{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T18:44:32Z","timestamp":1793385872807,"version":"4.5.0"},"reference-count":92,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2025,9,4]],"date-time":"2025-09-04T00:00:00Z","timestamp":1756944000000},"content-version":"vor","delay-in-days":3,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,9,1]],"date-time":"2025-09-01T00:00:00Z","timestamp":1756684800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["CNS Neurosci Ther"],"published-print":{"date-parts":[[2025,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aim<\/jats:title>\n                    <jats:p>This review provides a systematic evaluation of 94 stem cell clinical trials to treat neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Data were collected from using relevant search terms, focusing exclusively on stem cell therapy. Of the 8000+ participants in these trials, nearly 70% were enrolled in AD\u2010related studies. Only three Phase 3 studies were conducted, and most trials were in the early phases (Phases 1 and 2). Mesenchymal stem cells, neural stem cells, induced pluripotent stem cells, and embryonic stem cells are used the most to treat neurodegenerative diseases. This review also explores the emerging fields of preclinical and clinical investigations of stem cell\u2010derived exosome\u2010based therapies for neurodegenerative diseases.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Exosomes can cross the blood\u2013brain barrier to deliver therapeutic molecules directly to the brain, offering a less invasive alternative to stem cell transplantation. Mesenchymal stem cell\u2010derived exosomes, in particular, have demonstrated significant potential in preclinical models by reducing neuroinflammation, oxidative stress, and promoting neuronal regeneration. Additionally, recent advances in exosome engineering, including surface modifications, therapeutic agent loading, and transgenic modifications, have improved targeting, stability, blood\u2013brain barrier delivery, and neural cell interactions, enabling targeted and effective treatment. Exosome\u2010based therapies are in the preliminary phases of clinical investigation, with only three clinical trials.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Given the increasing interest in exosome therapy, clinical investigations are expected to increase. This growth will be driven by ongoing advancements in exosome technology, a deeper understanding of their therapeutic potential, and escalating demand for innovative treatment strategies for neurodegenerative diseases.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/cns.70577","type":"journal-article","created":{"date-parts":[[2025,9,4]],"date-time":"2025-09-04T07:20:18Z","timestamp":1756970418000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Advances in Neurodegenerative Disease Therapy: Stem Cell Clinical Trials and Promise of Engineered Exosomes"],"prefix":"10.1111","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7687-6082","authenticated-orcid":false,"given":"Sevim","family":"Isik","sequence":"first","affiliation":[{"name":"Department of Molecular Biology and Genetics Faculty of Engineering and Natural Sciences, Uskudar University  Uskudar Istanbul Turkey"},{"name":"Stem Cell Research and Application Center (USKOKMER), Uskudar University  Uskudar Istanbul Turkey"},{"name":"NPCELLAB Cellular Therapy, Stem Cell and Advanced Therapy Medicinal Products GMP Laboratory Uskudar University  Uskudar Istanbul Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-7840-2823","authenticated-orcid":false,"given":"Sajeda","family":"Osman","sequence":"additional","affiliation":[{"name":"Stem Cell Research and Application Center (USKOKMER), Uskudar University  Uskudar Istanbul Turkey"},{"name":"Department of Molecular Biology, Institute of Science Uskudar University  Uskudar Istanbul Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9667-3506","authenticated-orcid":false,"given":"Bercem","family":"Yeman\u2010Kiyak","sequence":"additional","affiliation":[{"name":"Stem Cell Research and Application Center (USKOKMER), Uskudar University  Uskudar Istanbul Turkey"},{"name":"NPCELLAB Cellular Therapy, Stem Cell and Advanced Therapy Medicinal Products GMP Laboratory Uskudar University  Uskudar Istanbul Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-2103-6750","authenticated-orcid":false,"given":"Suhair Rami Mohammed","family":"Shamshir","sequence":"additional","affiliation":[{"name":"Stem Cell Research and Application Center (USKOKMER), Uskudar University  Uskudar Istanbul Turkey"},{"name":"Department of Molecular Biology, Institute of Science Uskudar University  Uskudar Istanbul Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nesrin Majdi Edwan","family":"Sanchez","sequence":"additional","affiliation":[{"name":"Stem Cell Research and Application Center (USKOKMER), Uskudar University  Uskudar Istanbul Turkey"},{"name":"Department of Molecular Biology, Institute of Science Uskudar University  Uskudar Istanbul Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,9,4]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/1565"},{"issue":"4","key":"e_1_2_10_3_1","first-page":"879","article-title":"Aggregation of Alpha\u2010Synuclein in Lewy Bodies of Sporadic Parkinson's Disease and Dementia With Lewy Bodies","volume":"152","author":"Baba M.","year":"1998","journal-title":"American Journal of Pathology"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1006\/mcpr.1994.1046"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/378403a0"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells12071012"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a009423"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/14651858.CD013306.pub2"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.7759\/CUREUS.71476"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/J.ARR.2024.102357"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.14283\/JPAD.2022.30\/TABLES\/3"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000207663"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474\u20104422(22)00121\u20101"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2022.08.004"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41593\u2010020\u201000778\u20101"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/adfm.202402630"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1601\u20100825.2011.01870.x"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2021.738442"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1007\/S00415\u2010024\u201012329\u2010W"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1007\/S10571\u2010024\u201001460\u2010X"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.vesic.2023.100029"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.3390\/IJMS22042153"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells11193002"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21093103"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.3390\/CELLS13090779"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.29810"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22031433"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1056\/nejmoa1915872"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms18030538"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.3389\/fmolb.2023.1198044"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.3390\/biomedicines9081061"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.omtn.2019.11.023"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1515\/bmc\u20102015\u20100033"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms20020236"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598\u2010017\u201002786\u2010x"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40779\u2010023\u201000472\u2010w"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.780897"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.32604\/biocell.2024.053148"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.4103\/1673\u20105374.379036"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.1159\/000491543"},{"key":"e_1_2_10_42_1","doi-asserted-by":"publisher","DOI":"10.4103\/1673\u20105374.368300"},{"key":"e_1_2_10_43_1","doi-asserted-by":"publisher","DOI":"10.7150\/thno.74305"},{"key":"e_1_2_10_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcdb.2017.08.020"},{"key":"e_1_2_10_45_1","doi-asserted-by":"publisher","DOI":"10.1038\/s12276\u2010024\u201001209\u2010y"},{"key":"e_1_2_10_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.gendis.2022.03.021"},{"key":"e_1_2_10_47_1","doi-asserted-by":"publisher","DOI":"10.1111\/cas.14563"},{"key":"e_1_2_10_48_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.adl3406"},{"key":"e_1_2_10_49_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsnano.1c08473"},{"key":"e_1_2_10_50_1","doi-asserted-by":"publisher","DOI":"10.1080\/10717544.2020.1762262"},{"key":"e_1_2_10_51_1","doi-asserted-by":"publisher","DOI":"10.3390\/biomedicines12092113"},{"key":"e_1_2_10_52_1","doi-asserted-by":"publisher","DOI":"10.5966\/sctm.2012\u20100015"},{"key":"e_1_2_10_53_1","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2018.00317"},{"key":"e_1_2_10_54_1","doi-asserted-by":"publisher","DOI":"10.7150\/THNO.62069"},{"key":"e_1_2_10_55_1","doi-asserted-by":"publisher","DOI":"10.1002\/sctm.19\u20100327"},{"key":"e_1_2_10_56_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598\u2010023\u201042485\u20104"},{"key":"e_1_2_10_57_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2019.11.017"},{"key":"e_1_2_10_58_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M114.577213"},{"key":"e_1_2_10_59_1","doi-asserted-by":"publisher","DOI":"10.14336\/AD.2020.1221"},{"key":"e_1_2_10_60_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41419\u2010020\u20102473\u20105"},{"key":"e_1_2_10_61_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11010\u2010023\u201004700\u20108"},{"key":"e_1_2_10_62_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12951\u2010022\u201001356\u20102"},{"key":"e_1_2_10_63_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2016.09.069"},{"key":"e_1_2_10_64_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yexcr.2015.12.009"},{"key":"e_1_2_10_65_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2019.01070"},{"key":"e_1_2_10_66_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21103651"},{"key":"e_1_2_10_67_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neulet.2023.137493"},{"key":"e_1_2_10_68_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2012.00228"},{"key":"e_1_2_10_69_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12035\u2010023\u201003437\u20101"},{"key":"e_1_2_10_70_1","doi-asserted-by":"publisher","DOI":"10.14802\/jmd.16054\/J"},{"key":"e_1_2_10_71_1","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp\u20102018\u2010EHDN.238"},{"key":"e_1_2_10_72_1","doi-asserted-by":"publisher","DOI":"10.1111\/ejn.13275"},{"key":"e_1_2_10_73_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12964\u2010022\u201000959\u20104"},{"key":"e_1_2_10_74_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392\u2010023\u201001704\u20100"},{"key":"e_1_2_10_75_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells13080670"},{"key":"e_1_2_10_76_1","doi-asserted-by":"publisher","DOI":"10.1080\/1061186X.2021.1929257"},{"key":"e_1_2_10_77_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13578\u2010021\u201000650\u20100"},{"key":"e_1_2_10_78_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12979\u2010019\u20100150\u20102"},{"key":"e_1_2_10_79_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010018\u201003733\u20108"},{"key":"e_1_2_10_80_1","doi-asserted-by":"publisher","DOI":"10.1002\/mds.25978"},{"key":"e_1_2_10_81_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12967\u2010023\u201004461\u20104"},{"key":"e_1_2_10_82_1","doi-asserted-by":"publisher","DOI":"10.1038\/mt.2016.126"},{"key":"e_1_2_10_83_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.omtn.2021.01.022"},{"key":"e_1_2_10_84_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12967\u2010023\u201004638\u2010x"},{"key":"e_1_2_10_85_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neulet.2023.137437"},{"key":"e_1_2_10_86_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2020.105218"},{"key":"e_1_2_10_87_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jconrel.2015.03.033"},{"key":"e_1_2_10_88_1","doi-asserted-by":"publisher","DOI":"10.1111\/jcmm.17993"},{"key":"e_1_2_10_89_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0229850"},{"key":"e_1_2_10_90_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2024.123014"},{"key":"e_1_2_10_91_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10561\u2010022\u201010008\u20106"},{"key":"e_1_2_10_92_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10787\u2010024\u201001476\u20101"},{"key":"e_1_2_10_93_1","doi-asserted-by":"publisher","DOI":"10.1002\/smll.201906273"}],"container-title":["CNS Neuroscience &amp; Therapeutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cns.70577","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/cns.70577","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cns.70577","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T13:46:36Z","timestamp":1777902396000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/cns.70577"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9]]},"references-count":92,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2025,9]]}},"alternative-id":["10.1111\/cns.70577"],"URL":"https:\/\/doi.org\/10.1111\/cns.70577","archive":["Portico"],"relation":{},"ISSN":["1755-5930","1755-5949"],"issn-type":[{"value":"1755-5930","type":"print"},{"value":"1755-5949","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9]]},"assertion":[{"value":"2025-03-17","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-08-14","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-09-04","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70577"}}