Pharmaceutical Research

, Volume 34, Issue 5, pp 1053–1066 | Cite as

Achieving the Promise of Therapeutic Extracellular Vesicles: The Devil is in Details of Therapeutic Loading

  • Dhruvitkumar S. Sutaria
  • Mohamed Badawi
  • Mitch A. Phelps
  • Thomas D. SchmittgenEmail author
Expert Review


Extracellular vesicles (EVs) represent a class of cell secreted organelles which naturally contain biomolecular cargo such as miRNA, mRNA and proteins. EVs mediate intercellular communication, enabling the transfer of functional nucleic acids from the cell of origin to the recipient cells. In addition, EVs make an attractive delivery vehicle for therapeutics owing to their increased stability in circulation, biocompatibility, low immunogenicity and toxicity profiles. EVs can also be engineered to display targeting moieties on their surfaces which enables targeting to desired tissues, organs or cells. While much has been learned on the role of EVs as cell communicators, the field of therapeutic EV application is currently under development. Critical to the future success of EV delivery system is the description of methods by which therapeutics can be successfully and efficiently loaded within the EVs. Two methods of loading of EVs with therapeutic cargo exist, endogenous and exogenous loading. We have therefore focused this review on describing the various published approaches for loading EVs with therapeutics.


drug loading EV therapeutics exosomes extracellular vesicles microvesicles 



Adeno-associated virus


Central nervous system


Dendritic cells


Extracellular vesicle


Heterogeneous nuclear riboprotein A2B1


Huntingtin gene


Induced pluripotent stem cells


Mesenchymal stem cells


Multivesicular body


Outer membrane vesicles


Targeted and modular EV loading



This work was supported by the NIH UH2-UH3 award (1UH2TR000914-01) to T.D.S and M.A.P.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.


  1. 1.
    Pan BT, Johnstone RM. Fate of the transferrin receptor during maturation of sheep reticulocytes in vitro: selective externalization of the receptor. Cell. 1983;33(3):967–78.Google Scholar
  2. 2.
    Valadi H, Ekstrom K, Bossios A, Sjostrand M, Lee JJ, Lotvall JO. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol. 2007;9(6):654–9.Google Scholar
  3. 3.
    Kalra H, Simpson RJ, Ji H, Aikawa E, Altevogt P, Askenase P, et al. Vesiclepedia: a compendium for extracellular vesicles with continuous community annotation. PLoS Biol. 2012;10(12):e1001450.PubMedPubMedCentralGoogle Scholar
  4. 4.
    Hunter MP, Ismail N, Zhang X, Aguda BD, Lee EJ, Yu L, et al. Detection of microRNA expression in human peripheral blood microvesicles. PLoS ONE. 2008;3(11):e3694.PubMedPubMedCentralGoogle Scholar
  5. 5.
    Kogure T, Yan IK, Lin WL, Patel T. Extracellular vesicle-mediated transfer of a novel long noncoding RNA TUC339: a mechanism of intercellular signaling in human hepatocellular cancer. Genes Cancer. 2013;4(7-8):261–72.PubMedPubMedCentralGoogle Scholar
  6. 6.
    Gezer U, Ozgur E, Cetinkaya M, Isin M, Dalay N. Long non-coding RNAs with low expression levels in cells are enriched in secreted exosomes. Cell Biol Int. 2014;38(9):1076–9.PubMedGoogle Scholar
  7. 7.
    Johnstone RM, Adam M, Hammond JR, Orr L, Turbide C. Vesicle formation during reticulocyte maturation. association of plasma membrane activities with released vesicles (exosomes). J Biol Chem. 1987;262(19):9412–20.PubMedGoogle Scholar
  8. 8.
    Jin Y, Chen K, Wang Z, Wang Y, Liu J, Lin L, et al. DNA in serum extracellular vesicles is stable under different storage conditions. BMC Cancer. 2016;16(1):753.PubMedPubMedCentralGoogle Scholar
  9. 9.
    Cai J, Han Y, Ren H, Chen C, He D, Zhou L, et al. Extracellular vesicle-mediated transfer of donor genomic DNA to recipient cells is a novel mechanism for genetic influence between cells. J Mol Cell Biol. 2013;5(4):227–38.PubMedPubMedCentralGoogle Scholar
  10. 10.
    Nowak R. Mining treasures from ‘junk DNA’. Science. 1994;263(5147):608–10.PubMedGoogle Scholar
  11. 11.
    Jiang L, Shen Y, Guo D, Yang D, Liu J, Fei X, et al. EpCAM-dependent extracellular vesicles from intestinal epithelial cells maintain intestinal tract immune balance. Nat Commun. 2016;7:13045.PubMedPubMedCentralGoogle Scholar
  12. 12.
    Ridder K, Sevko A, Heide J, Dams M, Rupp AK, Macas J, et al. Extracellular vesicle-mediated transfer of functional RNA in the tumor microenvironment. Oncoimmunology. 2015;4(6):e1008371.PubMedPubMedCentralGoogle Scholar
  13. 13.
    Giricz Z, Varga ZV, Baranyai T, Sipos P, Pálóczi K, Kittel Á, et al. Cardioprotection by remote ischemic preconditioning of the rat heart is mediated by extracellular vesicles. J Mol Cell Cardiol. 2014;68:75–8.PubMedGoogle Scholar
  14. 14.
    Zhang X, Abels ER, Redzic JS, Margulis J, Finkbeiner S, Breakefield XO. Potential transfer of polyglutamine and CAG-repeat RNA in extracellular vesicles in huntington’s disease: background and evaluation in cell culture. Cell Mol Neurobiol. 2016;36(3):459–70.PubMedPubMedCentralGoogle Scholar
  15. 15.
    Batrakova EV, Kim MS. Using exosomes, naturally-equipped nanocarriers, for drug delivery. J Contrl Rel. 2015.Google Scholar
  16. 16.
    Ingato D, Lee JU, Sim SJ, Kwon YJ. Good things come in small packages: overcoming challenges to harness extracellular vesicles for therapeutic delivery. J Control Release. 2016;241:174–85.PubMedGoogle Scholar
  17. 17.
    Marcus ME, Leonard JN. FedExosomes: engineering therapeutic biological nanoparticles that truly deliver. Pharmaceuticals (Basel). 2013;6(5):659–80.Google Scholar
  18. 18.
    Stremersch S, De Smedt SC, Raemdonck K. Therapeutic and diagnostic applications of extracellular vesicles. J Control Release. 2016.Google Scholar
  19. 19.
    Lotvall J, Hill AF, Hochberg F, Buzas EI, Di Vizio D, Gardiner C. 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;3:26913.PubMedGoogle Scholar
  20. 20.
    Witwer KW, Buzas EI, Bemis LT, Bora A, Lasser C, Lotvall J, et al. Standardization of sample collection, isolation and analysis methods in extracellular vesicle research. J Extracell Vesicles. 2013;2.Google Scholar
  21. 21.
    Heijnen HF, Schiel AE, Fijnheer R, Geuze HJ, Sixma JJ. Activated platelets release two types of membrane vesicles: microvesicles by surface shedding and exosomes derived from exocytosis of multivesicular bodies and alpha-granules. Blood. 1999;94(11):3791–9.PubMedGoogle Scholar
  22. 22.
    Trajkovic K, Hsu C, Chiantia S, Rajendran L, Wenzel D, Wieland F, et al. Ceramide triggers budding of exosome vesicles into multivesicular endosomes. Science. 2008;319(5867):1244–7.PubMedGoogle Scholar
  23. 23.
    Harding C, Heuser J, Stahl P. Receptor-mediated endocytosis of transferrin and recycling of the transferrin receptor in rat reticulocytes. J Cell Biol. 1983;97(2):329–39.PubMedGoogle Scholar
  24. 24.
    Stoorvogel W, Strous GJ, Geuze HJ, Oorschot V, Schwartz AL. Late endosomes derive from early endosomes by maturation. Cell. 1991;65(3):417–27.PubMedGoogle Scholar
  25. 25.
    Savina A, Furlan M, Vidal M, Colombo MI. Exosome release is regulated by a calcium-dependent mechanism in K562 cells. J Biol Chem. 2003;278(22):20083–90.PubMedGoogle Scholar
  26. 26.
    Gruenberg J, Maxfield FR. Membrane transport in the endocytic pathway. Curr Opin Cell Biol. 1995;7(4):552–63.PubMedGoogle Scholar
  27. 27.
    Booth AM, Fang Y, Fallon JK, Yang JM, Hildreth JE, Gould SJ. Exosomes and HIV Gag bud from endosome-like domains of the T cell plasma membrane. J Cell Biol. 2006;172(6):923–35.PubMedPubMedCentralGoogle Scholar
  28. 28.
    Al-Nedawi K, Meehan B, Rak J. Microvesicles: messengers and mediators of tumor progression. Cell Cycle. 2009;8(13):2014–8.PubMedGoogle Scholar
  29. 29.
    Mavroudis D, Kouroussis C, Kakolyris S, Agelaki S, Kalbakis K, Androulakis N, et al. Phase I study of paclitaxel (taxol) and pegylated liposomal doxorubicin (caelyx) administered every 2 weeks in patients with advanced solid tumors. Oncology. 2002;62(3):216–22.PubMedGoogle Scholar
  30. 30.
    Marshall E. Gene therapy death prompts review of adenovirus vector. Science. 1999;286(5448):2244–5.PubMedGoogle Scholar
  31. 31.
    Munyendo WL, Lv H, Benza-Ingoula H, Baraza LD, Zhou J. Cell penetrating peptides in the delivery of biopharmaceuticals. Biomolecules. 2012;2(2):187–202.PubMedPubMedCentralGoogle Scholar
  32. 32.
    Lowenstein PR, Mandel RJ, Xiong WD, Kroeger K, Castro MG. Immune responses to adenovirus and adeno-associated vectors used for gene therapy of brain diseases: the role of immunological synapses in understanding the cell biology of neuroimmune interactions. Curr Gene Ther. 2007;7(5):347–60.PubMedPubMedCentralGoogle Scholar
  33. 33.
    Daniel R, Smith JA. Integration site selection by retroviral vectors: molecular mechanism and clinical consequences. Hum Gene Ther. 2008;19(6):557–68.PubMedPubMedCentralGoogle Scholar
  34. 34.
    Kanasty R, Dorkin JR, Vegas A, Anderson D. Delivery materials for siRNA therapeutics. Nat Mater. 2013;12(11):967–77.PubMedGoogle Scholar
  35. 35.
    Zhang JS, Liu F, Huang L. Implications of pharmacokinetic behavior of lipoplex for its inflammatory toxicity. Adv Drug Deliv Rev. 2005;57(5):689–98.PubMedGoogle Scholar
  36. 36.
    Ishida T, Ichihara M, Wang X, Yamamoto K, Kimura J, Majima E, et al. Injection of PEGylated liposomes in rats elicits PEG-specific IgM, which is responsible for rapid elimination of a second dose of PEGylated liposomes. J Control Release. 2006;112(1):15–25.PubMedGoogle Scholar
  37. 37.
    Johnsen KB, Gudbergsson JM, Skov MN, Pilgaard L, Moos T, Duroux M. A comprehensive overview of exosomes as drug delivery vehicles - endogenous nanocarriers for targeted cancer therapy. Biochim Biophys Acta. 2014;1846(1):75–87.PubMedGoogle Scholar
  38. 38.
    Pegtel DM, Cosmopoulos K, Thorley-Lawson DA, van Eijndhoven MA, Hopmans ES, Lindenberg JL, et al. Functional delivery of viral miRNAs via exosomes. Proc Natl Acad Sci U S A. 2010;107(14):6328–33.PubMedPubMedCentralGoogle Scholar
  39. 39.
    Ratajczak J, Miekus K, Kucia M, Zhang J, Reca R, Dvorak P, et al. Embryonic stem cell-derived microvesicles reprogram hematopoietic progenitors: evidence for horizontal transfer of mRNA and protein delivery. Leukemia. 2006;20(5):847–56.PubMedGoogle Scholar
  40. 40.
    Didiot MC, Hall LM, Coles AH, Haraszti RA, Godinho BM, Chase K, et al. Exosome-mediated delivery of hydrophobically modified siRNA for Huntingtin mRNA silencing. Molec Therap : J Am Soc Gene Therap. 2016.Google Scholar
  41. 41.
    Mathivanan S, Fahner CJ, Reid GE, Simpson RJ. ExoCarta 2012: database of exosomal proteins, RNA and lipids. Nucleic Acids Res. 2012;40(Database issue):D1241–4.PubMedGoogle Scholar
  42. 42.
    An Q, van Bel AJ, Hückelhoven R. Do plant cells secrete exosomes derived from multivesicular bodies? Plant Signal Behav. 2007;2(1):4–7.PubMedPubMedCentralGoogle Scholar
  43. 43.
    Schorey JS, Cheng Y, Singh PP, Smith VL. Exosomes and other extracellular vesicles in host-pathogen interactions. EMBO Rep. 2015;16(1):24–43.PubMedGoogle Scholar
  44. 44.
    Kim JH, Lee J, Park J, Gho YS. Gram-negative and Gram-positive bacterial extracellular vesicles. Semin Cell Dev Biol. 2015;40:97–104.PubMedGoogle Scholar
  45. 45.
    Ju S, Mu J, Dokland T, Zhuang X, Wang Q, Jiang H, et al. Grape exosome-like nanoparticles induce intestinal stem cells and protect mice from DSS-induced colitis. Mol Ther. 2013;21(7):1345–57.PubMedPubMedCentralGoogle Scholar
  46. 46.
    Munagala R, Aqil F, Jeyabalan J, Gupta RC. Bovine milk-derived exosomes for drug delivery. Cancer Lett. 2016;371(1):48–61.PubMedGoogle Scholar
  47. 47.
    García-Castro J, Trigueros C, Madrenas J, Pérez-Simón JA, Rodriguez R, Menendez P. Mesenchymal stem cells and their use as cell replacement therapy and disease modelling tool. J Cell Mol Med. 2008;12(6B):2552–65.PubMedPubMedCentralGoogle Scholar
  48. 48.
    Lai RC, Arslan F, Lee MM, Sze NS, Choo A, Chen TS, et al. Exosome secreted by MSC reduces myocardial ischemia/reperfusion injury. Stem Cell Res. 2010;4(3):214–22.PubMedGoogle Scholar
  49. 49.
    Lai RC, Tan SS, Teh BJ, Sze SK, Arslan F, de Kleijn DP, et al. Proteolytic potential of the MSC exosome proteome: implications for an exosome-mediated delivery of therapeutic proteasome. Int J Proteomics. 2012;2012:971907.PubMedPubMedCentralGoogle Scholar
  50. 50.
    Hu GW, Li Q, Niu X, Hu B, Liu J, Zhou SM. Exosomes secreted by human-induced pluripotent stem cell-derived mesenchymal stem cells attenuate limb ischemia by promoting angiogenesis in mice. Stem Cell Res Ther. 2015;6:10.PubMedPubMedCentralGoogle Scholar
  51. 51.
    Qi X, Zhang J, Yuan H, Xu Z, Li Q, Niu X, et al. Exosomes secreted by human-induced pluripotent stem cell-derived mesenchymal stem cells repair critical-sized bone defects through enhanced angiogenesis and osteogenesis in osteoporotic rats. Int J Biol Sci. 2016;12(7):836–49.PubMedPubMedCentralGoogle Scholar
  52. 52.
    Thomas P, Smart TG. HEK293 cell line: a vehicle for the expression of recombinant proteins. J Pharmacol Toxicol Methods. 2005;51(3):187–200.PubMedGoogle Scholar
  53. 53.
    Ohno S, Takanashi M, Sudo K, Ueda S, Ishikawa A, Matsuyama N, et al. Systemically injected exosomes targeted to EGFR deliver antitumor microRNA to breast cancer cells. Molec Therap : J Am Soc Gene Therap. 2013;21(1):185–91.Google Scholar
  54. 54.
    Mizrak A, Bolukbasi MF, Ozdener GB, Brenner GJ, Madlener S, Erkan EP, et al. Genetically engineered microvesicles carrying suicide mRNA/protein inhibit schwannoma tumor growth. Mol Ther. 2013;21(1):101–8.PubMedGoogle Scholar
  55. 55.
    Li J, Chen X, Yi J, Liu Y, Li D, Wang J, et al. Identification and characterization of 293T cell-derived exosomes by profiling the protein, mRNA and MicroRNA components. PLoS One. 2016;11(9):e0163043.PubMedPubMedCentralGoogle Scholar
  56. 56.
    Kulp A, Kuehn MJ. Biological functions and biogenesis of secreted bacterial outer membrane vesicles. Annu Rev Microbiol. 2010;64:163–84.PubMedPubMedCentralGoogle Scholar
  57. 57.
    Schwechheimer C, Kuehn MJ. Outer-membrane vesicles from Gram-negative bacteria: biogenesis and functions. Nat Rev Microbiol. 2015;13(10):605–19.PubMedPubMedCentralGoogle Scholar
  58. 58.
    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. 2007;9(14-15):1614–22.PubMedGoogle Scholar
  59. 59.
    Beauvillain C, Juste MO, Dion S, Pierre J, Dimier-Poisson I. Exosomes are an effective vaccine against congenital toxoplasmosis in mice. Vaccine. 2009;27(11):1750–7.PubMedGoogle Scholar
  60. 60.
    Zhu L, Song H, Zhang X, Xia X, Sun H. Inhibition of porcine reproductive and respiratory syndrome virus infection by recombinant adenovirus- and/or exosome-delivered the artificial microRNAs targeting sialoadhesin and CD163 receptors. Virol J. 2014;11:225.PubMedPubMedCentralGoogle Scholar
  61. 61.
    Kim OY, Hong BS, Park KS, Yoon YJ, Choi SJ, Lee WH, et al. Immunization with Escherichia coli outer membrane vesicles protects bacteria-induced lethality via Th1 and Th17 cell responses. J Immunol. 2013;190(8):4092–102.PubMedGoogle Scholar
  62. 62.
    Alaniz RC, Deatherage BL, Lara JC, Cookson BT. Membrane vesicles are immunogenic facsimiles of Salmonella typhimurium that potently activate dendritic cells, prime B and T cell responses, and stimulate protective immunity in vivo. J Immunol. 2007;179(11):7692–701.PubMedGoogle Scholar
  63. 63.
    Tian Y, Li S, Song J, Ji T, Zhu M, Anderson GJ, et al. A doxorubicin delivery platform using engineered natural membrane vesicle exosomes for targeted tumor therapy. Biomaterials. 2014;35(7):2383–90.PubMedGoogle Scholar
  64. 64.
    Lamichhane TN, Raiker RS, Jay SM. Exogenous DNA loading into extracellular vesicles via electroporation is size-dependent and enables limited gene delivery. Mol Pharm. 2015;12(10):3650–7.PubMedPubMedCentralGoogle Scholar
  65. 65.
    Shtam TA, Kovalev RA, Varfolomeeva EY, Makarov EM, Kil YV, Filatov MV. Exosomes are natural carriers of exogenous siRNA to human cells in vitro. Cell Commun Signal. 2013;11:88.PubMedPubMedCentralGoogle Scholar
  66. 66.
    Alvarez-Erviti L, Seow Y, Yin H, Betts C, Lakhal S, Wood MJ. Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nat Biotechnol. 2011;29(4):341–5.Google Scholar
  67. 67.
    Banizs AB, Huang T, Dryden K, Berr SS, Stone JR, Nakamoto RK, et al. In vitro evaluation of endothelial exosomes as carriers for small interfering ribonucleic acid delivery. Int J Nanomedicine. 2014;9:4223–30.PubMedPubMedCentralGoogle Scholar
  68. 68.
    Wahlgren J, De L, Karlson T, Brisslert M, Vaziri Sani F, Telemo E, et al. Plasma exosomes can deliver exogenous short interfering RNA to monocytes and lymphocytes. Nucleic Acids Res. 2012;40(17):e130.PubMedPubMedCentralGoogle Scholar
  69. 69.
    Weaver JC. Electroporation: a general phenomenon for manipulating cells and tissues. J Cell Biochem. 1993;51(4):426–35.PubMedGoogle Scholar
  70. 70.
    Hood JL, Scott MJ, Wickline SA. Maximizing exosome colloidal stability following electroporation. Anal Biochem. 2014;448:41–9.PubMedGoogle Scholar
  71. 71.
    Johnsen KB, Gudbergsson JM, Skov MN, Christiansen G, Gurevich L, Moos T, et al. Evaluation of electroporation-induced adverse effects on adipose-derived stem cell exosomes. Cytotechnology. 2016.Google Scholar
  72. 72.
    Kooijmans SA, Stremersch S, Braeckmans K, de Smedt SC, Hendrix A, Wood MJ, et al. Electroporation-induced siRNA precipitation obscures the efficiency of siRNA loading into extracellular vesicles. J Control Release. 2013;172(1):229–38.PubMedGoogle Scholar
  73. 73.
    Stoicheva NG, Hui SW. Electrofusion of cell-size liposomes. Biochim Biophys Acta. 1994;1195(1):31–8.PubMedGoogle Scholar
  74. 74.
    Jamur MC, Oliver C. Permeabilization of cell membranes. Methods Mol Biol. 2010;588:63–6.PubMedGoogle Scholar
  75. 75.
    Jacob MC, Favre M, Bensa JC. Membrane cell permeabilization with saponin and multiparametric analysis by flow cytometry. Cytometry. 1991;12(6):550–8.PubMedGoogle Scholar
  76. 76.
    Haney MJ, Klyachko NL, Zhao Y, Gupta R, Plotnikova EG, He Z, et al. Exosomes as drug delivery vehicles for Parkinson’s disease therapy. J Control Release. 2015;207:18–30.PubMedPubMedCentralGoogle Scholar
  77. 77.
    Ambani LM, Van Woert MH, Murphy S. Brain peroxidase and catalase in Parkinson disease. Arch Neurol. 1975;32(2):114–8.PubMedGoogle Scholar
  78. 78.
    Abraham S, Soundararajan CC, Vivekanandhan S, Behari M. Erythrocyte antioxidant enzymes in Parkinson’s disease. Indian J Med Res. 2005;121(2):111–5.PubMedGoogle Scholar
  79. 79.
    Fuhrmann G, Serio A, Mazo M, Nair R, Stevens MM. Active loading into extracellular vesicles significantly improves the cellular uptake and photodynamic effect of porphyrins. J Control Release. 2015;205:35–44.PubMedGoogle Scholar
  80. 80.
    Tan S, Wu T, Zhang D, Zhang Z. Cell or cell membrane-based drug delivery systems. Theranostics. 2015;5(8):863–81.PubMedPubMedCentralGoogle Scholar
  81. 81.
    Stremersch S, Vandenbroucke RE, Van Wonterghem E, Hendrix A, De Smedt SC, Raemdonck K. Comparing exosome-like vesicles with liposomes for the functional cellular delivery of small RNAs. J Control Release. 2016;232:51–61.PubMedGoogle Scholar
  82. 82.
    Immordino ML, Dosio F, Cattel L. Stealth liposomes: review of the basic science, rationale, and clinical applications, existing and potential. Int J Nanomedicine. 2006;1(3):297–315.PubMedPubMedCentralGoogle Scholar
  83. 83.
    Sun D, Zhuang X, Xiang X, Liu Y, Zhang S, Liu C, et al. A novel nanoparticle drug delivery system: the anti-inflammatory activity of curcumin is enhanced when encapsulated in exosomes. Molec Therap : J Am Soc Gene Therap. 2010;18(9):1606–14.Google Scholar
  84. 84.
    Zhuang X, Xiang X, Grizzle W, Sun D, Zhang S, Axtell RC, et al. Treatment of brain inflammatory diseases by delivering exosome encapsulated anti-inflammatory drugs from the nasal region to the brain. Molec Therap : J Am Soc Gene Therap. 2011;19(10):1769–79.Google Scholar
  85. 85.
    Yang T, Martin P, Fogarty B, Brown A, Schurman K, Phipps R, et al. Exosome delivered anticancer drugs across the blood-brain barrier for brain cancer therapy in Danio rerio. Pharm Res. 2015;32(6):2003–14.PubMedPubMedCentralGoogle Scholar
  86. 86.
    Pascucci L, Coccè V, Bonomi A, Ami D, Ceccarelli P, Ciusani E, et al. Paclitaxel is incorporated by mesenchymal stromal cells and released in exosomes that inhibit in vitro tumor growth: a new approach for drug delivery. J Control Release. 2014;192:262–70.PubMedGoogle Scholar
  87. 87.
    Rani S, Ryan AE, Griffin MD, Ritter T. Mesenchymal stem cell-derived extracellular vesicles: toward cell-free therapeutic applications. Mol Ther. 2015;23(5):812–23.PubMedPubMedCentralGoogle Scholar
  88. 88.
    Zomer A, Maynard C, Verweij FJ, Kamermans A, Schäfer R, Beerling E, et al. In Vivo imaging reveals extracellular vesicle-mediated phenocopying of metastatic behavior. Cell. 2015;161(5):1046–57.PubMedPubMedCentralGoogle Scholar
  89. 89.
    Akao Y, Iio A, Itoh T, Noguchi S, Itoh Y, Ohtsuki Y, et al. Microvesicle-mediated RNA molecule delivery system using monocytes/macrophages. Mol Ther. 2011;19(2):395–9.PubMedGoogle Scholar
  90. 90.
    Kosaka N, Iguchi H, Yoshioka Y, Takeshita F, Matsuki Y, Ochiya T. Secretory mechanisms and intercellular transfer of microRNAs in living cells. J Biol Chem. 2010;285(23):17442–52.PubMedPubMedCentralGoogle Scholar
  91. 91.
    Su MJ, Aldawsari H, Amiji M. Pancreatic cancer cell exosome-mediated macrophage reprogramming and the role of MicroRNAs 155 and 125b2 transfection using nanoparticle delivery systems. Sci Rep. 2016;6:30110.PubMedPubMedCentralGoogle Scholar
  92. 92.
    Wang B, Yao K, Huuskes BM, Shen HH, Zhuang J, Godson C, et al. Mesenchymal stem cells deliver exogenous MicroRNA-let7c via exosomes to attenuate renal fibrosis. Mol Ther. 2016;24(7):1290–301.PubMedPubMedCentralGoogle Scholar
  93. 93.
    Lou G, Song X, Yang F, Wu S, Wang J, Chen Z, et al. Exosomes derived from miR-122-modified adipose tissue-derived MSCs increase chemosensitivity of hepatocellular carcinoma. J Hematol Oncol. 2015;8:122.PubMedPubMedCentralGoogle Scholar
  94. 94.
    Munoz JL, Bliss SA, Greco SJ, Ramkissoon SH, Ligon KL, Rameshwar P. Delivery of functional anti-miR-9 by mesenchymal stem cell-derived exosomes to glioblastoma multiforme cells conferred chemosensitivity. Mol Ther Nucleic Acids. 2013;2:e126.PubMedPubMedCentralGoogle Scholar
  95. 95.
    Shimbo K, Miyaki S, Ishitobi H, Kato Y, Kubo T, Shimose S, et al. Exosome-formed synthetic microRNA-143 is transferred to osteosarcoma cells and inhibits their migration. Biochem Biophys Res Commun. 2014;445(2):381–7.PubMedGoogle Scholar
  96. 96.
    Akao Y, Nakagawa Y, Hirata I, Iio A, Itoh T, Kojima K, et al. Role of anti-oncomirs miR-143 and -145 in human colorectal tumors. Cancer Gene Ther. 2010;17(6):398–408.PubMedGoogle Scholar
  97. 97.
    Liu Y, Li D, Liu Z, Zhou Y, Chu D, Li X, et al. Targeted exosome-mediated delivery of opioid receptor Mu siRNA for the treatment of morphine relapse. Sci Rep. 2015;5:17543.PubMedPubMedCentralGoogle Scholar
  98. 98.
    Ohno SI, Takanashi M, Sudo K, Ueda S, Ishikawa A, Matsuyama N, et al. Systemically injected exosomes targeted to EGFR deliver antitumor MicroRNA to breast cancer cells. Molec Therap : J Am Soc Gene Therap. 2012.Google Scholar
  99. 99.
    Hung ME, Leonard JN. A platform for actively loading cargo RNA to elucidate limiting steps in EV-mediated delivery. J Extracell Vesicles. 2016;5:31027.PubMedGoogle Scholar
  100. 100.
    Jang SC, Kim OY, Yoon CM, Choi DS, Roh TY, Park J, et al. Bioinspired exosome-mimetic nanovesicles for targeted delivery of chemotherapeutics to malignant tumors. ACS Nano. 2013;7(9):7698–710.PubMedGoogle Scholar
  101. 101.
    Jang SC, Gho YS. Could bioengineered exosome-mimetic nanovesicles be an efficient strategy for the delivery of chemotherapeutics? Nanomedicine (Lond). 2014;9(2):177–80.Google Scholar
  102. 102.
    Lunavat TR, Jang SC, Nilsson L, Park HT, Repiska G, Lässer C, et al. RNAi delivery by exosome-mimetic nanovesicles - implications for targeting c-Myc in cancer. Biomaterials. 2016;102:231–8.PubMedGoogle Scholar
  103. 103.
    Muramatsu S, Fujimoto K, Kato S, Mizukami H, Asari S, Ikeguchi K, et al. A phase I study of aromatic L-amino acid decarboxylase gene therapy for Parkinson’s disease. Mol Ther. 2010;18(9):1731–5.PubMedPubMedCentralGoogle Scholar
  104. 104.
    Bennett J, Ashtari M, Wellman J, Marshall KA, Cyckowski LL, Chung DC. AAV2 gene therapy readministration in three adults with congenital blindness. Sci Transl Med. 2012;4(120):120ra15.PubMedPubMedCentralGoogle Scholar
  105. 105.
    Jiang H, Couto LB, Patarroyo-White S, Liu T, Nagy D, Vargas JA, et al. Effects of transient immunosuppression on adenoassociated, virus-mediated, liver-directed gene transfer in rhesus macaques and implications for human gene therapy. Blood. 2006;108(10):3321–8.PubMedPubMedCentralGoogle Scholar
  106. 106.
    Maguire CA, Balaj L, Sivaraman S, Crommentuijn MH, Ericsson M, Mincheva-Nilsson L, et al. Microvesicle-associated AAV vector as a novel gene delivery system. Mol Ther. 2012;20(5):960–71.PubMedPubMedCentralGoogle Scholar
  107. 107.
    György B, Fitzpatrick Z, Crommentuijn MH, Mu D, Maguire CA. Naturally enveloped AAV vectors for shielding neutralizing antibodies and robust gene delivery in vivo. Biomaterials. 2014;35(26):7598–609.PubMedPubMedCentralGoogle Scholar
  108. 108.
    Hudry E, Martin C, Gandhi S, György B, Scheffer DI, Mu D, et al. Exosome-associated AAV vector as a robust and convenient neuroscience tool. Gene Ther. 2016;23(4):380–92.PubMedPubMedCentralGoogle Scholar
  109. 109.
    Villarroya-Beltri C, Gutierrez-Vazquez C, Sanchez-Cabo F, Perez-Hernandez D, Vazquez J, Martin-Cofreces N, et al. Sumoylated hnRNPA2B1 controls the sorting of miRNAs into exosomes through binding to specific motifs. Nat Commun. 2013;4:2980.PubMedPubMedCentralGoogle Scholar
  110. 110.
    Munro TP, Magee RJ, Kidd GJ, Carson JH, Barbarese E, Smith LM, et al. Mutational analysis of a heterogeneous nuclear ribonucleoprotein A2 response element for RNA trafficking. J Biol Chem. 1999;274(48):34389–95.PubMedPubMedCentralGoogle Scholar
  111. 111.
    Lan X, Yan J, Ren J, Zhong B, Li J, Li Y, et al. A novel long noncoding RNA Lnc-HC binds hnRNPA2B1 to regulate expressions of Cyp7a1 and Abca1 in hepatocytic cholesterol metabolism. Hepatology. 2016;64(1):58–72.PubMedGoogle Scholar
  112. 112.
    Bolukbasi MF, Mizrak A, Ozdener GB, Madlener S, Ströbel T, Erkan EP. miR-1289 and “Zipcode”-like sequence enrich mRNAs in microvesicles. Mol Ther Nucleic Acids. 2012;1:e10.PubMedPubMedCentralGoogle Scholar
  113. 113.
    Kim MS, Haney MJ, Zhao Y, Mahajan V, Deygen I, Klyachko NL, et al. Development of exosome-encapsulated paclitaxel to overcome MDR in cancer cells. Nanomedicine. 2016;12(3):655–64.PubMedGoogle Scholar
  114. 114.
    Yim N, Ryu SW, Choi K, Lee KR, Lee S, Choi H, et al. Exosome engineering for efficient intracellular delivery of soluble proteins using optically reversible protein-protein interaction module. Nat Commun. 2016;7:12277.PubMedPubMedCentralGoogle Scholar
  115. 115.
    Silva AH, Locatelli C, Filippin-Monteiro FB, Martin P, Liptrott NJ, Zanetti-Ramos BG, et al. Toxicity and inflammatory response in Swiss albino mice after intraperitoneal and oral administration of polyurethane nanoparticles. Toxicol Lett. 2016;246:17–27.PubMedGoogle Scholar
  116. 116.
    Silva AH, Locatelli C, Filippin-Monteiro FB, Zanetti-Ramos BG, Conte A, Creczynski-Pasa TB. Solid lipid nanoparticles induced hematological changes and inflammatory response in mice. Nanotoxicology. 2014;8(2):212–9.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Dhruvitkumar S. Sutaria
    • 1
    • 2
  • Mohamed Badawi
    • 1
  • Mitch A. Phelps
    • 1
  • Thomas D. Schmittgen
    • 2
    Email author
  1. 1.Division of Pharmaceutics and Pharmaceutical Sciences, College of PharmacyThe Ohio State UniversityColumbusUSA
  2. 2.Department of Pharmaceutics, College of PharmacyUniversity of FloridaGainesvilleUSA

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