Metabolic Brain Disease

, Volume 28, Issue 4, pp 551–562 | Cite as

Synthetic nucleic acids delivered by exosomes: a potential therapeutic for generelated metabolic brain diseases

  • Rutao Liu
  • Jing Liu
  • Xiaofei Ji
  • Yang Liu
Review Article


Many brain diseases, including Alzheimer’s disease, are associated with genetic abnormalities. The search for more effective therapeutic approaches involving nucleic acids like interfering RNA, antisense oligonucleotides and mRNA has drawn much attention in the development of alternatives to virus-based gene therapy. Potentially, nucleic acids could not only specifically down-regulate and degrade misfolded proteins, but also relieve protein deficiencies by directing the translation of functional proteins. However, clinical applications have been stalled by the lack of proper delivery systems. Exosomes are nano-scale extracellular vesicles secreted by nearly all somatic cells. Recent work has revealed that exosomes play special roles in intercellular communication via the horizontal transfer of various RNAs among cells. Recently, the use of exosomes for the delivery of therapeutic nucleic acids to targeted cells has been demonstrated to be a practical approach. Here, we briefly review the general properties of exosomes and introduce three therapeutic nucleic acids. Based upon comparison with other delivery methods, exosomes are proposed as an ideal nucleic acid delivery system for metabolic brain disease therapy.


Metabolic brain diseases Nucleic acids Exosomes Drug delivery system 



This work was funded by the Chinese National Natural Science Foundation (No. 81071009, No. 1271412), International S&T Cooperation Project of the Ministry of S&T of China (No. 2010DFR30850), The People’s Livelihood S&T Project, Bureau of S&T of Dalian (No. 2010E11SF008, 2011E12SF030), and the Scientific Research Foundation for Returned Overseas Chinese Scholars, State Education Ministry.


  1. Aguzzi A, O’Connor T (2010) Protein aggregation diseases: pathogenicity and therapeutic perspectives. Nat Rev Drug Discov 9:237–248PubMedGoogle Scholar
  2. Aliotta JM, Pereira M, Johnson KW, de Paz N, Dooner MS et al (2010) Microvesicle entry into marrow cells mediates tissue-specific changes in mRNA by direct delivery of mRNA and induction of transcription. Exp Hematol 38(3):233–245PubMedGoogle Scholar
  3. Alvarez-Erviti L, Seow Y, Yin H, Betts C, Lakhal S, Wood MJ (2011) Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nat Biotechnol 29:341–345PubMedGoogle Scholar
  4. Ambros V (2008) The evolution of our thinking about microRNAs. Nat Med 14:1036–1040PubMedGoogle Scholar
  5. Arslan F, Lai RC, Smeets MB, Akeroyd L, Choo A 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(3):301–312PubMedGoogle Scholar
  6. Baietti MF, Zhang Z, Mortier E, Melchior A, Degeest G, Geeraerts A (2012) Syndecan-syntenin-ALIX-regulates the biogenesis of exosomes. Nat Cell Biol 14(7):677–685PubMedGoogle Scholar
  7. Batagov AO, Kuznetsov VA, Kurochkin IL (2011) Identification of nucleotide patterns enriched in secreted RNAsas putative cis-acting elements targeting them to exosome nano-vesicles. BMC Genom 12(Suppl 3):S18Google Scholar
  8. Boudreau RL, Rodríguez-Lebrón E, Davidson BL (2011) RNAi medicine for the brain: progresses and challenges. Hum Mol Genet 20(R1):R21–R27PubMedGoogle Scholar
  9. Büeler H (2009) Impaired mitochondrial dynamics and function in the pathogenesis of Parkinson’s disease. Exp Neurol 218(2):235–246PubMedGoogle Scholar
  10. Caby MP, Lankar D, Vincendeau-Scherrer C, Raposo G, Bonnerot C (2005) Exosomal like vesicles are present in human blood plasma. Int Immunol 17:879–887PubMedGoogle Scholar
  11. Castellani RJ, Rolston RK, Smith MA (2010) Alzheimer disease. Dis Mon 56(9):484–546PubMedGoogle Scholar
  12. Chen TS, Lai RC, Lee MM, Choo ABH, Lee CN et al (2010) Mesenchymal stem cell secretes microparticles enriched in pre-microRNAs. Nucleic Acids Res 38:215–224PubMedGoogle Scholar
  13. Cocucci E, Racchetti G, Meldolesi J (2009) Shedding microvesicles: artefacts no more. Trends Cell Biol 19:43–51PubMedGoogle Scholar
  14. Collino F, Deregibus MC, Bruno S, Sterpone L, Aghemo G, Viltono L et al (2010) Microvesicles derived from adult human bone marrow and tissue specific mesenchymal stem cells shuttle selected pattern of miRNAs. PLoS One 5(7):e11803PubMedGoogle Scholar
  15. Cortez MA, Bueso-Ramos C, Ferdin J, Lopez-Berestein G, Sood AK, Calin GA (2011) MicroRNAs in body fluids—the mix of hormones and biomarkers. Nat Rev Clin Oncol 8(8):467–477PubMedGoogle Scholar
  16. Corti O, Lesage S, Brice A (2011) What genetics tells US about the causes and mechanisms of Parkinson’s Disease. Physiol Rev 91:1161–1218PubMedGoogle Scholar
  17. Dai S, Wei D, Wu Z et al (2008) Phase I clinical trial of autologous ascites-derived exosomes combined with GM-CSF for colorectal cancer. Mol Ther 16:782–790PubMedGoogle Scholar
  18. Deleavey GF, Damha MJ (2012) Designing chemically modified oligonucleic acid for targeted gene silencing. Chem Biol 19(8):937–954PubMedGoogle Scholar
  19. Devi L, Ohno M (2012) Mitochondrial dysfunction and accumulation of the β-secretase cleaved C-terminal fragment of APP in Alzheimer’s disease transgenic mice. Neurobiol Dis 45(1):417–424PubMedGoogle Scholar
  20. Duchen MR (2012) Mitochondria, calcium-dependent neuronal death and neurodegenerative disease. Pflugers Arch - Eur J Physiol 464:111–121Google Scholar
  21. Eketjäll S, Janson J, Jeppsson F, Svanhagen A, Kolmodin K et al (2013) AZ-4217: a high potency bace inhibitor displaying acute central efficacy in different in vivo models and reduced amyloid deposition in Tg2576 mice. J Neurosci 33(24):10075–10084PubMedGoogle Scholar
  22. Elmore S (2007) Apoptosis: a review of programmed cell death. Toxicol Pathol 35:495–516PubMedGoogle Scholar
  23. Escudier B, Dorval T, Chaput N et al (2005) Vaccination of metastatic melanoma patients with autologous dendritic cell (DC) derived-exosomes: results of thefirst Phase I clinical trial. J Transl Med 3:10PubMedGoogle Scholar
  24. Feng D, Zhao WL, Ye YY, Bai XC, Liu RQ et al (2010) Cellular internalization of exosomes occurs through phagocytosis. Traffic 11(5):675–687PubMedGoogle Scholar
  25. Fonsato V, Collino F, Herrera MB, Cavallari C, Deregibus MC, Cisterna B (2012) Human liver stem cell-derived microvesicles inhibit hepatoma growth in SCID mice by delivering antitumor MicroRNAs. Stem Cells 30(9):1985–1998PubMedGoogle Scholar
  26. Franich NR, Fitzsimons HL, Fong DM, Klugmann M, During MJ, Young D (2008) AAV vector-mediated RNAi of mutant huntingtin expression is neuroprotective in a novel genetic rat model of Huntington’s disease. Mol Ther 16:947–956PubMedGoogle Scholar
  27. Friedman RC, Farh KK, Burge CB, Bartel DP (2009) Most mammalian mRNAs are conserved targets of microRNAs. Genome Res 19:92–105PubMedGoogle Scholar
  28. Galindo MF et al (2010) Mitochondrial biology in Alzheimer’s disease pathogenesis. J Neurochem 14:933–945Google Scholar
  29. Gass J, Prudencio M, Stetler C, Petrucelli L (2012) Progranulin: an emerging target for FTLD therapies. Brainresearch 1462:118–128Google Scholar
  30. Ge R, Tan E, Sharghi-Namini S, Asada HH (2012) Exosomes in cancer microenvironment and beyond: have we overlooked these extracellular messengers? Cancer Microenviron 5(3):323–332PubMedGoogle Scholar
  31. Gonzales PA, Pisitkun T, Hoffert JD, Tchapyjnikov D, Star RA et al (2009) Large-scale proteomics and phosphoproteomics of urinary exosomes. J Am Soc Nephrol 20:363–379PubMedGoogle Scholar
  32. Gravenfors Y, Viklund J, Blid J, Ginman T, Karlström S et al (2012) New aminoimidazoles as β-secretase (BACE-1) inhibitors showing amyloid-β (Aβ) lowering in brain. J Med Chem 55(21):9297–9311PubMedGoogle Scholar
  33. Gross JC, Chaudhary V, Bartscherer K, Boutros M (2012) Active Wnt proteins are secreted on exosomes. Nat Cell Biol 14(10):1036–1045PubMedGoogle Scholar
  34. Gu Y, Li M, Wang T, Liang Y, Zhong Z, Wang X et al (2012) Lactation-related MicroRNA expression profiles of porcine breast milk exosomes. PLOS ONE 7:e43691PubMedGoogle Scholar
  35. Hacein-Bey-Abina S, Hauer J, Lim A et al (2010) Efficacy of gene therapy for X-linked severe combined immunodeficiency. N Engl J Med 363:355–364PubMedGoogle Scholar
  36. Harper SQ, Staber PD, He X, Eliason SL, Martins IH et al (2005) RNA interference improves motor and neuropathological abnormalities in a Huntington’s disease mouse model. Proc Natl Acad Sci U S A 102(16):5820–5825PubMedGoogle Scholar
  37. Heng D, Guo L, Yan S, Sosunov AA et al (2010) Early deficits in synaptic mitochondria in an Alzheimer’s disease mouse model. PNAS 107(43):18670–18675Google Scholar
  38. Herrera MB, Fonsato V, Gatti S, Deregibus MC, Sordi A, Cantarella D (2010) Human liver stem cell-derived microvesicles accelerate hepatic regeneration in hepatectomized rats. J Cell Mol Med 14(6B):1605–1618PubMedGoogle Scholar
  39. Hickey P, Stacy M (2013) AAV2-neurturin (CERE-120) for Parkinson’s disease. Expert Opin Biol Ther 13(1):137–145PubMedGoogle Scholar
  40. Honmou O, Houkin K, Matsunaga T, Niitsu Y, Ishiai S et al (2011) Intravenous administration of auto serum-expanded autologous mesenchymal stem cells in stroke. Brain 134(Pt 6):1790–1807PubMedGoogle Scholar
  41. Houlden H, Singleton AB (2012) The genetics and neuropathology of Parkinson’s disease. Acta Neuropathol 124:325–338PubMedGoogle Scholar
  42. Hu J, Liu J, Corey DR (2010) Allele-selective inhibition of huntingtin expression by switching to an miRNA-like RNAi mechanism. Chem Biol 17:1183–1188PubMedGoogle Scholar
  43. Huotari J, Helenius A (2011) Endosome maturation. The EMBO J 30:3481–3500Google Scholar
  44. Kaiser J (2003) Gene therapy. Seeking the cause of induced leukemias in X-SCID trial. Science 299(5606):495PubMedGoogle Scholar
  45. Kanasty RL, Whitehead KA, Vegas AJ, Anderson DG (2012) Action and reaction: the biological response to siRNA and its delivery vehicles. Mol Ther 20(3):513–524PubMedGoogle Scholar
  46. Katakowski M, Buller B, Zheng X, Lu Y, Rogers T et al (2013) Exosomes from marrow stromal cells expressing miR-146b inhibit glioma growth. Cancer Lett 335(1):201–204PubMedGoogle Scholar
  47. Katsuda T, Tsuchiya R, Kosaka N, Yoshioka Y, Takagaki K et al (2013) Human adipose tissue-derived mesenchymal stem cells secrete functional neprilysin-bound exosomes. Sci Rep 3:1197PubMedGoogle Scholar
  48. Kim HS, Choi DY, Yun SJ, Choi SM, Kang JW et al (2012) Proteomic analysis of microvesicles derived from human mesenchymal stem cells. J Proteome Res 11(2):839–849PubMedGoogle Scholar
  49. Kole R, Krainer AR, Altman S (2012) RNA therapeutics: beyond RNA interference and antisense oligonucleic acid. Nat Rev Drug Discov 11(2):125–140PubMedGoogle Scholar
  50. Kormann MS, Hasenpusch G, Aneja MK, Nica G, Flemmer AW, Herber-Jonat S et al (2011) Expression of therapeutic proteins after delivery of chemically modified mRNA in mice. Nat Biotechnol 29(2):154–157PubMedGoogle Scholar
  51. Kuhn AN, Beiβert T, Simon P, Vallazza B, Buck J, Davies BP et al (2012) mRNA as a versatile tool for exogenous protein expression. Curr Gene Ther 12(5):347–361PubMedGoogle Scholar
  52. Kumar P, Wu H, McBride JL, Jung KE, Kim MH et al (2007) Transvascular delivery of small interfering RNA to the central nervous system. Nature 448:39–43PubMedGoogle Scholar
  53. Lai RC, Arslan F, Lee MM, Sze NS, Choo A, Chen TS (2010) Exosome secreted by MSC reduces myocardial ischemia/reperfusion injury. Stem Cell Res 4(3):214–222PubMedGoogle Scholar
  54. Lai RC, Yeo RW, Tan KH, Lim SK (2013) Mesenchymal stem cell exosome ameliorates reperfusion injury through proteomic complementation. Regen Med 8(2):197–209PubMedGoogle Scholar
  55. Laird FM, Cai H, Savonenko AV, Farah MH, He K et al (2005) BACE1, a major determinant of selective vulnerability of the brain to amyloid-beta amyloidogenesis, is essential for cognitive, emotional, and synaptic functions. J Neurosci 25(50):11693–11709PubMedGoogle Scholar
  56. Lamparski HG, Metha-Damani A, Yao JY, Patel S, Hsu DH, Ruegg C, Le Pecq JB (2002) Production and characterization of clinical grade exosomes derived from dendritic cells. J Immunol Methods 270(2):211–226PubMedGoogle Scholar
  57. Lee C, Mitsialis SA, Aslam M, Vitali SH, Vergadi E et al (2012) Exosomes mediate the cytoprotective action of mesenchymal stromal cells on hypoxia-induced pulmonary hypertension. Circulation 126(22):2601–2611PubMedGoogle Scholar
  58. Liu R, Wang S, Liu J (2013) Exosomes: the novel vehicles for intercellular communication. Progr Biochem Biophys 40(8):1–9Google Scholar
  59. Mathivanan S, Fahner CJ, Reid GE, Simpson RJ (2012a) ExoCarta 2012: database of exosomal proteins, RNA and lipids. Nucleic Acids Res 40(D1):D1241–D1244PubMedGoogle Scholar
  60. Mathivanan S, Fahner CJ et al (2012b) ExoCarta 2012: database of exosomal proteins, RNA and lipids. Nucleic Acids Res 40(D1):D1241–D1244PubMedGoogle Scholar
  61. Mazzulli JR, Xu YH, Sun Y, Knight AL, McLean PJ, Caldwell GA et al (2011) Gaucher disease glucocerebrosidase and alpha-synuclein form a bidirectional pathogenic loop in synucleinopathies. Cell 46:37–52Google Scholar
  62. Mizrak A, Bolukbasi MF, Ozdener GB, Brenner GJ, Madlener S et al (2013) Genetically engineered microvesicles carrying suicide mRNA/protein inhibit schwannoma tumor growth. Mol Ther 21(1):101–108PubMedGoogle Scholar
  63. Montecalvo A, Larregina AT, Shufesky WJ, Stolz DB, Sullivan ML et al (2012) Mechanism of transfer of functional microRNAs between mouse dendritic cells via exosomes. Blood 119(3):756–766PubMedGoogle Scholar
  64. Murakami K, Murata N, Noda Y, Tahara S, Kaneko T et al (2011) SOD1 (copper/zinc superoxide dismutase) deficiency drives amyloid β protein oligomerization and memory loss in mouse model of Alzheimer disease. J Biol Chem 286(52):44557–44568PubMedGoogle Scholar
  65. Nolte-‘t Hoen EN, Buermans HP, Waasdorp M, Stoorvogel W, Wauben MH, ‘t Hoen PA (2012) Deep sequencing of RNA from immune cell-derived vesicles uncovers the selective incorporation of small non-coding RNA biotypes with potential regulatory functions. Nucleic Acids Res 40(18):9272–9285PubMedGoogle Scholar
  66. Ohno M, Cole SL, Yasvoina M, Zhao J, Citron M et al (2007) BACE1 gene deletion prevents neuron loss and memory deficits in 5XFAD APP/PS1 transgenic mice. Neurobiol Dis 26:134–145PubMedGoogle Scholar
  67. Ohno S, Takanashi M, Sudo K, Ueda S et al (2013) Systemically injected exosomes targeted to egfr deliver antitumor MicroRNA to breast cancer cells. Mol Ther 21(1):185–191PubMedGoogle Scholar
  68. Olson SD, Kambal A, Pollock K, Mitchell GM, Stewart H, Kalomoiris S et al (2012) Examination of mesenchymal stem cell-mediated RNAi transfer to Huntington’s disease affected neuronal cells for reduction of huntingtin. Mol Cell Neurosci 49:271–281PubMedGoogle Scholar
  69. Pan Q, Ramakrishnaiah V, Henry S, Fouraschen S, de Ruiter PE et al (2012) Hepatic cell-to-cell transmission of small silencing RNA can extend the therapeutic reach of RNA interference (RNAi). Gut 61:1330–1339PubMedGoogle Scholar
  70. Parolini I, Federici C, Raggi C, Lugini L, Palleschi S et al (2009) Microenvironmental pH is a key factor for exosome traffic in tumor cells. J Biol Chem 284(49):34211–34222PubMedGoogle Scholar
  71. Peinado H, Alečković M, Lavotshkin S et al (2012) Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. Nat Med 18(6):883–889PubMedGoogle Scholar
  72. Perez-Hernandez D, Gutiérrez-Vázquez C, Jorge I, López-Martín S, Ursa A et al (2013) The intracellular interactome of tetraspanin-enriched microdomains reveals their function as sorting machineries toward exosomes. J Biol Chem 288(17):11649–11661PubMedGoogle Scholar
  73. Quesenberry PJ, Aliotta JM (2010) Cellular phenotype switching and microvesicles. Adv Drug Deliv Rev 62(12):1141–1148PubMedGoogle Scholar
  74. Rana S, Zöller M (2011) Exosome target cell selection and the importance of exosomal tetraspanins: a hypothesis. Biochem Soc Trans 39(2):559–562PubMedGoogle Scholar
  75. Ratajczak J, Miekus K, Kucia M, Zhang J, Reca R et al (2006) Embryonic stem cell-derived microvesicles reprogram hematopoietic progenitors: evidence for horizontal transfer of mRNA and protein delivery. Leukemia 20(5):847–856PubMedGoogle Scholar
  76. Record M, Subra C, Silvente-Poirot S, Poirot M (2011) Exosomes as intercellular signalosomes and pharmacological effectors. Biochem Pharmacol 81:1171–1182PubMedGoogle Scholar
  77. Reis LA, Borges FT, Simões MJ, Borges AA, Sinigaglia-Coimbra R, Schor N (2012) Bone marrow-derived mesenchymal stem cells repaired but did not prevent gentamicin-induced acute kidney injury through paracrine effects in rats. PLoS One 7(9):e44092PubMedGoogle Scholar
  78. Ren X, Zhang T, Gong X, Hu G, Ding W, Wang X (2013) AAV2-mediated striatum delivery of human CDNF prevents the deterioration of midbrain dopamine neurons in a 6-hydroxydopamine induced parkinsonian rat model. Exp Neurol 248C:148–156Google Scholar
  79. Ripa RS, Haack-Sørensen M, Wang Y, Jørgensen E, Mortensen S et al (2007) Bone marrow derived mesenchymal cell mobilization by granulocyte-colony stimulating factor after acute myocardial infarction: results from the Stem Cells in Myocardial Infarction (STEMMI) trial. Circulation 116(11 Suppl):I24–I30PubMedGoogle Scholar
  80. Robbins M, Judge A, MacLachlan I (2009) siRNA and innate immunity. Oligonucleotides 19:89–102PubMedGoogle Scholar
  81. Rodríguez-Lebrón E, Gouvion CM, Moore SA, Davidson BL, Paulson HL (2009) Allele-specific RNAi mitigates phenotypic progression in a transgenic model of Alzheimer’s disease. Mol Ther 17(9):1563–1573PubMedGoogle Scholar
  82. Sahu R, Kaushik SC (2011) Microautophagy of cytosolic proteins by late endosomes. Dev Cell 20:131–139PubMedGoogle Scholar
  83. Simons M, Raposo G (2009) Exosomes – vesicular carriers for intercellular communication. Curr Opin Cell Biol 21(4):575–581PubMedGoogle Scholar
  84. Singer O, Marr RA, Rockenstein E, Crews L (2005) Targeting BACE1 with siRNAs ameliorates Alzheimer disease neuropathology in a transgenic model. Nat Neurosci 8:1343–1349PubMedGoogle Scholar
  85. Skog J, Würdinger T, van Rijn S, Meijer DH, Gainche L et al (2008) Glioblastoma microvesicles transport RNA and protein that promote tumor growth and provide diagnostic biomarkers. Nat Cell Biol 10:1470–1476PubMedGoogle Scholar
  86. Stein S, Ott MG, Schultze-Strasser S, Jauch A, Burwinkel B et al (2010) Genomic instability and myelodysplasia with monosomy 7 consequent to EVI1 activation after gene therapy for chronic granulomatous disease. Nat Med 16(2):198–204PubMedGoogle Scholar
  87. Stuffers S, Sem WC, Stenmark H, Brech A (2009) Multivesicular endosome biogenesis in the absence of ESCRTs. Traffic 10(7):925–937PubMedGoogle Scholar
  88. Subra C, Laulagnier K, Perret B, Record M (2007) Exosome lipidomics unravels lipid sorting at the level of multivesicular bodies. Biochimie 89:205–212PubMedGoogle Scholar
  89. Subra C, Grand D, Laulagnier K, Stella A, Lambeau G, Paillasse M et al (2010) Exosomes account for vesicle-mediated transcellular transport of activatable phospholipases and prostaglandins. J Lipid Res 51:2105–2120PubMedGoogle Scholar
  90. Szabo TG, Misjak P, Aradi B et al. (2012) Comparative meta-analysis of proteomic data on extracellular vesicle subsets. F1000 Posters 3: 471Google Scholar
  91. Tan J, Wu W, Xu X, Liao L, Zheng F et al (2012) Induction therapy with autologous mesenchymal stem cells in living-related kidney transplants: a randomized controlled trial. JAMA 307(11):1169–1177PubMedGoogle Scholar
  92. Tan A, Rajadas J, Seifalian AM (2013) Exosomes as nano-theranostic platforms for gene therapy. Adv Drug Deliv Rev 65(3):357–67PubMedGoogle Scholar
  93. Théry C, Zitvogel L, Amigorena S (2002) Exosomes: composition, biogenesis and function. Nat Rev Immunol 2(8):569–579PubMedGoogle Scholar
  94. Thery C, Amigorena S, Raposo G, Clayton A (2006) Isolation and characterization of exosomes from cell culture supernatants and biological fluids. Curr Protoc Cell Biol. doi: 10.1002/0471143030.cb0322s30
  95. Timmers L, Lim SK, Arslan F, Armstrong JS, Hoefer IE et al (2007) Reduction of myocardial infarct size by human mesenchymal stem cell conditioned medium. Stem Cell Res 1(2):129–137PubMedGoogle Scholar
  96. Turner JJ, Jones SW, Moschos SA, Lindsay MA, Gait MJ (2007) MALDI-TOF mass spectral analysis of siRNA degradation in serum confirms an RNAse A-like activity. Mol Biosyst 3:43–50PubMedGoogle Scholar
  97. Valadi H, Ekstrom K, Bossios A, Sjostrand M, Lee JJ, Lotvall JO (2007) Exosome mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol 9:654–659PubMedGoogle Scholar
  98. van den Boorn JG, Schlee M, Coch C, Hartmann G (2011) SiRNA delivery with exosome nanoparticles. Nat Biotechnol 29:325–326PubMedGoogle Scholar
  99. van der Goot FG, Gruenberg J (2006) Intra-endosomal membrane traffic. Trends Cell Biol 16:514–521PubMedGoogle Scholar
  100. van Niel G, Porto-Carreiro I, Simoes S, Raposo G (2006) Exosomes: a common pathway for a specialized function. J Biochem 140(1):13–21PubMedGoogle Scholar
  101. Wahlgren J, De L, Karlson T, Brisslert M et al (2012) Plasma exosomes can deliver exogenous short interfering RNA to monocytes and lymphocytes. Nucleic Acids Res 40(17):e130PubMedGoogle Scholar
  102. Walsh DM, Selkoe DJ (2007) A beta oligomers - a decade of discovery. J Neurochem 101(5):1172–1184PubMedGoogle Scholar
  103. Wang S, Cesca F, Loers G et al (2011) Synapsin I is an oligomannose-carrying glycoprotein, acts as an oligomannose-binding lectin, and promotes neurite outgrowth and neuronal survival when released via glia-derived exosomes. J Neurosci 31(20):7275–7290PubMedGoogle Scholar
  104. Whitehead KA, Dahlman JE, Langer RS, Anderson DG (2011) Silencing or stimulation? siRNA delivery and the immune system. Annu Rev Chem Biomol Eng 2:77–96PubMedGoogle Scholar
  105. Xia CF, Boado RJ, Zhang Y, Chu C, Pardridge WM (2008) Intravenous glial-derived neurotrophic factor gene therapy of experimental Parkinson’s disease with Trojan horse liposomes and a tyrosine hydroxylase promoter. J Gene Med 10(3):306–315PubMedGoogle Scholar
  106. Xin H, Li Y, Buller B et al (2012) Exosome-mediated transfer of miR-133b from multipotent mesenchymal stromal cells to neural cells contributes to neurite outgrowth. Stem cells 30(7):1556–1564PubMedGoogle Scholar
  107. Xin H, Li Y, Liu Z, Wang X, Shang X, et al (2013) Mir-133b promotes neural plasticity and functional recovery after treatment of stroke with multipotentmesenchymal stromal cells in rats via transfer of exosome-enriched extracellular particles. Stem Cells. doi: 10.1002/stem.1409
  108. Xue YQ, Ma BF, Zhao LR, Tatom JB, Li B et al (2010) AAV9-mediated erythropoietin gene delivery into the brain protects nigral dopaminergic neurons in a rat model of Parkinson’s disease. Gene Ther 17(1):83–94PubMedGoogle Scholar
  109. Yan R, Bienkowski MJ, Shuck ME, Miao H, Tory MC et al (1999) Membrane-anchored aspartyl protease with Alzheimer’s disease beta-secretase activity. Nature 402:533–537PubMedGoogle Scholar
  110. Zamecnik PC, Stephenson ML (1978) Inhibition of Rous sarcoma virus replication and cell transformation by a specific oligodeoxynucleotide. Proc Natl Acad Sci U S A 75:280–284PubMedGoogle Scholar
  111. Zhang Y, Liu D, Chen X, Li J, Li L, Bian Z (2010) Secreted monocytic miR-150 enhances targeted endothelial cell migration. Mol Cell 39(1):133–144PubMedGoogle Scholar
  112. Zhang Y, Satterlee A, Huang L (2012) In vivo gene delivery by nonviral vectors: overcoming hurdles? Mol Ther 20(7):1298–1304PubMedGoogle Scholar

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© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.First Affiliated Hospital of Dalian Medical UniversityDalianChina

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