. Immunol. 108:S91–94 [Google Scholar]
  150. Farshid M, Taffs RE, Scott D, Asher DM, Brorson K. 150.  2005. The clearance of viruses and transmissible spongiform encephalopathy agents from biologicals. Curr. Opin. Biotechnol. 16:561–67 [Google Scholar]
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