{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T20:44:01Z","timestamp":1777409041490,"version":"3.51.4"},"reference-count":169,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2023,1,16]],"date-time":"2023-01-16T00:00:00Z","timestamp":1673827200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Instituto de Salud Carlos III (ISCIII) grant Sara Borrell","award":["CD22\/00125"],"award-info":[{"award-number":["CD22\/00125"]}]},{"name":"Instituto de Salud Carlos III (ISCIII) grant Sara Borrell","award":["PID2021-122473OA-I00"],"award-info":[{"award-number":["PID2021-122473OA-I00"]}]},{"name":"Ministerio de Ciencia e Innovaci\u00f3n, Proyectos de Generaci\u00f3n de Conocimiento","award":["CD22\/00125"],"award-info":[{"award-number":["CD22\/00125"]}]},{"name":"Ministerio de Ciencia e Innovaci\u00f3n, Proyectos de Generaci\u00f3n de Conocimiento","award":["PID2021-122473OA-I00"],"award-info":[{"award-number":["PID2021-122473OA-I00"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Neurodegenerative diseases constitute a group of pathologies whose etiology remains unknown in many cases, and there are no treatments that stop the progression of such diseases. Moreover, the existence of the blood\u2013brain barrier is an impediment to the penetration of exogenous molecules, including those found in many drugs. Exosomes are extracellular vesicles secreted by a wide variety of cells, and their primary functions include intercellular communication, immune responses, human reproduction, and synaptic plasticity. Due to their natural origin and molecular similarities with most cell types, exosomes have emerged as promising therapeutic tools for numerous diseases. Specifically, neurodegenerative diseases have shown to be a potential target for this nanomedicine strategy due to the difficult access to the brain and the strategy\u2019s pathophysiological complexity. In this regard, this review explores the most important biological-origin drug delivery systems, innovative isolation methods of exosomes, their physicochemical characterization, drug loading, cutting-edge functionalization strategies to target them within the brain, the latest research studies in neurodegenerative diseases, and the future challenges of exosomes as nanomedicine-based therapeutic tools.<\/jats:p>","DOI":"10.3390\/pharmaceutics15010298","type":"journal-article","created":{"date-parts":[[2023,1,16]],"date-time":"2023-01-16T03:40:34Z","timestamp":1673840434000},"page":"298","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":39,"title":["Exosomes-Based Nanomedicine for Neurodegenerative Diseases: Current Insights and Future Challenges"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9567-4283","authenticated-orcid":false,"given":"Amanda","family":"Cano","sequence":"first","affiliation":[{"name":"Ace Alzheimer Center Barcelona\u2014International University of Catalunya (UIC), 08028 Barcelona, Spain"},{"name":"Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), 28029 Madrid, Spain"},{"name":"Institute of Nanoscience and Nanotechnology (IN2UB), 08028 Barcelona, Spain"},{"name":"Department of Pharmacy, Pharmaceutical Technology and Physical Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, 08028 Barcelona, Spain"}]},{"given":"\u00c1lvaro","family":"Mu\u00f1oz-Morales","sequence":"additional","affiliation":[{"name":"Ace Alzheimer Center Barcelona\u2014International University of Catalunya (UIC), 08028 Barcelona, Spain"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2571-108X","authenticated-orcid":false,"given":"Elena","family":"S\u00e1nchez-L\u00f3pez","sequence":"additional","affiliation":[{"name":"Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), 28029 Madrid, Spain"},{"name":"Institute of Nanoscience and Nanotechnology (IN2UB), 08028 Barcelona, Spain"},{"name":"Department of Pharmacy, Pharmaceutical Technology and Physical Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, 08028 Barcelona, Spain"},{"name":"Unit of Synthesis and Biomedical Applications of Peptides, IQAC-CSIC, 08034 Barcelona, Spain"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4301-7297","authenticated-orcid":false,"given":"Miren","family":"Ettcheto","sequence":"additional","affiliation":[{"name":"Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), 28029 Madrid, Spain"},{"name":"Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, 08028 Barcelona, Spain"},{"name":"Institute of Neurosciences, University of Barcelona, 08028 Barcelona, Spain"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9737-6017","authenticated-orcid":false,"given":"Eliana B.","family":"Souto","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal"},{"name":"REQUIMTE\/UCIBIO, Faculty of Pharmacy, University of Porto, 4050-313 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1229-5956","authenticated-orcid":false,"given":"Antonio","family":"Camins","sequence":"additional","affiliation":[{"name":"Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), 28029 Madrid, Spain"},{"name":"Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, 08028 Barcelona, Spain"},{"name":"Institute of Neurosciences, University of Barcelona, 08028 Barcelona, Spain"}]},{"given":"Merc\u00e8","family":"Boada","sequence":"additional","affiliation":[{"name":"Ace Alzheimer Center Barcelona\u2014International University of Catalunya (UIC), 08028 Barcelona, Spain"},{"name":"Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), 28029 Madrid, Spain"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2633-2495","authenticated-orcid":false,"given":"Agust\u00edn","family":"Ru\u00edz","sequence":"additional","affiliation":[{"name":"Ace Alzheimer Center Barcelona\u2014International University of Catalunya (UIC), 08028 Barcelona, Spain"},{"name":"Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), 28029 Madrid, Spain"}]}],"member":"1968","published-online":{"date-parts":[[2023,1,16]]},"reference":[{"key":"ref_1","unstructured":"(2023, January 14). Mental health: Neurological disorders World Health Organization (WHO). Available online: https:\/\/www.who.int\/features\/qa\/55\/en\/."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1155\/2017\/2525967","article-title":"Oxidative Stress in Neurodegenerative Diseases: From Molecular Mechanisms to Clinical Applications","volume":"2017","author":"Liu","year":"2017","journal-title":"Oxid. Med. Cell Longev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1016\/j.envres.2017.07.048","article-title":"Metals and neurodegenerative diseases: A systematic review","volume":"159","author":"Cicero","year":"2017","journal-title":"Environ. Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"239","DOI":"10.3389\/fonc.2018.00239","article-title":"Beyond the Blood-Brain Barrier: The importance of Central Nervous System (CNS) Pharmacokinetics for the Treatment of CNS Tumors, including Diffuse intrinsic Pontine Glioma","volume":"8","author":"Warren","year":"2018","journal-title":"Front. Oncol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"152","DOI":"10.3109\/09687688.2014.937468","article-title":"The blood-brain barrier: Structure, function and therapeutic approaches to cross it","volume":"31","author":"Tajes","year":"2014","journal-title":"Mol. Membr. Biol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"721","DOI":"10.7150\/ijbs.79063","article-title":"Extracellular vesicles, the emerging mirrors of brain physiopathology","volume":"19","author":"Cano","year":"2023","journal-title":"Int. J. Biol. Sci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"eaau6977","DOI":"10.1126\/science.aau6977","article-title":"The biology, function, and biomedical applications of exosomes","volume":"367","author":"Kalluri","year":"2020","journal-title":"Science"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1095","DOI":"10.4155\/tde.11.83","article-title":"Exosomes and the blood\u2013brain barrier: Implications for neurological diseases","volume":"2","author":"Wood","year":"2011","journal-title":"Ther. Deliv."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.pharmthera.2017.02.020","article-title":"Exosomes: Therapy delivery tools and biomarkers of diseases","volume":"174","author":"Barile","year":"2017","journal-title":"Pharmacol. Ther."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1038\/s41392-020-00261-0","article-title":"Exosomes: Key players in cancer and potential therapeutic strategy","volume":"5","author":"Dai","year":"2020","journal-title":"Signal Transduct. Target. Ther. Vol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"101321","DOI":"10.1016\/j.arr.2021.101321","article-title":"The emerging role of exosomes in Alzheimer \u2019 s disease","volume":"68","author":"Zhang","year":"2021","journal-title":"Ageing Res. Rev."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"15328","DOI":"10.1038\/s41598-020-72067-7","article-title":"Sarcoidosis exosomes stimulate monocytes to produce pro-inflammatory cytokines and CCL2","volume":"10","author":"Wahlund","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"767488","DOI":"10.3389\/fcvm.2021.767488","article-title":"Exosomes in Cardiovascular Diseases: Pathological Potential of Nano-Messenger","volume":"8","author":"Jadli","year":"2021","journal-title":"Front. Cardiovasc. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"194","DOI":"10.3389\/fnins.2017.00194","article-title":"Exosomes and the Prion Protein: More than One Truth","volume":"11","author":"Hartmann","year":"2017","journal-title":"Front. Neurosci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2165","DOI":"10.1007\/s11164-013-1338-2","article-title":"Advances and new technologies applied in controlled drug delivery system","volume":"41","author":"Bassyouni","year":"2015","journal-title":"Res. Chem. Intermed."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1186\/s12951-021-00864-x","article-title":"Nanomedicine-based technologies and novel biomarkers for the diagnosis and treatment of Alzheimer\u2019s disease: From current to future challenges","volume":"19","author":"Cano","year":"2021","journal-title":"J. Nanobiotechnol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2873","DOI":"10.2147\/OTT.S104691","article-title":"Recent advancements in erythrocytes, platelets, and albumin as delivery systems","volume":"9","author":"Xu","year":"2016","journal-title":"Onco. Targets. Ther."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"114394","DOI":"10.1016\/j.addr.2022.114394","article-title":"Cell-based drug delivery systems and their in vivo fate","volume":"187","author":"Yang","year":"2022","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1016\/j.tips.2020.11.008","article-title":"Biological cells as therapeutic delivery vehicles","volume":"42","author":"Bush","year":"2021","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Wang, Y., Shi, T., Srivastava, S., Kagan, J., Liu, T., and Rodland, K.D. (2020). Proteomic Analysis of Exosomes for Discovery of Protein Biomarkers for Prostate and Bladder Cancer. Cancers, 12.","DOI":"10.3390\/cancers12092335"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"6917","DOI":"10.2147\/IJN.S264498","article-title":"Exosome: A Review of Its Classification, Isolation Techniques, Storage, Diagnostic and Targeted Therapy Applications","volume":"15","author":"Zhang","year":"2020","journal-title":"Int. J. Nanomed."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"17319","DOI":"10.1038\/srep17319","article-title":"Isolation of exosomes by differential centrifugation: Theoretical analysis of a commonly used protocol","volume":"5","author":"Livshits","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1152","DOI":"10.1172\/JCI81129","article-title":"Extracellular vesicle isolation and characterization: Toward clinical application","volume":"126","author":"Xu","year":"2016","journal-title":"J. Clin. Investig."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Baranyai, T., Herczeg, K., On\u00f3di, Z., Voszka, I., M\u00f3dos, K., Marton, N., and Nagy, G. (2015). Isolation of Exosomes from Blood Plasma: Qualitative and Quantitative Comparison of Ultracentrifugation and Size Exclusion Chromatography Methods. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0145686"},{"key":"ref_25","first-page":"3","article-title":"Isolation and Characterization of Exosomes from Cell Culture Supernatants and Biological Fluids","volume":"30","author":"Amigorena","year":"2006","journal-title":"Curr. Protoc. Cell Biol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1038\/nmeth.4185","article-title":"EV-TRACK: Transparent reporting and centralizing knowledge in extracellular vesicle research","volume":"14","author":"Deun","year":"2017","journal-title":"Nat. Methods"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"27031","DOI":"10.3402\/jev.v4.27031","article-title":"Optimized exosome isolation protocol for cell culture supernatant and human plasma","volume":"4","author":"Lobb","year":"2015","journal-title":"J. Extracell Vesicles"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1007\/978-1-4939-6728-5_7","article-title":"A Protocol for Isolation and Proteomic Characterization of Distinct Extracellular Vesicle Subtypes by Sequential Centrifugal Ultrafiltration","volume":"1545","author":"Xu","year":"2017","journal-title":"Methods Mol. Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"23430","DOI":"10.3402\/jev.v3.23430","article-title":"Single-step isolation of extracellular vesicles by size-exclusion chromatography","volume":"3","author":"Pol","year":"2014","journal-title":"J. Extracell Vesicles"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"15297","DOI":"10.1038\/s41598-017-15717-7","article-title":"Ultrafiltration combined with size exclusion chromatography efficiently isolates extracellular vesicles from cell culture media for compositional and functional studies","volume":"7","author":"Benedikter","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e1800156","DOI":"10.1002\/pmic.201800156","article-title":"Optimizing Size Exclusion Chromatography for Extracellular Vesicle Enrichment and Proteomic Analysis from Clinically Relevant Samples","volume":"19","author":"Lane","year":"2019","journal-title":"Proteomics"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"14280","DOI":"10.1039\/C8NR02871K","article-title":"Immuno-modified superparamagnetic nanoparticles via host\u2013guest interactions for high-purity capture and mild release of exosomes","volume":"10","author":"Cai","year":"2018","journal-title":"Nanoscale"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1016\/j.nbt.2015.09.003","article-title":"Development of a magnetic bead-based method for the collection of circulating extracellular vesicles","volume":"33","author":"Shih","year":"2016","journal-title":"New Biotechnol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"23978","DOI":"10.1038\/srep23978","article-title":"ExtraPEG: A Polyethylene Glycol-Based Method for Enrichment of Extracellular Vesicles","volume":"6","author":"Rider","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_35","unstructured":"ExoQuick\u00ae (2022, December 28). System Bioscience, LLC. Available online: https:\/\/www.systembio.com\/the-original-exoquick."},{"key":"ref_36","unstructured":"exoEasy\u00ae Maxi kit (2022, December 28). QIAGEN\u00a9. Available online: https:\/\/www.qiagen.com\/us\/products\/discovery-and-translational-research\/exosomes-ctcs\/exosomes\/exoeasy-maxi-kit\/."},{"key":"ref_37","unstructured":"MinuteTM Hi-Efficiency Exosome Precipitation Reagent (2022, December 28). Invent Biotechnology, INC. Available online: https:\/\/inventbiotech.com\/products\/minuteTM-hi-efficiency-exosome-precipitation-reagent."},{"key":"ref_38","unstructured":"MagCapture TM (2022, December 28). Exosome Isolation Kit PS. ujifilm Wako, INC. Available online: https:\/\/labchem-wako.fujifilm.com\/europe\/product\/detail\/W01W0129-7760.html."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1016\/j.jconrel.2022.06.011","article-title":"Recent progresses in exosome-based systems for targeted drug delivery to the brain","volume":"348","author":"Bashyal","year":"2022","journal-title":"J. Control. Release"},{"key":"ref_40","first-page":"1","article-title":"Challenges in the Development of Drug Delivery Systems Based on Small Extracellular Vesicles for Therapy of Brain Diseases","volume":"13","author":"Matos","year":"2022","journal-title":"Front. Pharmacol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1344087","DOI":"10.1080\/20013078.2017.1344087","article-title":"Size and concentration analyses of extracellular vesicles by nanoparticle tracking analysis: A variation study","volume":"6","author":"Vestad","year":"2017","journal-title":"J. Extracell Vesicles"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Comfort, N., Cai, K., Bloomquist, T.R., Strait, M.D., Ferrante, A.W.J., and Baccarelli, A.A. (2021). Nanoparticle Tracking Analysis for the Quantification and Size Determination of Extracellular Vesicles. J. Vis. Exp., 28.","DOI":"10.3791\/62447-v"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"12295","DOI":"10.1038\/s41598-019-48181-6","article-title":"Improved methods for fluorescent labeling and detection of single extracellular vesicles using nanoparticle tracking analysis","volume":"9","author":"Thane","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/j.trac.2016.10.012","article-title":"Advances in exosome quantification techniques","volume":"86","author":"Chia","year":"2017","journal-title":"Trends Anal. Chem."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1007\/s11051-008-9435-7","article-title":"A comparison of atomic force microscopy (AFM) and dynamic light scattering (DLS) methods to characterize nanoparticle size distributions","volume":"10","author":"Hoo","year":"2008","journal-title":"J. Nanopart. Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1016\/j.ejpb.2020.07.026","article-title":"Exosomes as drug delivery systems: A brief overview and progress update","volume":"154","author":"Patil","year":"2020","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Malenica, M., Vukomanovi\u0107, M., Kurtjak, M., Masciotti, V., Zilio, S.D., Greco, S., and Lazzarino, M. (2021). Perspectives of Microscopy Methods for Morphology Characterisation of Extracellular Vesicles from Human Biofluids. Biomedicines, 9.","DOI":"10.3390\/biomedicines9060603"},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Emelyanov, A., Shtam, T., Kamyshinsky, R., Garaeva, L., Verlov, N., Miliukhina, I., and Kudrevatykh, A. (2020). Cryo-electron microscopy of extracellular vesicles from cerebrospinal fluid. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0227949"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"21045","DOI":"10.3402\/jev.v2i0.21045","article-title":"Characterisation of tissue factor-bearing extracellular vesicles with AFM: Comparison of air-tapping-mode AFM and liquid Peak Force AFM","volume":"2","author":"Hardij","year":"2013","journal-title":"J. Extracell Vesicles"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"012013","DOI":"10.1088\/1742-6596\/1942\/1\/012013","article-title":"Application of AFM, TEM, and NTA for characterization of exosomes produced by placenta-derived mesenchymal cells","volume":"142","author":"Bagrov","year":"2021","journal-title":"J. Phys. Conf. Ser."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1007\/978-1-4939-7253-1_12","article-title":"Extracellular Vesicle Isolation and Analysis by Western Blotting","volume":"1660","author":"Kowal","year":"2017","journal-title":"Methods Mol. Biol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"25530","DOI":"10.3402\/jev.v4.25530","article-title":"Simplified protocol for flow cytometry analysis of fluorescently labeled exosomes and microvesicles using dedicated flow cytometer","volume":"4","author":"Pospichalova","year":"2015","journal-title":"J. Extracell Vesicles"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/bs.mie.2020.06.011","article-title":"Immunocapture-based ELISA to characterize and quantify exosomes in both cell culture supernatants and body fluids","volume":"645","author":"Logozzi","year":"2020","journal-title":"Methods Enzym."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1878","DOI":"10.1038\/s41598-017-01731-2","article-title":"Labeling Extracellular Vesicles for Nanoscale Flow Cytometry","volume":"7","author":"Telford","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"593750","DOI":"10.3389\/fcell.2020.593750","article-title":"Employing Flow Cytometry to Extracellular Vesicles Sample Microvolume Analysis and Quality Control","volume":"8","author":"Maia","year":"2020","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"6206","DOI":"10.2174\/1381612823666170913164738","article-title":"The Transport Mechanism of Extracellular Vesicles at the Blood-Brain Barrier","volume":"23","author":"Matsumoto","year":"2017","journal-title":"Curr. Pharm. Des."},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Banks, W.A., Sharma, P., Bullock, K.M., Hansen, K.M., Ludwig, N., and Whiteside, T.L. (2020). Transport of Extracellular Vesicles across the Blood-Brain Barrier: Brain Pharmacokinetics and Effects of Inflammation. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21124407"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1186\/s13045-018-0637-x","article-title":"Immune cell subset differentiation and tissue inflammation","volume":"11","author":"Fang","year":"2018","journal-title":"J. Hematol. Oncol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1186\/s13578-021-00650-0","article-title":"Exosomal delivery of therapeutic modulators through the blood-brain barrier; promise and pitfalls","volume":"11","author":"Heidarzadeh","year":"2021","journal-title":"Cell Biosci."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1016\/j.jconrel.2020.07.042","article-title":"Surface functionalization of exosomes for target-specific delivery and in vivo imaging & tracking: Strategies and significance","volume":"326","author":"Salunkhe","year":"2020","journal-title":"J. Control. Release"},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Choi, H., Choi, K., Kim, D., Oh, B., Yim, H., Jo, S., and Choi, C. (2022). Strategies for Targeted Delivery of Exosomes to the Brain: Advantages and Challenges. Pharmaceutics, 14.","DOI":"10.3390\/pharmaceutics14030672"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1777","DOI":"10.1021\/bc500291r","article-title":"Surface Functionalization of Exosomes Using Click Chemistry","volume":"25","author":"Smyth","year":"2014","journal-title":"Bioconjugate Chem."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"2385","DOI":"10.1007\/s13346-021-01087-1","article-title":"Exosomal targeting and its potential clinical application","volume":"12","author":"He","year":"2022","journal-title":"Drug Deliv. Transl. Res."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"2004","DOI":"10.1002\/1521-3773(20010601)40:11<2004::AID-ANIE2004>3.0.CO;2-5","article-title":"Click Chemistry: Diverse Chemical Function from a Few Good Reactions","volume":"40","author":"Kolb","year":"2001","journal-title":"Angew. Chemie Int. Ed."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"754","DOI":"10.1038\/aps.2017.12","article-title":"Engineering exosomes as refined biological nanoplatforms for drug delivery","volume":"38","author":"Luan","year":"2017","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1186\/s12951-018-0403-9","article-title":"Recent advancements in the use of exosomes as drug delivery systems","volume":"16","author":"Bunggulawa","year":"2018","journal-title":"J. Nanobiotechnol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"27441","DOI":"10.1021\/acsami.7b06464","article-title":"Chemically Edited Exosomes with Dual Ligand Purified by Microfluidic Device for Active Targeted Drug Delivery to Tumor Cells","volume":"9","author":"Wang","year":"2017","journal-title":"ACS Appl. Mater. Interfaces"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"16892","DOI":"10.1021\/ja053919x","article-title":"Shell click-crosslinked (SCC) nanoparticles: A new methodology for synthesis and orthogonal functionalization","volume":"127","author":"Joralemon","year":"2005","journal-title":"J. Am. Chem. Soc."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1186\/s12987-020-00209-0","article-title":"Differential expression of receptors mediating receptor-mediated transcytosis (RMT) in brain microvessels, brain parenchyma and peripheral tissues of the mouse and the human","volume":"17","author":"Zhang","year":"2020","journal-title":"Fluids Barriers CNS"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1111\/j.1471-4159.2011.07208.x","article-title":"Quantitative targeted absolute proteomics of human blood-brain barrier transporters and receptors","volume":"117","author":"Uchida","year":"2011","journal-title":"J. Neurochem."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1016\/j.jconrel.2019.11.009","article-title":"Systemic delivery of microRNA-21 antisense oligonucleotides to the brain using T7-peptide decorated exosomes","volume":"17","author":"Kim","year":"2020","journal-title":"J. Control Release"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.neuron.2013.10.061","article-title":"Increased brain penetration and potency of a therapeutic antibody using a monovalent molecular shuttle","volume":"81","author":"Niewoehner","year":"2014","journal-title":"Neuron"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"233","DOI":"10.3892\/etm.2014.1727","article-title":"Transferrin receptor (TfR) trafficking determines brain uptake of TfR antibody affinity variants","volume":"211","author":"Yu","year":"2014","journal-title":"J. Exp. Med."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"807","DOI":"10.1023\/A:1016244500596","article-title":"Human insulin receptor monoclonal antibody undergoes high affinity binding to human brain capillaries in vitro and rapid transcytosis through the blood-brain barrier in vivo in the primate","volume":"12","author":"Pardridge","year":"1995","journal-title":"Pharm. Res."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"3122","DOI":"10.1523\/JNEUROSCI.4785-13.2014","article-title":"Comparison of five peptide vectors for improved brain delivery of the lysosomal enzyme arylsulfatase A","volume":"34","author":"Cramer","year":"2014","journal-title":"J. Neurosci."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1186\/s13024-015-0043-6","article-title":"A brain-targeted, modified neurosin (kallikrein-6) reduces \u03b1-synuclein accumulation in a mouse model of multiple system atrophy","volume":"10","author":"Spencer","year":"2015","journal-title":"Mol. Neurodegener"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"3324","DOI":"10.1016\/j.biomaterials.2012.01.025","article-title":"The targeted delivery of anticancer drugs to brain glioma by PEGylated oxidized multi-walled carbon nanotubes modified with angiopep-2","volume":"33","author":"Ren","year":"2012","journal-title":"Biomaterials"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"8167","DOI":"10.1016\/j.biomaterials.2012.07.046","article-title":"Anti-glioblastoma efficacy and safety of paclitaxel-loading Angiopep-conjugated dual targeting PEG-PCL nanoparticles","volume":"33","author":"Xin","year":"2012","journal-title":"Biomaterials"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1195","DOI":"10.7150\/thno.22662","article-title":"de Molecular Magnetic Resonance Imaging of Endothelial Activation in the Central Nervous System","volume":"8","author":"Gauberti","year":"2018","journal-title":"Theranostics"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"6015","DOI":"10.1182\/blood-2008-10-186650","article-title":"Elevated levels of soluble P-selectin in mice alter blood-brain barrier function, exacerbate stroke, and promote atherosclerosis","volume":"113","author":"Kisucka","year":"2009","journal-title":"Blood"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"993940","DOI":"10.3389\/fneur.2022.993940","article-title":"Increased PRR14 and VCAM-1 level in serum of patients with Parkinson\u2019s disease","volume":"13","author":"Zheng","year":"2022","journal-title":"Front. Neurol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"17543","DOI":"10.1038\/srep17543","article-title":"Targeted exosome-mediated delivery of opioid receptor Mu siRNA for the treatment of morphine relapse","volume":"5","author":"Liu","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.bbrc.2016.02.058","article-title":"Development of exosome surface display technology in living human cells","volume":"472","author":"Stickney","year":"2016","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"406","DOI":"10.1016\/j.tips.2017.01.003","article-title":"Cell-Penetrating Peptides: From Basic Research to Clinics","volume":"38","author":"Guidotti","year":"2017","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"697","DOI":"10.3389\/fphar.2020.00697","article-title":"Cell-Penetrating Peptides in Diagnosis and Treatment of Human Diseases: From Preclinical Research to Clinical Application","volume":"11","author":"Xie","year":"2020","journal-title":"Front. Pharmacol."},{"key":"ref_86","doi-asserted-by":"crossref","unstructured":"Sharma, G., Lakkadwala, S., Modgil, A., and Singh, J. (2016). The Role of Cell-Penetrating Peptide and Transferrin on Enhanced Delivery of Drug to Brain. Int. J. Mol. Sci., 17.","DOI":"10.3390\/ijms17060806"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"17523","DOI":"10.1038\/s41598-018-35976-2","article-title":"Brain-Specific Ultrastructure of Capillary Endothelial Glycocalyx and Its Possible Contribution for Blood Brain Barrier","volume":"8","author":"Ando","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"471","DOI":"10.3389\/fncel.2014.00471","article-title":"Differential neuroprotective potential of CRMP2 peptide aptamers conjugated to cationic, hydrophobic, and amphipathic cell penetrating peptides","volume":"8","author":"Moutal","year":"2015","journal-title":"Front. Cell Neurosci."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1038\/nbt.1807","article-title":"Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes","volume":"29","author":"Seow","year":"2011","journal-title":"Nat. Biotechnol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1186\/s12979-019-0150-2","article-title":"RVG-modified exosomes derived from mesenchymal stem cells rescue memory deficits by regulating inflammatory responses in a mouse model of Alzheimer\u2019s disease","volume":"16","author":"Cui","year":"2019","journal-title":"Immun. Ageing"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/j.biomaterials.2017.09.020","article-title":"Bio-inspired engineering of cell- and virus-like nanoparticles for drug delivery","volume":"147","author":"Parodi","year":"2017","journal-title":"Biomaterials"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"1900111","DOI":"10.1002\/adtp.201900111","article-title":"Chemical Modulation of Bioengineered Exosomes for Tissue-Specific Biodistribution","volume":"2","author":"Hwang","year":"2019","journal-title":"Adv. Ther."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1016\/j.actbio.2017.05.013","article-title":"Augmented liver targeting of exosomes by surface modification with cationized pullulan","volume":"57","author":"Tamura","year":"2017","journal-title":"Acta Biomater."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"6790","DOI":"10.1021\/acsami.6b01315","article-title":"Cellular Engineering with Membrane Fusogenic Liposomes to Produce Functionalized Extracellular Vesicles","volume":"8","author":"Lee","year":"2016","journal-title":"ACS Appl. Mater. Interfaces"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"1605604","DOI":"10.1002\/adma.201605604","article-title":"Virus-Mimetic Fusogenic Exosomes for Direct Delivery of Integral Membrane Proteins to Target Cell Membranes","volume":"29","author":"Yang","year":"2017","journal-title":"Adv. Mater."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"8278","DOI":"10.1038\/s41598-019-44569-6","article-title":"Surface modification of gold nanoparticles with neuron-targeted exosome for enhanced blood-brain barrier penetration","volume":"9","author":"Khongkow","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"1923","DOI":"10.1039\/C9MH00482C","article-title":"Switchable nanoparticle for programmed gene-chem delivery with enhanced neuronal recovery and CT imaging for neurodegenerative disease treatment","volume":"6","author":"Liu","year":"2019","journal-title":"Mater. Horiz."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"eaba3967","DOI":"10.1126\/sciadv.aba3967","article-title":"Targeted exosome coating gene-chem nanocomplex as \u201cnanoscavenger\u201d for clearing \u03b1-synuclein and immune activation of Parkinson\u2019s disease","volume":"6","author":"Liu","year":"2020","journal-title":"Sci. Adv."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/j.actbio.2020.06.036","article-title":"Exosomes as a next-generation drug delivery system: An update on drug loading approaches, characterization, and clinical application challenges","volume":"113","author":"Mehryab","year":"2020","journal-title":"Acta Biomater."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"751079","DOI":"10.3389\/fcell.2021.751079","article-title":"Exosomes, a New Star for Targeted Delivery","volume":"9","author":"Chen","year":"2021","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"2106","DOI":"10.1021\/acsbiomaterials.1c00217","article-title":"Potential Use of Exosomes as Diagnostic Biomarkers and in Targeted Drug Delivery: Progress in Clinical and Preclinical Applications","volume":"7","author":"Huda","year":"2021","journal-title":"ACS Biomater. Sci. Eng."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1007\/978-1-59745-324-0_9","article-title":"Permeabilization of cell membranes","volume":"588","author":"Jamur","year":"2010","journal-title":"Methods Mol. Biol."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"18825","DOI":"10.1039\/C9NR06183E","article-title":"Efficient encapsulation of theranostic nanoparticles in cell-derived exosomes: Leveraging the exosomal biogenesis pathway to obtain hollow gold nanoparticle-hybrids","volume":"11","author":"Arruebo","year":"2019","journal-title":"Nanoscale"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"L110","DOI":"10.1152\/ajplung.00423.2016","article-title":"Enrichment of selective miRNAs in exosomes and delivery of exosomal miRNAs in vitro and in vivo","volume":"312","author":"Zhang","year":"2017","journal-title":"Am. J. Physiol. Lung Cell Mol. Physiol."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1016\/j.actbio.2019.07.006","article-title":"Cell-free synthesis of connexin 43-integrated exosome-mimetic nanoparticles for siRNA delivery","volume":"96","author":"Lu","year":"2018","journal-title":"Acta Biomater."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"102285","DOI":"10.1016\/j.nano.2020.102285","article-title":"Exosome mediated delivery of functional nucleic acid nanoparticles (NANPs)","volume":"30","author":"Nordmeier","year":"2020","journal-title":"Nanomedicine"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"e113","DOI":"10.1002\/ctm2.113","article-title":"HucMSC-exosomes carrying miR-326 inhibit neddylation to relieve inflammatory bowel disease in mice","volume":"10","author":"Wang","year":"2020","journal-title":"Clin. Transl. Med."},{"key":"ref_108","first-page":"742","article-title":"Electroporation of eukaryotes and prokaryotes: A general approach to the introduction of macromolecules into cells","volume":"6","author":"Shigekawa","year":"1988","journal-title":"Biotechniques"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1016\/j.nano.2015.10.012","article-title":"Development of exosome-encapsulated paclitaxel to overcome MDR in cancer cells","volume":"13","author":"Kim","year":"2016","journal-title":"Nanomedicine"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1007\/s11481-019-09884-9","article-title":"V Macrophage-derived extracellular vesicles as drug delivery systems for triple negative breast cancer (TNBC) therapy","volume":"15","author":"Haney","year":"2020","journal-title":"J. Neuroimmune Pharmacol."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"8182","DOI":"10.1002\/jcp.27615","article-title":"Therapeutic use of curcumin-encapsulated and curcumin-primed exosomes","volume":"234","author":"Oskouie","year":"2019","journal-title":"J. Cell Physiol."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.jconrel.2015.03.033","article-title":"Exosomes as drug delivery vehicles for Parkinson\u2019s disease therapy","volume":"207","author":"Haney","year":"2015","journal-title":"J. Control Release"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"21933","DOI":"10.1038\/srep21933","article-title":"Engineering hybrid exosomes by membrane fusion with liposomes","volume":"6","author":"Sato","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_114","doi-asserted-by":"crossref","unstructured":"Antimisiaris, S.G., Mourtas, S., and Marazioti, A. (2018). Exosomes and Exosome-Inspired Vesicles for Targeted Drug Delivery. Pharmaceutics, 10.","DOI":"10.20944\/preprints201810.0507.v1"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"100261","DOI":"10.1016\/j.impact.2020.100261","article-title":"Exosome engineering: Current progress in cargo loading and targeted delivery","volume":"20","author":"Fu","year":"2020","journal-title":"NanoImpact"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"110237","DOI":"10.1016\/j.biopha.2020.110237","article-title":"Exosomes as drug carriers for cancer therapy and challenges regarding exosome uptake","volume":"128","author":"Zhao","year":"2020","journal-title":"Biomed. Pharmacother."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"1580","DOI":"10.1016\/j.ymthe.2017.03.021","article-title":"Functional Delivery of Lipid-Conjugated siRNA by Extracellular Vesicles","volume":"25","author":"Jong","year":"2017","journal-title":"Mol. Ther."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"1239","DOI":"10.2217\/nnm-2019-0443","article-title":"Current advances in the development of novel polymeric nanoparticles for the treatment of neurodegenerative diseases","volume":"15","author":"Cano","year":"2020","journal-title":"Nanomedicine"},{"key":"ref_119","first-page":"3402","article-title":"Extracellular vesicle in vivo biodistribution is determined by cell source, route of administration and targeting","volume":"10","author":"Wiklander","year":"2015","journal-title":"J. Extracell Vesicles"},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"1305","DOI":"10.1038\/s41467-018-03733-8","article-title":"Designer exosomes produced by implanted cells intracerebrally deliver therapeutic cargo for Parkinson\u2019s disease treatment","volume":"9","author":"Kojima","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_121","doi-asserted-by":"crossref","unstructured":"Chen, Y.-A., Lu, C.-H., Ke, C.-C., Chiu, S.-J., Jeng, F.-S., Chang, C.-W., Yang, B.-H., and Liu, R.-S. (2021). Mesenchymal Stem Cell-Derived Exosomes Ameliorate Alzheimer\u2019s Disease Pathology and Improve Cognitive Deficits. Biomedicines, 9.","DOI":"10.3390\/biomedicines9060594"},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1080\/10717544.2020.1762262","article-title":"Brain delivery of quercetin-loaded exosomes improved cognitive function in AD mice by inhibiting phosphorylated tau-mediated neurofibrillary tangles","volume":"27","author":"Qi","year":"2020","journal-title":"Drug Deliv."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"654","DOI":"10.1096\/fj.201700600R","article-title":"Exosomes derived from hypoxia-preconditioned mesenchymal stromal cells ameliorate cognitive decline by rescuing synaptic dysfunction and regulating inflammatory responses in APP\/PS1 mice","volume":"32","author":"Cui","year":"2018","journal-title":"FASEB J."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"24488","DOI":"10.1074\/jbc.M114.577213","article-title":"Decreased amyloid-\u03b2 pathologies by intracerebral loading of glycosphingolipid-enriched exosomes in Alzheimer model mice","volume":"289","author":"Yuyama","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"E3536","DOI":"10.1073\/pnas.1703920114","article-title":"Intranasal MSC-derived A1-exosomes ease inflammation, and prevent abnormal neurogenesis and memory dysfunction after status epilepticus","volume":"114","author":"Long","year":"2017","journal-title":"PNAS"},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1007\/s11011-014-9490-y","article-title":"Conditioned medium of human adipose-derived mesenchymal stem cells mediates protection in neurons following glutamate excitotoxicity by regulating energy metabolism and GAP-43 expression","volume":"29","author":"Hao","year":"2014","journal-title":"Metab. Brain Dis."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"105218","DOI":"10.1016\/j.nbd.2020.105218","article-title":"Exosome-mediated delivery of antisense oligonucleotides targeting \u03b1 -synuclein ameliorates the pathology in a mouse model of Parkinson \u2019 s disease","volume":"148","author":"Yang","year":"2021","journal-title":"Neurobiol. Dis."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"146331","DOI":"10.1016\/j.brainres.2019.146331","article-title":"Serum secreted miR-137-containing exosomes affects oxidative stress of neurons by regulating OXR1 in Parkinson\u2019s disease","volume":"1722","author":"Jiang","year":"2019","journal-title":"Brain Res."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1016\/j.intimp.2018.12.001","article-title":"Exosomes derived from mesenchymal stem cells attenuate in fl ammation and demyelination of the central nervous system in EAE rats by regulating the polarization of microglia","volume":"67","author":"Li","year":"2019","journal-title":"Int. Immunopharmacol."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"107207","DOI":"10.1016\/j.intimp.2020.107207","article-title":"Intranasal administration of small extracellular vesicles derived from mesenchymal stem cells ameliorated the experimental autoimmune encephalomyelitis","volume":"90","author":"Fathollahi","year":"2021","journal-title":"Int. Immunopharmacol."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/j.jconrel.2019.02.032","article-title":"Immunomodulatory properties of MSC-derived exosomes armed with high a ffi nity aptamer toward mylein as a platform for reducing multiple sclerosis clinical score","volume":"299","author":"Alibolandi","year":"2019","journal-title":"J. Control. Release"},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"011503","DOI":"10.1063\/1.5087122","article-title":"Challenges and opportunities in exosome research\u2014Perspectives from biology, engineering, and cancer therapy","volume":"3","author":"Li","year":"2019","journal-title":"APL Bioeng."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.jneuroim.2013.10.014","article-title":"IFN \u03b3 -stimulated dendritic cell exosomes as a potential therapeutic for remyelination","volume":"266","author":"Pusic","year":"2014","journal-title":"J. Neuroimmunol."},{"key":"ref_134","doi-asserted-by":"crossref","unstructured":"Bonafede, R., Turano, E., Scambi, I., Busato, A., Bontempi, P., Virla, F., Schia, L., Marzola, P., and Bonetti, B. (2020). ASC-Exosomes Ameliorate the Disease Progression in SOD1(G93A) Murine Model Underlining Their Potential Therapeutic Use in Human ALS. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21103651"},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1016\/j.yexcr.2015.12.009","article-title":"Exosome derived from murine adipose-derived stromal cells: Neuroprotective effect on in vitro model of amyotrophic lateral sclerosis","volume":"340","author":"Bonafede","year":"2016","journal-title":"Exp. Cell Res."},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"7105","DOI":"10.1074\/jbc.M112.410944","article-title":"Neuronal Exosomal miRNA-dependent Translational Regulation of Astroglial Glutamate Transporter GLT1*","volume":"288","author":"Morel","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1016\/S1474-4422(18)30403-4","article-title":"Global, regional, and national burden of Alzheimer \u2019 s disease and other dementias, 1990\u20132016: A systematic analysis for the Global Burden of Disease Study 2016","volume":"18","author":"Nichols","year":"2019","journal-title":"Lancet Neurol."},{"key":"ref_138","doi-asserted-by":"crossref","unstructured":"Soliman, H.M., Ghonaim, G.A., Gharib, S.M., Chopra, H., Farag, A.K., Emam, S.E., Hassan, A.E.A., and Attia, M.S. (2021). Exosomes in Alzheimer \u2019 s Disease: From Being Pathological Players to Potential Diagnostics and Therapeutics. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms221910794"},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1111\/epi.12550","article-title":"A practical clinical definition of epilepsy","volume":"55","author":"Fisher","year":"2014","journal-title":"Epilepsy"},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1016\/S1474-4422(18)30454-X","article-title":"Global, regional, and national burden of epilepsy, 1990\u20132016: A systematic analysis for the Global Burden of Disease Study 2016","volume":"18","author":"Beghi","year":"2019","journal-title":"Lancet Neurol."},{"key":"ref_141","doi-asserted-by":"crossref","unstructured":"Zhang, Y., and Bhavnani, B. (2006). Glutamate-induced apoptosis in neuronal cells is mediated via caspase-dependent and independent mechanisms involving calpain and caspase-3 proteases as well as apoptosis inducing factor (AIF) and this process is inhibited by equine estrogens. BMC Neurosci., 22.","DOI":"10.1186\/1471-2202-7-49"},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"939","DOI":"10.1016\/S1474-4422(18)30295-3","article-title":"Global, regional and national burden of Parkinson\u2019 s disease, 1990\u20132016: A systematic analysis for the Global Burden of Disease Study 2016","volume":"17","author":"Bill","year":"2018","journal-title":"Lancet Neurol."},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"802","DOI":"10.1016\/j.amjmed.2019.03.001","article-title":"Parkinson\u2019 s Disease and Parkinsonism","volume":"132","author":"Hayes","year":"2019","journal-title":"Am. J. Med."},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"1334","DOI":"10.1016\/j.omtn.2021.01.022","article-title":"Exosomes derived from miR-188-3p-modified adipose-derived mesenchymal stem cells protect Parkinson \u2019 s disease","volume":"23","author":"Li","year":"2021","journal-title":"Mol. Ther. Nucleic Acid"},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"238","DOI":"10.2174\/1570159X13666151030103027","article-title":"Targeting the Autophagy\/Lysosomal Degradation Pathway in Parkinson\u2019s Disease","volume":"14","author":"Hilfiker","year":"2016","journal-title":"Curr. Neuropharmacol."},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/j.bbrc.2016.01.183","article-title":"Circular RNA expression alterations are involved in OGD\/R-induced neuron injury","volume":"471","author":"Lin","year":"2016","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"6779","DOI":"10.1038\/ncomms7779","article-title":"APF lncRNA regulates autophagy and myocardial infarction by targeting miR-188-3p","volume":"6","author":"Wang","year":"2015","journal-title":"Nat. Commun."},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"7567","DOI":"10.1038\/s41598-019-43772-9","article-title":"Amido-bridged nucleic acid (AmNA)-modified antisense oligonucleotides targeting \u03b1-synuclein as a novel therapy for Parkinson\u2019s disease","volume":"9","author":"Uehara","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1016\/j.mito.2017.12.005","article-title":"Metabolic defects in multiple sclerosis","volume":"44","author":"Adiele","year":"2019","journal-title":"Mitochondrion"},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1056\/NEJMra1401483","article-title":"Multiple Sclerosis","volume":"378","author":"Reich","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_151","first-page":"49","article-title":"Neurodegeneration in multiple sclerosis involves multiple pathogenic mechanisms","volume":"4","author":"Levin","year":"2014","journal-title":"Degener. Neurol. Neuromuscul. Dis."},{"key":"ref_152","doi-asserted-by":"crossref","unstructured":"Correale, J., Marrodan, M., and Ysrraelit, M.C. (2019). Mechanisms of Neurodegeneration and Axonal Dysfunction in Progressive Multiple Sclerosis. Biomedicines, 7.","DOI":"10.3390\/biomedicines7010014"},{"key":"ref_153","doi-asserted-by":"crossref","unstructured":"Sandi, D., Fricska-Nagy, Z., Bencsik, K., and V\u00e9csei, L. (2021). Neurodegeneration in Multiple Sclerosis: Symptoms of Silent Progression, Biomarkers and Neuroprotective Therapy\u2014Kynurenines Are Important Players. Molecules, 26.","DOI":"10.3390\/molecules26113423"},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"749192","DOI":"10.3389\/fimmu.2021.749192","article-title":"Effects of Mesenchymal Stem Cell-Derived Exosomes on Autoimmune Diseases","volume":"12","author":"Shen","year":"2021","journal-title":"Front. Immunol."},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"879","DOI":"10.4252\/wjsc.v12.i8.879","article-title":"Role of mesenchymal stem cell derived extracellular vesicles in autoimmunity: A systematic review","volume":"12","author":"Wang","year":"2020","journal-title":"World J. Stem. Cells"},{"key":"ref_156","doi-asserted-by":"crossref","unstructured":"Nastasijevic, B., Wright, B.R., Smestad, J., Warrington, A.E., Rodriguez, M., and Maher III, J.L. (2012). Remyelination Induced by a DNA Aptamer in a Mouse Model of Multiple Sclerosis. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0039595"},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1007\/s00018-020-03619-3","article-title":"Extracellular vesicles and amyotrophic lateral sclerosis: From misfolded protein vehicles to promising clinical biomarkers","volume":"78","author":"Gagliardi","year":"2021","journal-title":"Cell Mol. Life Sci."},{"key":"ref_158","doi-asserted-by":"crossref","first-page":"1083","DOI":"10.1016\/S1474-4422(18)30404-6","article-title":"Global, regional, and national burden of motor neuron diseases 1990\u20132016: A systematic analysis for the Global Burden of Disease Study 2016","volume":"17","author":"Logroscino","year":"2018","journal-title":"Lancet Neurol."},{"key":"ref_159","doi-asserted-by":"crossref","first-page":"12408","DOI":"10.1038\/ncomms12408","article-title":"Projected increase in amyotrophic lateral sclerosis from 2015 to 2040","volume":"7","author":"Arthur","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_160","doi-asserted-by":"crossref","first-page":"3509","DOI":"10.2147\/IJN.S307843","article-title":"Drug Delivery to the Bone Microenvironment Mediated by Exosomes: An Axiom or Enigma","volume":"16","author":"Samal","year":"2021","journal-title":"Int. J. Nanomed."},{"key":"ref_161","doi-asserted-by":"crossref","unstructured":"Ludwig, N., Whiteside, T.L., and Reichert, T.E. (2019). Challenges in Exosome Isolation and Analysis in Health and Disease. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20194684"},{"key":"ref_162","doi-asserted-by":"crossref","first-page":"3684","DOI":"10.7150\/thno.41580","article-title":"Progress, opportunity, and perspective on exosome isolation-efforts for efficient exosome-based theranostics","volume":"10","author":"Yang","year":"2020","journal-title":"Theranostics"},{"key":"ref_163","doi-asserted-by":"crossref","first-page":"6480","DOI":"10.1158\/0008-5472.CAN-17-0994","article-title":"The Biology of Cancer Exosomes: Insights and New Perspectives","volume":"77","author":"Ruivo","year":"2017","journal-title":"Cancer Res."},{"key":"ref_164","doi-asserted-by":"crossref","first-page":"851","DOI":"10.1038\/icb.2010.64","article-title":"MHC class II-associated proteins in B-cell exosomes and potential functional implications for exosome biogenesis","volume":"88","author":"Buschow","year":"2010","journal-title":"Immunol. Cell Biol."},{"key":"ref_165","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1016\/j.bcmd.2005.05.002","article-title":"The immunogenicity of dendritic cell-derived exosomes","volume":"35","author":"Quah","year":"2005","journal-title":"Blood Cells Mol. Dis."},{"key":"ref_166","doi-asserted-by":"crossref","first-page":"56279","DOI":"10.18632\/oncotarget.10783","article-title":"Procoagulant and immunogenic properties of melanoma exosomes, microvesicles and apoptotic vesicles","volume":"7","author":"Saunderson","year":"2016","journal-title":"Oncotarget"},{"key":"ref_167","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1080\/10717544.2020.1748758","article-title":"Prospects and challenges of extracellular vesicle-based drug delivery system: Considering cell source","volume":"27","author":"Meng","year":"2020","journal-title":"Drug Deliv."},{"key":"ref_168","doi-asserted-by":"crossref","first-page":"744","DOI":"10.1002\/wnan.1395","article-title":"Development and regulation of exosome-based therapy products","volume":"8","author":"Batrakova","year":"2016","journal-title":"Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol."},{"key":"ref_169","doi-asserted-by":"crossref","first-page":"93","DOI":"10.2217\/nnm-2018-0120","article-title":"Nanopharmaceuticals and nanomedicines currently on the market: Challenges and opportunities","volume":"14","author":"Farjadian","year":"2019","journal-title":"Nanomedicine"}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/15\/1\/298\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:07:09Z","timestamp":1760119629000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/15\/1\/298"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,1,16]]},"references-count":169,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2023,1]]}},"alternative-id":["pharmaceutics15010298"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics15010298","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,1,16]]}}}