{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T08:25:21Z","timestamp":1790324721790,"version":"4.1.0"},"reference-count":20,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2015,12,3]],"date-time":"2015-12-03T00:00:00Z","timestamp":1449100800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2015,12,3]],"date-time":"2015-12-03T00:00:00Z","timestamp":1449100800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Cell-derived exosomes have been demonstrated to be efficient carriers of small RNAs to neighbouring or distant cells, highlighting the preponderance of exosomes as carriers for gene therapy over other artificial delivery tools. In the present study, we employed modified exosomes expressing the neuron-specific rabies viral glycoprotein (RVG) peptide on the membrane surface to deliver opioid receptor mu (MOR) siRNA into the brain to treat morphine addiction. We found that MOR siRNA could be efficiently packaged into RVG exosomes and was associated with argonaute 2 (AGO2) in exosomes. These exosomes efficiently and specifically delivered MOR siRNA into Neuro2A cells and the mouse brain. Functionally, siRNA-loaded RVG exosomes significantly reduced MOR mRNA and protein levels. Surprisingly, MOR siRNA delivered by the RVG exosomes strongly inhibited morphine relapse via the down-regulation of MOR expression levels. In conclusion, our results demonstrate that targeted RVG exosomes can efficiently transfer siRNA to the central nervous system and mediate the treatment of morphine relapse by down-regulating MOR expression levels. Our study provides a brand new strategy to treat drug relapse and diseases of the central nervous system.<\/jats:p>","DOI":"10.1038\/srep17543","type":"journal-article","created":{"date-parts":[[2015,12,3]],"date-time":"2015-12-03T05:42:49Z","timestamp":1449121369000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":242,"title":["Targeted exosome-mediated delivery of opioid receptor Mu siRNA for the treatment of morphine relapse"],"prefix":"10.1038","volume":"5","author":[{"given":"Yuchen","family":"Liu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dameng","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhengya","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danping","family":"Chu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xihan","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaohong","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongxia","family":"Hou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xi","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuda","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhanzhao","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Jin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Waner","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenfei","family":"Tian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geyu","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ke","family":"Zen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junfeng","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yujing","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen-Yu","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2015,12,3]]},"reference":[{"key":"BFsrep17543_CR1","doi-asserted-by":"publisher","first-page":"5262","DOI":"10.1158\/1078-0432.CCR-07-1157","volume":"13","author":"SH Wrzesinski","year":"2007","unstructured":"Wrzesinski, S. H., Wan, Y. Y. & Flavell, R. A. Transforming growth factor-beta and the immune response: implications for anticancer therapy. Clin Cancer Res 13, 5262\u20135270 (2007).","journal-title":"Clin Cancer Res"},{"key":"BFsrep17543_CR2","doi-asserted-by":"publisher","first-page":"487","DOI":"10.1021\/mp800032f","volume":"5","author":"MA Dobrovolskaia","year":"2008","unstructured":"Dobrovolskaia, M. A., Aggarwal, P., Hall, J. B. & McNeil, S. E. Preclinical studies to understand nanoparticle interaction with the immune system and its potential effects on nanoparticle biodistribution. Mol Pharm 5, 487\u2013495 (2008).","journal-title":"Mol Pharm"},{"key":"BFsrep17543_CR3","doi-asserted-by":"publisher","first-page":"325","DOI":"10.1038\/nbt.1830","volume":"29","author":"JG van den Boorn","year":"2011","unstructured":"van den Boorn, J. G., Schlee, M., Coch, C. & Hartmann, G. SiRNA delivery with exosome nanoparticles. Nat Biotechnol 29, 325\u2013326 (2011).","journal-title":"Nat Biotechnol"},{"key":"BFsrep17543_CR4","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1016\/j.tcb.2008.11.003","volume":"19","author":"E Cocucci","year":"2009","unstructured":"Cocucci, E., Racchetti, G. & Meldolesi, J. Shedding microvesicles: artefacts no more. Trends Cell Biol 19, 43\u201351 (2009).","journal-title":"Trends Cell Biol"},{"key":"BFsrep17543_CR5","doi-asserted-by":"publisher","first-page":"569","DOI":"10.1038\/nri855","volume":"2","author":"C Thery","year":"2002","unstructured":"Thery, C., Zitvogel, L. & Amigorena, S. Exosomes: composition, biogenesis and function. Nat Rev Immunol 2, 569\u2013579 (2002).","journal-title":"Nat Rev Immunol"},{"key":"BFsrep17543_CR6","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1016\/j.molcel.2010.06.010","volume":"39","author":"Y Zhang","year":"2010","unstructured":"Zhang, Y. et al. Secreted monocytic miR-150 enhances targeted endothelial cell migration. Molecular cell 39, 133\u2013144 (2010).","journal-title":"Molecular cell"},{"key":"BFsrep17543_CR7","doi-asserted-by":"publisher","first-page":"4390","DOI":"10.1016\/j.biomaterials.2014.02.003","volume":"35","author":"Y Zhang","year":"2014","unstructured":"Zhang, Y. et al. Microvesicle-mediated delivery of transforming growth factor beta1 siRNA for the suppression of tumor growth in mice. Biomaterials 35, 4390\u20134400 (2014).","journal-title":"Biomaterials"},{"key":"BFsrep17543_CR8","doi-asserted-by":"publisher","first-page":"23586","DOI":"10.1074\/jbc.M113.489302","volume":"288","author":"J Li","year":"2013","unstructured":"Li, J. et al. Microvesicle-mediated transfer of microRNA-150 from monocytes to endothelial cells promotes angiogenesis. The Journal of biological chemistry 288, 23586\u201323596 (2013).","journal-title":"The Journal of biological chemistry"},{"key":"BFsrep17543_CR9","doi-asserted-by":"publisher","first-page":"932","DOI":"10.1007\/s13238-013-3092-z","volume":"4","author":"Y Liu","year":"2013","unstructured":"Liu, Y. et al. Microvesicle-delivery miR-150 promotes tumorigenesis by up-regulating VEGF and the neutralization of miR-150 attenuate tumor development. Protein Cell 4, 932\u2013941 (2013).","journal-title":"Protein Cell"},{"key":"BFsrep17543_CR10","doi-asserted-by":"publisher","first-page":"341","DOI":"10.1038\/nbt.1807","volume":"29","author":"L Alvarez-Erviti","year":"2011","unstructured":"Alvarez-Erviti, L. et al. Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nat Biotechnol 29, 341\u2013345 (2011).","journal-title":"Nat Biotechnol"},{"key":"BFsrep17543_CR11","doi-asserted-by":"publisher","first-page":"1164","DOI":"10.1038\/cr.2014.121","volume":"24","author":"Y Yin","year":"2014","unstructured":"Yin, Y. et al. Tumor-secreted miR-214 induces regulatory T cells: a major link between immune evasion and tumor growth. Cell Res 24, 1164\u20131180 (2014).","journal-title":"Cell Res"},{"key":"BFsrep17543_CR12","doi-asserted-by":"publisher","first-page":"613","DOI":"10.1002\/ijc.20757","volume":"114","author":"JA Cho","year":"2005","unstructured":"Cho, J. A. et al. Exosomes: a new delivery system for tumor antigens in cancer immunotherapy. Int J Cancer 114, 613\u2013622 (2005).","journal-title":"Int J Cancer"},{"key":"BFsrep17543_CR13","doi-asserted-by":"publisher","first-page":"e130","DOI":"10.1093\/nar\/gks463","volume":"40","author":"J Wahlgren","year":"2012","unstructured":"Wahlgren, J. et al. Plasma exosomes can deliver exogenous short interfering RNA to monocytes and lymphocytes. Nucleic Acids Res 40, e130 (2012).","journal-title":"Nucleic Acids Res"},{"key":"BFsrep17543_CR14","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1186\/1478-811X-11-88","volume":"11","author":"TA Shtam","year":"2013","unstructured":"Shtam, T. A. et al. Exosomes are natural carriers of exogenous siRNA to human cells in vitro. Cell Commun Signal 11, 88 (2013).","journal-title":"Cell Commun Signal"},{"key":"BFsrep17543_CR15","doi-asserted-by":"publisher","first-page":"731","DOI":"10.1038\/nrd896","volume":"1","author":"P Pouletty","year":"2002","unstructured":"Pouletty, P. Drug addictions: towards socially accepted and medically treatable diseases. Nat Rev Drug Discov 1, 731\u2013736 (2002).","journal-title":"Nat Rev Drug Discov"},{"key":"BFsrep17543_CR16","doi-asserted-by":"publisher","first-page":"710","DOI":"10.1038\/nrd897","volume":"1","author":"MJ Kreek","year":"2002","unstructured":"Kreek, M. J., LaForge, K. S. & Butelman, E. Pharmacotherapy of addictions. Nat Rev Drug Discov 1, 710\u2013726 (2002).","journal-title":"Nat Rev Drug Discov"},{"key":"BFsrep17543_CR17","doi-asserted-by":"publisher","first-page":"7752","DOI":"10.1073\/pnas.96.14.7752","volume":"96","author":"GR Uhl","year":"1999","unstructured":"Uhl, G. R., Sora, I. & Wang, Z. The mu opiate receptor as a candidate gene for pain: polymorphisms, variations in expression, nociception and opiate responses. Proc Natl Acad Sci USA 96, 7752\u20137755 (1999).","journal-title":"Proc Natl Acad Sci USA"},{"key":"BFsrep17543_CR18","doi-asserted-by":"publisher","first-page":"819","DOI":"10.1038\/383819a0","volume":"383","author":"HW Matthes","year":"1996","unstructured":"Matthes, H. W. et al. Loss of morphine-induced analgesia, reward effect and withdrawal symptoms in mice lacking the mu-opioid-receptor gene. Nature 383, 819\u2013823 (1996).","journal-title":"Nature"},{"key":"BFsrep17543_CR19","doi-asserted-by":"publisher","first-page":"e46957","DOI":"10.1371\/journal.pone.0046957","volume":"7","author":"L Li","year":"2012","unstructured":"Li, L. et al. Argonaute 2 complexes selectively protect the circulating microRNAs in cell-secreted microvesicles. PLoS One 7, e46957 (2012).","journal-title":"PLoS One"},{"key":"BFsrep17543_CR20","doi-asserted-by":"publisher","first-page":"505","DOI":"10.1016\/j.jnutbio.2014.12.002","volume":"26","author":"H Liang","year":"2015","unstructured":"Liang, H. et al. Effective detection and quantification of dietetically absorbed plant microRNAs in human plasma. J Nutr Biochem 26, 505\u2013512 (2015).","journal-title":"J Nutr Biochem"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/srep17543","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep17543.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep17543.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,5]],"date-time":"2023-01-05T14:20:48Z","timestamp":1672928448000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/srep17543"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,12,3]]},"references-count":20,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2015,12,22]]}},"alternative-id":["BFsrep17543"],"URL":"https:\/\/doi.org\/10.1038\/srep17543","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.725982642.793570284","asserted-by":"object"}]},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,12,3]]},"assertion":[{"value":"23 July 2015","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 November 2015","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 December 2015","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing financial interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"17543"}}