{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T12:13:44Z","timestamp":1788783224246,"version":"build-2803163510"},"reference-count":66,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T00:00:00Z","timestamp":1781740800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"},{"start":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T00:00:00Z","timestamp":1788739200000},"content-version":"vor","delay-in-days":81,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["1R41NS122704"],"award-info":[{"award-number":["1R41NS122704"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"DOI":"10.1038\/s41598-026-58290-8","type":"journal-article","created":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T10:49:52Z","timestamp":1781779792000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Alkaline loading of extracellular vesicles produced from human neural stem cell-derived neurospheres enables CNS drug delivery"],"prefix":"10.1038","volume":"16","author":[{"given":"Amar M.","family":"Singh","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles M.","family":"White","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adeline","family":"Phillips","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Logan P.","family":"Crowe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Marti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Morgan C.","family":"Finnerty","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martonio Ponte","family":"Viana","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William","family":"Antoniades","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael G.","family":"Bartlett","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Viviana","family":"Martinez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raymond","family":"Swetenburg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven L.","family":"Stice","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,18]]},"reference":[{"issue":"12","key":"58290_CR1","doi-asserted-by":"publisher","first-page":"2067","DOI":"10.1007\/s11064-009-0081-y","volume":"34","author":"J Correale","year":"2009","unstructured":"Correale, J. & Villa, A. Cellular elements of the blood-brain barrier. Neurochem Res 34(12), 2067\u20132077. https:\/\/doi.org\/10.1007\/s11064-009-0081-y (2009).","journal-title":"Neurochem Res"},{"issue":"5","key":"58290_CR2","doi-asserted-by":"publisher","first-page":"362","DOI":"10.1038\/s41573-021-00139-y","volume":"20","author":"GC Terstappen","year":"2021","unstructured":"Terstappen, G. C. et al. Strategies for delivering therapeutics across the blood-brain barrier. Nat Rev Drug Discov 20(5), 362\u2013383. https:\/\/doi.org\/10.1038\/s41573-021-00139-y (2021).","journal-title":"Nat Rev Drug Discov"},{"key":"58290_CR3","doi-asserted-by":"publisher","DOI":"10.1158\/1541-7786.MCR-25-0908","author":"JL Jimenez Macias","year":"2026","unstructured":"Jimenez Macias, J. L. et al. Decoding the biology of the blood-brain tumor barrier in brain cancer. Mol Cancer Res https:\/\/doi.org\/10.1158\/1541-7786.MCR-25-0908 (2026).","journal-title":"Mol Cancer Res"},{"issue":"11","key":"58290_CR4","doi-asserted-by":"publisher","first-page":"696","DOI":"10.1038\/s41571-021-00529-6","volume":"18","author":"PS Steeg","year":"2021","unstructured":"Steeg, P. S. The blood-tumour barrier in cancer biology and therapy. Nat Rev Clin Oncol 18(11), 696\u2013714. https:\/\/doi.org\/10.1038\/s41571-021-00529-6 (2021).","journal-title":"Nat Rev Clin Oncol"},{"key":"58290_CR5","doi-asserted-by":"publisher","first-page":"1019","DOI":"10.3389\/fnins.2018.01019","volume":"12","author":"VM Pulgar","year":"2018","unstructured":"Pulgar, V. M. Transcytosis to Cross the Blood Brain Barrier. New Adv Challenges. Front Neurosci 12, 1019. https:\/\/doi.org\/10.3389\/fnins.2018.01019 (2018).","journal-title":"New Adv Challenges. Front Neurosci"},{"key":"58290_CR6","doi-asserted-by":"publisher","first-page":"237","DOI":"10.1016\/j.jconrel.2019.01.005","volume":"295","author":"KB Johnsen","year":"2019","unstructured":"Johnsen, K. B. et al. Modulating the antibody density changes the uptake and transport at the blood-brain barrier of both transferrin receptor-targeted gold nanoparticles and liposomal cargo. J Control Release 295, 237\u2013249. https:\/\/doi.org\/10.1016\/j.jconrel.2019.01.005 (2019).","journal-title":"J Control Release"},{"issue":"Pt 2","key":"58290_CR7","doi-asserted-by":"publisher","first-page":"521","DOI":"10.1242\/jcs.104.2.521","volume":"104","author":"RL Roberts","year":"1993","unstructured":"Roberts, R. L., Fine, R. E. & Sandra, A. Receptor-mediated endocytosis of transferrin at the blood-brain barrier. J Cell Sci 104(Pt 2), 521\u2013532. https:\/\/doi.org\/10.1242\/jcs.104.2.521 (1993).","journal-title":"J Cell Sci"},{"issue":"1","key":"58290_CR8","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1083\/jcb.145.1.123","volume":"145","author":"DR Sheff","year":"1999","unstructured":"Sheff, D. R. et al. The receptor recycling pathway contains two distinct populations of early endosomes with different sorting functions. J Cell Biol 145(1), 123\u2013139. https:\/\/doi.org\/10.1083\/jcb.145.1.123 (1999).","journal-title":"J Cell Biol"},{"issue":"84","key":"58290_CR9","doi-asserted-by":"publisher","first-page":"84ra44","DOI":"10.1126\/scitranslmed.3002230","volume":"3","author":"YJ Yu","year":"2011","unstructured":"Yu, Y. J. et al. Boosting brain uptake of a therapeutic antibody by reducing its affinity for a transcytosis target. Sci Transl Med 3(84), 84ra44. https:\/\/doi.org\/10.1126\/scitranslmed.3002230 (2011).","journal-title":"Sci Transl Med"},{"key":"58290_CR10","doi-asserted-by":"publisher","DOI":"10.3390\/ijms222111654","author":"RGR Pinheiro","year":"2021","unstructured":"Pinheiro, R. G. R. et al. Nanoparticles for targeted brain drug delivery: What do we know?. Int J Mol Sci https:\/\/doi.org\/10.3390\/ijms222111654 (2021).","journal-title":"Int J Mol Sci"},{"issue":"2","key":"58290_CR11","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1038\/s41578-020-00277-6","volume":"6","author":"KW Witwer","year":"2021","unstructured":"Witwer, K. W. & Wolfram, J. Extracellular vesicles versus synthetic nanoparticles for drug delivery. Nat Rev Mater 6(2), 103\u2013106. https:\/\/doi.org\/10.1038\/s41578-020-00277-6 (2021).","journal-title":"Nat Rev Mater"},{"key":"58290_CR12","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21124407","author":"WA Banks","year":"2020","unstructured":"Banks, W. A. et al. Transport of extracellular vesicles across the blood-brain barrier: Brain pharmacokinetics and effects of inflammation. Int J Mol Sci https:\/\/doi.org\/10.3390\/ijms21124407 (2020).","journal-title":"Int J Mol Sci"},{"issue":"1","key":"58290_CR13","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1186\/s12987-022-00359-3","volume":"19","author":"HM Ramos-Zaldivar","year":"2022","unstructured":"Ramos-Zaldivar, H. M. et al. Extracellular vesicles through the blood-brain barrier: a review. Fluids Barriers CNS 19(1), 60. https:\/\/doi.org\/10.1186\/s12987-022-00359-3 (2022).","journal-title":"Fluids Barriers CNS"},{"issue":"7","key":"58290_CR14","doi-asserted-by":"publisher","first-page":"1761","DOI":"10.1021\/acs.accounts.9b00109","volume":"52","author":"OG de Jong","year":"2019","unstructured":"de Jong, O. G. et al. Drug Delivery with Extracellular Vesicles: From Imagination to Innovation. Acc Chem Res 52(7), 1761\u20131770. https:\/\/doi.org\/10.1021\/acs.accounts.9b00109 (2019).","journal-title":"Acc Chem Res"},{"issue":"7","key":"58290_CR15","doi-asserted-by":"publisher","first-page":"748","DOI":"10.1038\/s41565-021-00931-2","volume":"16","author":"IK Herrmann","year":"2021","unstructured":"Herrmann, I. K., Wood, M. J. A. & Fuhrmann, G. Extracellular vesicles as a next-generation drug delivery platform. Nat Nanotechnol 16(7), 748\u2013759. https:\/\/doi.org\/10.1038\/s41565-021-00931-2 (2021).","journal-title":"Nat Nanotechnol"},{"key":"58290_CR16","doi-asserted-by":"publisher","unstructured":"Edelmann, M.J. and P.E. Kima, Current understanding of extracellular vesicle homing\/tropism. Zoonoses (Burlingt), 2022. 2. https:\/\/doi.org\/10.15212\/zoonoses-2022-0004.","DOI":"10.15212\/zoonoses-2022-0004"},{"key":"58290_CR17","doi-asserted-by":"publisher","first-page":"26316","DOI":"10.3402\/jev.v4.26316","volume":"4","author":"OP Wiklander","year":"2015","unstructured":"Wiklander, O. P. et al. Extracellular vesicle in vivo biodistribution is determined by cell source, route of administration and targeting. J Extracell Vesicles 4, 26316. https:\/\/doi.org\/10.3402\/jev.v4.26316 (2015).","journal-title":"J Extracell Vesicles"},{"issue":"7578","key":"58290_CR18","doi-asserted-by":"publisher","first-page":"329","DOI":"10.1038\/nature15756","volume":"527","author":"A Hoshino","year":"2015","unstructured":"Hoshino, A. et al. Tumour exosome integrins determine organotropic metastasis. Nature 527(7578), 329\u2013335. https:\/\/doi.org\/10.1038\/nature15756 (2015).","journal-title":"Nature"},{"issue":"5","key":"58290_CR19","doi-asserted-by":"publisher","first-page":"530","DOI":"10.1007\/s12975-017-0599-2","volume":"9","author":"RL Webb","year":"2018","unstructured":"Webb, R. L. et al. Human Neural Stem Cell Extracellular Vesicles Improve Tissue and Functional Recovery in the Murine Thromboembolic Stroke Model. Transl Stroke Res 9(5), 530\u2013539. https:\/\/doi.org\/10.1007\/s12975-017-0599-2 (2018).","journal-title":"Transl Stroke Res"},{"key":"58290_CR20","doi-asserted-by":"publisher","first-page":"148","DOI":"10.1016\/j.neubiorev.2021.02.027","volume":"125","author":"S Zhao","year":"2021","unstructured":"Zhao, S. et al. Astrocyte-derived extracellular vesicles: A double-edged sword in central nervous system disorders. Neurosci Biobehav Rev 125, 148\u2013159. https:\/\/doi.org\/10.1016\/j.neubiorev.2021.02.027 (2021).","journal-title":"Neurosci Biobehav Rev"},{"key":"58290_CR21","doi-asserted-by":"publisher","unstructured":"Haney, M.J., et al., Extracellular Vesicles as Drug Delivery System for Treatment of Neurodegenerative Disorders: Optimization of the Cell Source. Adv Nanobiomed Res, 2021. 1(12). https:\/\/doi.org\/10.1002\/anbr.202100064.","DOI":"10.1002\/anbr.202100064"},{"issue":"9","key":"58290_CR22","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1523\/Eneuro.0148-24.2024","volume":"11","author":"B Lendemeijer","year":"2024","unstructured":"Lendemeijer, B. et al. Human Pluripotent Stem Cell-Derived Astrocyte Functionality Compares Favorably with Primary Rat Astrocytes. Eneuro 11(9), 1\u201321. https:\/\/doi.org\/10.1523\/Eneuro.0148-24.2024 (2024).","journal-title":"Eneuro"},{"issue":"1","key":"58290_CR23","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1016\/j.neuron.2015.11.013","volume":"89","author":"Y Zhang","year":"2016","unstructured":"Zhang, Y. et al. Purification and Characterization of Progenitor and Mature Human Astrocytes Reveals Transcriptional and Functional Differences with Mouse. Neuron 89(1), 37\u201353. https:\/\/doi.org\/10.1016\/j.neuron.2015.11.013 (2016).","journal-title":"Neuron"},{"issue":"5","key":"58290_CR24","doi-asserted-by":"publisher","first-page":"454","DOI":"10.1111\/j.1432-0436.2007.00256.x","volume":"76","author":"SK Dhara","year":"2008","unstructured":"Dhara, S. K. et al. Human neural progenitor cells derived from embryonic stem cells in feeder-free cultures. Differentiation 76(5), 454\u2013464. https:\/\/doi.org\/10.1111\/j.1432-0436.2007.00256.x (2008).","journal-title":"Differentiation"},{"issue":"3","key":"58290_CR25","doi-asserted-by":"publisher","first-page":"633","DOI":"10.1002\/jcb.21891","volume":"105","author":"SK Dhara","year":"2008","unstructured":"Dhara, S. K. & Stice, S. L. Neural differentiation of human embryonic stem cells. J Cell Biochem 105(3), 633\u2013640. https:\/\/doi.org\/10.1002\/jcb.21891 (2008).","journal-title":"J Cell Biochem"},{"issue":"3","key":"58290_CR26","doi-asserted-by":"publisher","first-page":"266","DOI":"10.1089\/scd.2005.14.266","volume":"14","author":"S Shin","year":"2005","unstructured":"Shin, S., Dalton, S. & Stice, S. L. Human motor neuron differentiation from human embryonic stem cells. Stem Cells Dev 14(3), 266\u2013269. https:\/\/doi.org\/10.1089\/scd.2005.14.266 (2005).","journal-title":"Stem Cells Dev"},{"issue":"1","key":"58290_CR27","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1634\/stemcells.2004-0150","volume":"24","author":"S Shin","year":"2006","unstructured":"Shin, S. et al. Long-term proliferation of human embryonic stem cell-derived neuroepithelial cells using defined adherent culture conditions. Stem Cells 24(1), 125\u2013138. https:\/\/doi.org\/10.1634\/stemcells.2004-0150 (2006).","journal-title":"Stem Cells"},{"issue":"5","key":"58290_CR28","doi-asserted-by":"publisher","first-page":"1298","DOI":"10.1634\/stemcells.2006-0660","volume":"25","author":"S Shin","year":"2007","unstructured":"Shin, S. et al. Whole genome analysis of human neural stem cells derived from embryonic stem cells and stem and progenitor cells isolated from fetal tissue. Stem Cells 25(5), 1298\u20131306. https:\/\/doi.org\/10.1634\/stemcells.2006-0660 (2007).","journal-title":"Stem Cells"},{"issue":"1","key":"58290_CR29","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1007\/s12015-006-0011-1","volume":"2","author":"PG Wilson","year":"2006","unstructured":"Wilson, P. G. & Stice, S. S. Development and differentiation of neural rosettes derived from human embryonic stem cells. Stem Cell Rev 2(1), 67\u201377. https:\/\/doi.org\/10.1007\/s12015-006-0011-1 (2006).","journal-title":"Stem Cell Rev"},{"issue":"6","key":"58290_CR30","doi-asserted-by":"publisher","first-page":"1476","DOI":"10.14336\/AD.2021.0708","volume":"12","author":"B Jurgielewicz","year":"2021","unstructured":"Jurgielewicz, B., Stice, S. & Yao, Y. Therapeutic Potential of Nucleic Acids when Combined with Extracellular Vesicles. Aging Dis 12(6), 1476\u20131493. https:\/\/doi.org\/10.14336\/AD.2021.0708 (2021).","journal-title":"Aging Dis"},{"issue":"4","key":"58290_CR31","doi-asserted-by":"publisher","first-page":"776","DOI":"10.1007\/s12975-019-00753-4","volume":"11","author":"SE Spellicy","year":"2020","unstructured":"Spellicy, S. E. et al. Neural Stem Cell Extracellular Vesicles Disrupt Midline Shift Predictive Outcomes in Porcine Ischemic Stroke Model. Transl Stroke Res 11(4), 776\u2013788. https:\/\/doi.org\/10.1007\/s12975-019-00753-4 (2020).","journal-title":"Transl Stroke Res"},{"issue":"11","key":"58290_CR32","doi-asserted-by":"publisher","first-page":"1358","DOI":"10.1089\/neu.2019.6443","volume":"37","author":"MK Sun","year":"2020","unstructured":"Sun, M. K. et al. Extracellular Vesicles Mediate Neuroprotection and Functional Recovery after Traumatic Brain Injury. J Neurotrauma 37(11), 1358\u20131369. https:\/\/doi.org\/10.1089\/neu.2019.6443 (2020).","journal-title":"J Neurotrauma"},{"issue":"5","key":"58290_CR33","doi-asserted-by":"publisher","first-page":"1248","DOI":"10.1161\/STROKEAHA.117.020353","volume":"49","author":"RL Webb","year":"2018","unstructured":"Webb, R. L. et al. Human Neural Stem Cell Extracellular Vesicles Improve Recovery in a Porcine Model of Ischemic Stroke. Stroke 49(5), 1248\u20131256. https:\/\/doi.org\/10.1161\/STROKEAHA.117.020353 (2018).","journal-title":"Stroke"},{"issue":"4","key":"58290_CR34","doi-asserted-by":"publisher","first-page":"394","DOI":"10.1016\/j.cbpa.2007.05.034","volume":"11","author":"JA King","year":"2007","unstructured":"King, J. A. & Miller, W. M. Bioreactor development for stem cell expansion and controlled differentiation. Curr Opin Chem Biol 11(4), 394\u2013398. https:\/\/doi.org\/10.1016\/j.cbpa.2007.05.034 (2007).","journal-title":"Curr Opin Chem Biol"},{"issue":"1","key":"58290_CR35","doi-asserted-by":"publisher","first-page":"492","DOI":"10.1038\/s42003-020-01218-3","volume":"3","author":"L Rohani","year":"2020","unstructured":"Rohani, L. et al. Stirred suspension bioreactors maintain naive pluripotency of human pluripotent stem cells. Commun Biol 3(1), 492. https:\/\/doi.org\/10.1038\/s42003-020-01218-3 (2020).","journal-title":"Commun Biol"},{"key":"58290_CR36","doi-asserted-by":"publisher","DOI":"10.12688\/f1000research.12533.1","author":"M Stephenson","year":"2018","unstructured":"Stephenson, M. & Grayson, W. Recent advances in bioreactors for cell-based therapies. F1000Res https:\/\/doi.org\/10.12688\/f1000research.12533.1 (2018).","journal-title":"F1000Res"},{"issue":"1","key":"58290_CR37","doi-asserted-by":"publisher","first-page":"22069","DOI":"10.1038\/s41598-024-73074-8","volume":"14","author":"MC Finnerty","year":"2024","unstructured":"Finnerty, M. C. et al. Identification of blood lipid markers of docetaxel treatment in prostate cancer patients. Sci Rep 14(1), 22069. https:\/\/doi.org\/10.1038\/s41598-024-73074-8 (2024).","journal-title":"Sci Rep"},{"key":"58290_CR38","doi-asserted-by":"publisher","DOI":"10.1088\/1758-5090\/ac7eeb","author":"J Wu","year":"2022","unstructured":"Wu, J. et al. Scale-out production of extracellular vesicles derived from natural killer cells via mechanical stimulation in a seesaw-motion bioreactor for cancer therapy. Biofabrication https:\/\/doi.org\/10.1088\/1758-5090\/ac7eeb (2022).","journal-title":"Biofabrication"},{"issue":"1-2","key":"58290_CR39","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.ijpharm.2017.01.002","volume":"519","author":"R Luo","year":"2017","unstructured":"Luo, R. et al. Distinct biodistribution of doxorubicin and the altered dispositions mediated by different liposomal formulations. Int J Pharm 519(1\u20132), 1\u201310. https:\/\/doi.org\/10.1016\/j.ijpharm.2017.01.002 (2017).","journal-title":"Int J Pharm"},{"issue":"6","key":"58290_CR40","doi-asserted-by":"publisher","first-page":"2511","DOI":"10.1088\/0031-9155\/60\/6\/2511","volume":"60","author":"M Aryal","year":"2015","unstructured":"Aryal, M. et al. Enhancement in blood-tumor barrier permeability and delivery of liposomal doxorubicin using focused ultrasound and microbubbles: evaluation during tumor progression in a rat glioma model. Phys Med Biol 60(6), 2511\u20132527. https:\/\/doi.org\/10.1088\/0031-9155\/60\/6\/2511 (2015).","journal-title":"Phys Med Biol"},{"key":"58290_CR41","doi-asserted-by":"publisher","first-page":"74","DOI":"10.1016\/j.jconrel.2014.05.033","volume":"187","author":"Z Kovacs","year":"2014","unstructured":"Kovacs, Z. et al. Prolonged survival upon ultrasound-enhanced doxorubicin delivery in two syngenic glioblastoma mouse models. J Control Release 187, 74\u201382. https:\/\/doi.org\/10.1016\/j.jconrel.2014.05.033 (2014).","journal-title":"J Control Release"},{"key":"58290_CR42","doi-asserted-by":"publisher","first-page":"965","DOI":"10.2147\/IJN.S29229","volume":"7","author":"FY Yang","year":"2012","unstructured":"Yang, F. Y. Treating glioblastoma multiforme with selective high-dose liposomal doxorubicin chemotherapy induced by repeated focused ultrasound. Int J Nanomedicine 7, 965\u2013974. https:\/\/doi.org\/10.2147\/IJN.S29229 (2012).","journal-title":"Int J Nanomedicine"},{"issue":"19","key":"58290_CR43","doi-asserted-by":"publisher","first-page":"2127","DOI":"10.1002\/rcm.6671","volume":"27","author":"P Li","year":"2013","unstructured":"Li, P. et al. A rapid analytical method for the quantification of paclitaxel in rat plasma and brain tissue by high-performance liquid chromatography and tandem mass spectrometry. Rapid Commun Mass Spectrom 27(19), 2127\u20132134. https:\/\/doi.org\/10.1002\/rcm.6671 (2013).","journal-title":"Rapid Commun Mass Spectrom"},{"issue":"7","key":"58290_CR44","doi-asserted-by":"publisher","first-page":"1287","DOI":"10.1007\/s00216-022-04248-4","volume":"415","author":"C Chen","year":"2023","unstructured":"Chen, C. et al. Single-particle assessment of six different drug-loading strategies for incorporating doxorubicin into small extracellular vesicles. Anal Bioanal Chem 415(7), 1287\u20131298. https:\/\/doi.org\/10.1007\/s00216-022-04248-4 (2023).","journal-title":"Anal Bioanal Chem"},{"issue":"3","key":"58290_CR45","doi-asserted-by":"publisher","first-page":"487","DOI":"10.1007\/s11481-019-09884-9","volume":"15","author":"MJ Haney","year":"2020","unstructured":"Haney, M. J. et al. Macrophage-Derived Extracellular Vesicles as Drug Delivery Systems for Triple Negative Breast Cancer (TNBC) Therapy. J Neuroimmune Pharmacol 15(3), 487\u2013500. https:\/\/doi.org\/10.1007\/s11481-019-09884-9 (2020).","journal-title":"J Neuroimmune Pharmacol"},{"issue":"3","key":"58290_CR46","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0214545","volume":"14","author":"C Schindler","year":"2019","unstructured":"Schindler, C. et al. Exosomal delivery of doxorubicin enables rapid cell entry and enhanced in vitro potency. PLoS ONE 14(3), e0214545. https:\/\/doi.org\/10.1371\/journal.pone.0214545 (2019).","journal-title":"PLoS ONE"},{"key":"58290_CR47","doi-asserted-by":"publisher","first-page":"510","DOI":"10.1016\/j.jconrel.2021.07.004","volume":"336","author":"JY Wu","year":"2021","unstructured":"Wu, J. Y. et al. Exosomes and biomimetic nanovesicles-mediated anti-glioblastoma therapy: A head-to-head comparison. J Control Release 336, 510\u2013521. https:\/\/doi.org\/10.1016\/j.jconrel.2021.07.004 (2021).","journal-title":"J Control Release"},{"issue":"1","key":"58290_CR48","doi-asserted-by":"publisher","DOI":"10.1080\/09537104.2023.2237134","volume":"34","author":"YW Wu","year":"2023","unstructured":"Wu, Y. W. et al. Platelet extracellular vesicles are efficient delivery vehicles of doxorubicin, an anti-cancer drug: Preparation and in vitro characterization. Platelets 34(1), 2237134. https:\/\/doi.org\/10.1080\/09537104.2023.2237134 (2023).","journal-title":"Platelets"},{"issue":"12","key":"58290_CR49","doi-asserted-by":"publisher","first-page":"13283","DOI":"10.1007\/s12274-023-5921-6","volume":"16","author":"Y Zhou","year":"2023","unstructured":"Zhou, Y. et al. Glioblastoma cell-derived exosomes functionalized with peptides as efficient nanocarriers for synergistic chemotherapy of glioblastoma with improved biosafety. Nano Res. 16(12), 13283\u201313293. https:\/\/doi.org\/10.1007\/s12274-023-5921-6 (2023).","journal-title":"Nano Res."},{"key":"58290_CR50","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2020.553444","volume":"8","author":"M de Almeida Fuzeta","year":"2020","unstructured":"de Almeida Fuzeta, M. et al. Scalable production of human mesenchymal stromal cell-derived extracellular vesicles under serum-\/xeno-free conditions in a microcarrier-based bioreactor culture system. Front Cell Dev Biol 8, 553444. https:\/\/doi.org\/10.3389\/fcell.2020.553444 (2020).","journal-title":"Front Cell Dev Biol"},{"key":"58290_CR51","doi-asserted-by":"publisher","DOI":"10.1155\/2022\/6409346","volume":"2022","author":"M Abedi","year":"2022","unstructured":"Abedi, M. et al. Exosome derived from human neural stem cells improves motor activity and neurogenesis in a traumatic brain injury model. BioMed Res. Int. 2022, 6409346. https:\/\/doi.org\/10.1155\/2022\/6409346 (2022).","journal-title":"BioMed Res. Int."},{"issue":"1","key":"58290_CR52","doi-asserted-by":"publisher","first-page":"2019","DOI":"10.1038\/s41598-022-05848-x","volume":"12","author":"H Branscome","year":"2022","unstructured":"Branscome, H. et al. Retroviral infection of human neurospheres and use of stem cell EVs to repair cellular damage. Sci. Rep. 12(1), 2019. https:\/\/doi.org\/10.1038\/s41598-022-05848-x (2022).","journal-title":"Sci. Rep."},{"key":"58290_CR53","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1007\/978-1-0716-1783-0_8","volume":"2389","author":"NN Koopaei","year":"2022","unstructured":"Koopaei, N. N. et al. Method for Isolating Extracellular Vesicles from Human Neural Stem Cells Expanded Under Neurosphere Culture. Methods Mol Biol 2389, 87\u201394. https:\/\/doi.org\/10.1007\/978-1-0716-1783-0_8 (2022).","journal-title":"Methods Mol Biol"},{"issue":"1","key":"58290_CR54","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1016\/s0005-2736(02)00507-2","volume":"1565","author":"SA Abraham","year":"2002","unstructured":"Abraham, S. A. et al. Formation of transition metal-doxorubicin complexes inside liposomes. Biochim. Biophys. Acta 1565(1), 41\u201354. https:\/\/doi.org\/10.1016\/s0005-2736(02)00507-2 (2002).","journal-title":"Biochim. Biophys. Acta"},{"issue":"10","key":"58290_CR55","doi-asserted-by":"publisher","first-page":"1633","DOI":"10.1016\/j.bbamem.2006.05.028","volume":"1758","author":"A Fritze","year":"2006","unstructured":"Fritze, A. et al. Remote loading of doxorubicin into liposomes driven by a transmembrane phosphate gradient. Biochim. Biophys. Acta 1758(10), 1633\u20131640. https:\/\/doi.org\/10.1016\/j.bbamem.2006.05.028 (2006).","journal-title":"Biochim. Biophys. Acta"},{"key":"58290_CR56","unstructured":"DrugBank. Doxorubicin. [cited 2026; Available from: https:\/\/go.drugbank.com\/drugs\/DB00997."},{"key":"58290_CR57","unstructured":"Pubchem, N.L.o.M., National Institutes of Health. Compound: Doxorubicin. [cited 2026; Available from: https:\/\/pubchem.ncbi.nlm.nih.gov\/compound\/Doxorubicin."},{"issue":"1","key":"58290_CR58","doi-asserted-by":"publisher","DOI":"10.1002\/jex2.70031","volume":"4","author":"D Mladenovic","year":"2025","unstructured":"Mladenovic, D. et al. Quantitative fluorescent nanoparticle tracking analysis and nano-flow cytometry enable advanced characterization of single extracellular vesicles. J. Extracellular Biol. 4(1), e70031. https:\/\/doi.org\/10.1002\/jex2.70031 (2025).","journal-title":"J. Extracellular Biol."},{"issue":"10","key":"58290_CR59","doi-asserted-by":"publisher","DOI":"10.1002\/jex2.70016","volume":"3","author":"S Xu","year":"2024","unstructured":"Xu, S. et al. Comparison of nanoimaging and nanoflow based detection of extracellular vesicles at a single particle resolution. J. Extracellular Biol. 3(10), e70016. https:\/\/doi.org\/10.1002\/jex2.70016 (2024).","journal-title":"J. Extracellular Biol."},{"issue":"4","key":"58290_CR60","doi-asserted-by":"publisher","DOI":"10.1002\/adhm.201801082","volume":"8","author":"G Go","year":"2019","unstructured":"Go, G. et al. Extracellular vesicle-mimetic ghost nanovesicles for delivering anti-inflammatory drugs to mitigate gram-negative bacterial outer membrane vesicle-induced systemic inflammatory response syndrome. Adv Healthcare Mater 8(4), e1801082. https:\/\/doi.org\/10.1002\/adhm.201801082 (2019).","journal-title":"Adv Healthcare Mater"},{"key":"58290_CR61","doi-asserted-by":"publisher","DOI":"10.1016\/j.addr.2024.115196","volume":"207","author":"Y Chen","year":"2024","unstructured":"Chen, Y. et al. Intranasal drug delivery: The interaction between nanoparticles and the nose-to-brain pathway. Adv Drug Deliv Rev 207, 115196. https:\/\/doi.org\/10.1016\/j.addr.2024.115196 (2024).","journal-title":"Adv Drug Deliv Rev"},{"key":"58290_CR62","doi-asserted-by":"publisher","DOI":"10.3390\/pharmaceutics14030629","author":"TP Crowe","year":"2022","unstructured":"Crowe, T. P. & Hsu, W. H. Evaluation of recent intranasal drug delivery systems to the central nervous system. Pharmaceutics https:\/\/doi.org\/10.3390\/pharmaceutics14030629 (2022).","journal-title":"Pharmaceutics"},{"key":"58290_CR63","doi-asserted-by":"publisher","DOI":"10.3389\/fbioe.2023.1271489","volume":"11","author":"J Zhao","year":"2023","unstructured":"Zhao, J. et al. Biomedical applications of artificial exosomes for intranasal drug delivery. Front Bioeng Biotechnol 11, 1271489. https:\/\/doi.org\/10.3389\/fbioe.2023.1271489 (2023).","journal-title":"Front Bioeng Biotechnol"},{"key":"58290_CR64","doi-asserted-by":"publisher","DOI":"10.3390\/ph16060802","author":"J Lee","year":"2023","unstructured":"Lee, J., Choi, M. K. & Song, I. S. Recent advances in doxorubicin formulation to enhance pharmacokinetics and tumor targeting. Pharmaceuticals (Basel) https:\/\/doi.org\/10.3390\/ph16060802 (2023).","journal-title":"Pharmaceuticals (Basel)"},{"key":"58290_CR65","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2023.115612","volume":"258","author":"H Zhao","year":"2023","unstructured":"Zhao, H. et al. Doxorubicin prodrug-based nanomedicines for the treatment of cancer. Eur J Med Chem 258, 115612. https:\/\/doi.org\/10.1016\/j.ejmech.2023.115612 (2023).","journal-title":"Eur J Med Chem"},{"issue":"11","key":"58290_CR66","doi-asserted-by":"publisher","first-page":"3621","DOI":"10.1089\/ten.tea.2009.0155","volume":"15","author":"SK Dhara","year":"2009","unstructured":"Dhara, S. K. et al. Genetic manipulation of neural progenitors derived from human embryonic stem cells. Tissue Eng Part A 15(11), 3621\u20133634. https:\/\/doi.org\/10.1089\/ten.tea.2009.0155 (2009).","journal-title":"Tissue Eng Part A"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-026-58290-8","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-026-58290-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-026-58290-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T12:04:23Z","timestamp":1788782663000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-026-58290-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,18]]},"references-count":66,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["58290"],"URL":"https:\/\/doi.org\/10.1038\/s41598-026-58290-8","relation":{"has-preprint":[{"id-type":"doi","id":"10.21203\/rs.3.rs-7622911\/v1","asserted-by":"object"}]},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,18]]},"assertion":[{"value":"15 September 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 June 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 June 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"A.M.S, C.M.W., A.P., L.P.C., R.M., M.P.V, W.A., and V.M., R.S. and S.L.S are former or current employees of Aruna Bio, Inc.","order":1,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"27892"}}