<?xml version="1.0" encoding="UTF-8"?>
<!DOCTYPE root>
<article xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" xmlns:ali="http://www.niso.org/schemas/ali/1.0/" article-type="review-article" dtd-version="1.2" xml:lang="en"><front><journal-meta><journal-id journal-id-type="publisher-id">Kazan medical journal</journal-id><journal-title-group><journal-title xml:lang="en">Kazan medical journal</journal-title><trans-title-group xml:lang="ru"><trans-title>Казанский медицинский журнал</trans-title></trans-title-group></journal-title-group><issn publication-format="print">0368-4814</issn><issn publication-format="electronic">2587-9359</issn><publisher><publisher-name xml:lang="en">Eco-Vector</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="publisher-id">696803</article-id><article-id pub-id-type="doi">10.17816/KMJ696803</article-id><article-id pub-id-type="edn">EEBSTJ</article-id><article-categories><subj-group subj-group-type="toc-heading" xml:lang="en"><subject>Reviews</subject></subj-group><subj-group subj-group-type="toc-heading" xml:lang="ru"><subject>Обзоры</subject></subj-group><subj-group subj-group-type="article-type"><subject>Review Article</subject></subj-group></article-categories><title-group><article-title xml:lang="en">Blood–brain barrier: structure and therapeutic approaches to crossing</article-title><trans-title-group xml:lang="ru"><trans-title>Гематоэнцефалический барьер: организация и пути его преодоления в терапевтических целях</trans-title></trans-title-group></title-group><contrib-group><contrib contrib-type="author"><contrib-id contrib-id-type="orcid">https://orcid.org/0000-0002-8128-4636</contrib-id><contrib-id contrib-id-type="spin">9629-8511</contrib-id><name-alternatives><name xml:lang="en"><surname>Izmailov</surname><given-names>Andrei A.</given-names></name><name xml:lang="ru"><surname>Измайлов</surname><given-names>Андрей Александрович</given-names></name></name-alternatives><address><country country="RU">Russian Federation</country></address><bio xml:lang="en"><p>MD, Cand. Sci. (Medicine), Assistant Professor, Depart. of Histology, Cytology, and Embryology</p></bio><bio xml:lang="ru"><p>канд. мед. наук, доцент, каф. гистологии, цитологии и эмбриологии</p></bio><email>andrei.izmaylov@kazangmu.ru</email><xref ref-type="aff" rid="aff1"/></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid">https://orcid.org/0000-0002-3789-0284</contrib-id><contrib-id contrib-id-type="spin">9403-2371</contrib-id><name-alternatives><name xml:lang="en"><surname>Markosyan</surname><given-names>Vage A.</given-names></name><name xml:lang="ru"><surname>Маркосян</surname><given-names>Ваге Аршалуйсович</given-names></name></name-alternatives><address><country country="RU">Russian Federation</country></address><bio xml:lang="en"><p>MD, Cand. Sci. (Medicine), Assistant Professor, Depart. of Operative Surgery and Topographical Anatomy</p></bio><bio xml:lang="ru"><p>канд. мед. наук, доцент, каф. оперативной хирургии и топографической анатомии</p></bio><email>vage.markosyan@gmail.com</email><xref ref-type="aff" rid="aff1"/></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid">https://orcid.org/0009-0000-7619-0750</contrib-id><contrib-id contrib-id-type="spin">1549-2439</contrib-id><name-alternatives><name xml:lang="en"><surname>Boychuk</surname><given-names>Natalia V.</given-names></name><name xml:lang="ru"><surname>Бойчук</surname><given-names>Наталья Валентиновна</given-names></name></name-alternatives><address><country country="RU">Russian Federation</country></address><bio xml:lang="en"><p>Cand. Sci. (Biology), Assistant Professor, Depart. of Histology, Cytology, and Embryology</p></bio><bio xml:lang="ru"><p>канд. биол. наук, доцент, каф. гистологии, цитологии и эмбриологии</p></bio><email>nboychuck@yandex.ru</email><xref ref-type="aff" rid="aff1"/></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid">https://orcid.org/0000-0002-6632-4636</contrib-id><contrib-id contrib-id-type="spin">5828-1849</contrib-id><name-alternatives><name xml:lang="en"><surname>Islamov</surname><given-names>Rustem R.</given-names></name><name xml:lang="ru"><surname>Исламов</surname><given-names>Рустем Робертович</given-names></name></name-alternatives><address><country country="RU">Russian Federation</country></address><bio xml:lang="en"><p>MD, Dr. Sci. (Medicine), Professor, Head, Depart. of Histology, Cytology, and Embryology</p></bio><bio xml:lang="ru"><p>д-р мед. наук, профессор, заведующий, каф. гистологии, цитологии и эмбриологии</p></bio><email>rustem.islamov@kazangmu.ru</email><xref ref-type="aff" rid="aff1"/></contrib></contrib-group><aff-alternatives id="aff1"><aff><institution xml:lang="en">Kazan State Medical University</institution></aff><aff><institution xml:lang="ru">Казанский государственный медицинский университет</institution></aff></aff-alternatives><pub-date date-type="preprint" iso-8601-date="2026-03-07" publication-format="electronic"><day>07</day><month>03</month><year>2026</year></pub-date><pub-date date-type="pub" iso-8601-date="2026-06-15" publication-format="electronic"><day>15</day><month>06</month><year>2026</year></pub-date><volume>107</volume><issue>3</issue><issue-title xml:lang="en"/><issue-title xml:lang="ru"/><fpage>362</fpage><lpage>374</lpage><history><date date-type="received" iso-8601-date="2025-11-22"><day>22</day><month>11</month><year>2025</year></date><date date-type="accepted" iso-8601-date="2025-12-30"><day>30</day><month>12</month><year>2025</year></date></history><permissions><copyright-statement xml:lang="en">Copyright ©; 2026, Eco-Vector</copyright-statement><copyright-statement xml:lang="ru">Copyright ©; 2026, Эко-Вектор</copyright-statement><copyright-year>2026</copyright-year><copyright-holder xml:lang="en">Eco-Vector</copyright-holder><copyright-holder xml:lang="ru">Эко-Вектор</copyright-holder><ali:free_to_read xmlns:ali="http://www.niso.org/schemas/ali/1.0/" start_date="2029-06-15"/><license><ali:license_ref xmlns:ali="http://www.niso.org/schemas/ali/1.0/">https://creativecommons.org/licenses/by-nc-nd/4.0/</ali:license_ref></license></permissions><self-uri xlink:href="https://kazanmedjournal.ru/kazanmedj/article/view/696803">https://kazanmedjournal.ru/kazanmedj/article/view/696803</self-uri><abstract xml:lang="en"><p>The blood–brain barrier is a highly selective morphofunctional structure that maintains central nervous system homeostasis and protects it from toxic and foreign substances in the systemic circulation. At the same time, the blood–brain barrier remains a major obstacle to effective pharmacotherapy of central nervous system diseases, as most drugs are unable to cross it.</p> <p>This review discusses current approaches to overcoming the blood–brain barrier, which rely on endogenous transport systems such as adsorptive transcytosis and receptor- or carrier-mediated transcytosis, as well as advanced nano- and biotechnologies. Of particular interest are promising strategies such as modification of therapeutic molecules with cell-penetrating peptides, the use of exosomes and biomimetic nanoplatforms, and cell-mediated delivery of biologically active molecules using autologous leukocytes as “Trojan horses.”</p> <p>Methods for transient disruption of blood–brain barrier integrity (e.g., osmotic modulation and focused ultrasound) and alternative delivery routes, such as intranasal administration providing direct access to the brain via the olfactory and trigeminal nerves, are discussed separately.</p> <p>It is emphasized that successful therapy of central nervous system diseases is not possible without safe, effective, and targeted delivery systems capable of crossing the blood–brain barrier without compromising its protective function. Recent advances in molecular and cellular biology, nanomedicine, and genetic engineering open new horizons for personalized therapeutic approaches aimed at effective traversal of the blood–brain barrier.</p></abstract><trans-abstract xml:lang="ru"><p>Гематоэнцефалический барьер представляет собой высокоселективную морфофункциональную структуру, обеспечивающую гомеостаз центральной нервной системы и защищающую её от токсических и чужеродных веществ, циркулирующих в системном кровотоке. В то же время гематоэнцефалический барьер остаётся главным препятствием для эффективной фармакотерапии заболеваний центральной нервной системы, поскольку большинство лекарственных препаратов не способно его преодолевать.</p> <p>В обзоре рассматриваются современные подходы к преодолению гематоэнцефалического барьера, основанные как на использовании естественных транспортных систем, включая адсорбционный трансцитоз, а также трансцитоз, опосредованный рецептором или белком-переносчиком, так и на применении передовых нано- и биотехнологий. Особое внимание уделяется перспективным стратегиям, таким как модификация терапевтических молекул проникающими в клетку пептидами, использование экзосом и биомиметических наноплатформ, а также клеточно-опосредованная доставка биологически активных молекул с помощью аутологичных лейкоцитов в качестве «троянских коней».</p> <p>Отдельно обсуждаются методы временного нарушения целостности гематоэнцефалического барьера (осмотическая модуляция, фокусированный ультразвук) и альтернативные пути доставки, такие как интраназальное введение, обеспечивающее прямой доступ в мозг через обонятельный и тройничный нервы.</p> <p>Подчёркивается, что успешная терапия заболеваний центральной нервной системы невозможна без разработки безопасных, эффективных и целенаправленных систем доставки, способных преодолевать гематоэнцефалический барьер без компрометации его защитной функции. Современные достижения в молекулярной и клеточной биологии, наномедицине и генной инженерии открывают новые горизонты для создания персонализированных терапевтических подходов, направленных на эффективное преодоление гематоэнцефалического барьера.</p></trans-abstract><kwd-group xml:lang="en"><kwd>blood–brain barrier</kwd><kwd>neurovascular unit</kwd><kwd>drug delivery systems</kwd><kwd>central nervous system diseases</kwd><kwd>pharmacotherapy</kwd><kwd>nanoparticles</kwd><kwd>exosomes</kwd><kwd>biological transport</kwd><kwd>gene therapy</kwd><kwd>review</kwd></kwd-group><kwd-group xml:lang="ru"><kwd>гематоэнцефалический барьер</kwd><kwd>нейроваскулярная единица</kwd><kwd>системы доставки лекарств</kwd><kwd>заболевания центральной нервной системы</kwd><kwd>лекарственная терапия</kwd><kwd>наночастицы</kwd><kwd>экзосомы</kwd><kwd>биологический транспорт</kwd><kwd>генная терапия</kwd><kwd>обзор</kwd></kwd-group><funding-group/></article-meta></front><body></body><back><ref-list><ref id="B1"><label>1.</label><mixed-citation>Ehrlich P. Das Sauerstoff-Bedürfniss Des Organismus; Eine Farbenanalytische Studie. Berlin: Hirschwald; 1885. Available from: https://www.worldcat.org/title/9718332</mixed-citation></ref><ref id="B2"><label>2.</label><mixed-citation>Pearce J. The blood brain barrier and Lina Solomonovna Stern (Shtern). Adv Clin Neurosci Rehabil. 2022. doi: 10.47795/EVRJ6805 EDN: PPAGRW</mixed-citation></ref><ref id="B3"><label>3.</label><mixed-citation>Stern L, Gautier R. Recherches Sur Le Liquide CÉphalo-Rachidien: I.-Les Rapports Entre Le Liquide CÉphalo-Rachidien et la Circulation Sanguine. Arch Int Physiol. 1921;17:138–192. doi: 10.3109/13813452109146211</mixed-citation></ref><ref id="B4"><label>4.</label><mixed-citation>Wu D, Chen Q, Chen X, et al. The blood-brain barrier: structure, regulation, and drug delivery. Signal Transduct Target Ther. 2023;8(1):217. doi: 10.1038/s41392-023-01481-w EDN: SDWRPN</mixed-citation></ref><ref id="B5"><label>5.</label><mixed-citation>Zhong J, Li G, Lv Z, et al. Neuromodulation of Cerebral Blood Flow: A Physiological Mechanism and Methodological Review of Neurovascular Coupling. Bioeng. 2025;12(5). doi: 10.3390/bioengineering12050442 EDN: RGPXSN</mixed-citation></ref><ref id="B6"><label>6.</label><mixed-citation>Pandit R, Chen L, Götz J. The blood-brain barrier: Physiology and strategies for drug delivery. Adv Drug Deliv Rev. 2020;165–166:1–14. doi: 10.1016/j.addr.2019.11.009 EDN: MPLNON</mixed-citation></ref><ref id="B7"><label>7.</label><mixed-citation>Gong Y, Wu M, Huang Y, et al. Research developments in the neurovascular unit and the blood brain barrier (Review). Biomed reports. 2025;22(5):88. doi: 10.3892/br.2025.1966</mixed-citation></ref><ref id="B8"><label>8.</label><mixed-citation>Katz BM, Walton LR, Houston KM, et al. Putative neurochemical and cell type contributions to hemodynamic activity in the rodent caudate putamen. J Cereb blood flow Metab Off J Int Soc Cereb Blood Flow Metab. 2023;43(4):481–498. doi: 10.1177/0271678X221142533 EDN: XTMMAJ</mixed-citation></ref><ref id="B9"><label>9.</label><mixed-citation>Omar OMF, Kimble AL, Cheemala A, et al. Endothelial TDP-43 depletion disrupts core blood-brain barrier pathways in neurodegeneration. Nat Neurosci. 2025;28(5):973–984. 10.1038/s41593-025-01914-5</mixed-citation></ref><ref id="B10"><label>10.</label><mixed-citation>Zhao Z, Nelson AR, Betsholtz C, Zlokovic BV. Establishment and Dysfunction of the Blood-Brain Barrier. Cell. 2015;163(5):1064–1078. doi: 10.1016/j.cell.2015.10.067</mixed-citation></ref><ref id="B11"><label>11.</label><mixed-citation>Kaya M, Ahishali B. Basic physiology of the blood-brain barrier in health and disease: a brief overview. Tissue barriers. 2021;9(1):1840913. doi: 10.1080/21688370.2020.1840913 EDN: BWVELM</mixed-citation></ref><ref id="B12"><label>12.</label><mixed-citation>Uspenskaya YuA, Morgun AV, Osipova ED, et al. Mechanisms of cerebral angiogenesis in normal conditions and cerebral pathology. Progress in physiological science. 2021;52(2):39–50. doi: 10.31857/S0301179821020090 EDN: ITUQYL</mixed-citation></ref><ref id="B13"><label>13.</label><mixed-citation>Roedel M, Brooks N, Lamb TJ. Pericytes: The forgotten controllers of a functional blood-brain barrier. PLoS Pathog. 2025;21(5):e1013145. doi: 10.1371/journal.ppat.1013145</mixed-citation></ref><ref id="B14"><label>14.</label><mixed-citation>Archie SR, Al Shoyaib A, Cucullo L. Blood-Brain Barrier Dysfunction in CNS Disorders and Putative Therapeutic Targets: An Overview. Pharmaceutics. 2021;13(11). doi: 10.3390/pharmaceutics13111779 EDN: FEKBGA</mixed-citation></ref><ref id="B15"><label>15.</label><mixed-citation>Yu T, Wang Z, Chen Y, et al. Blood-brain barrier (BBB) dysfunction in CNS diseases: paying attention to pericytes. CNS Neurosci Ther. 2025;31(5):e70422. doi: 10.1111/cns.70422 EDN: VIBZDX</mixed-citation></ref><ref id="B16"><label>16.</label><mixed-citation>Sun Z, Gao C, Gao D, et al. Reduction in pericyte coverage leads to blood-brain barrier dysfunction via endothelial transcytosis following chronic cerebral hypoperfusion. Fluids Barriers CNS. 2021;18(1):21. doi: 10.1186/s12987-021-00255-2</mixed-citation></ref><ref id="B17"><label>17.</label><mixed-citation>Patabendige A, Singh A, Jenkins S, et al. Astrocyte Activation in Neurovascular Damage and Repair Following Ischaemic Stroke. Int J Mol Sci. 2021;22(8). doi: 10.3390/ijms22084280 EDN: MPSDTO</mixed-citation></ref><ref id="B18"><label>18.</label><mixed-citation>Salmina AB, Morgun AV, Kuvacheva NV, et al. Establishment of neurogenic microenvironment in the neurovascular unit: the connexin 43 story. Rev Neurosci. 2014;25(1):97–111. doi: 10.1515/revneuro-2013-0044 EDN: SKNZPN</mixed-citation></ref><ref id="B19"><label>19.</label><mixed-citation>Hablitz LM, Nedergaard M. The Glymphatic System: A Novel Component of Fundamental Neurobiology. J Neurosci Off J Soc Neurosci. 2021;41(37):7698–7711. doi: 10.1523/JNEUROSCI.0619-21.2021 EDN: BNPOQC</mixed-citation></ref><ref id="B20"><label>20.</label><mixed-citation>Mayer MG, Fischer T. Microglia at the blood brain barrier in health and disease. Front Cell Neurosci. 2024;18:1360195. doi: 10.3389/fncel.2024.1360195 EDN: DWWQXG</mixed-citation></ref><ref id="B21"><label>21.</label><mixed-citation>Brown LS, Foster CG, Courtney JM, et al. Pericytes and Neurovascular Function in the Healthy and Diseased Brain. Front Cell Neurosci. 2019;13:282. doi: 10.3389/fncel.2019.00282</mixed-citation></ref><ref id="B22"><label>22.</label><mixed-citation>Zhan X, Wang S, Bèchet N, et al. Perivascular macrophages in the central nervous system: insights into their roles in health and disease. Cell Death Dis. 2025;16(1):350. doi: 10.1038/s41419-025-07592-2 EDN: QQFDGF</mixed-citation></ref><ref id="B23"><label>23.</label><mixed-citation>Mehrabadi AR, Korolainen MA, Odero G, et al. Poly(ADP-ribose) polymerase-1 regulates microglia mediated decrease of endothelial tight junction integrity. Neurochem Int. 2017;108:266–271. doi: 10.1016/j.neuint.2017.04.014</mixed-citation></ref><ref id="B24"><label>24.</label><mixed-citation>Haruwaka K, Ikegami A, Tachibana Y, et al. Dual microglia effects on blood brain barrier permeability induced by systemic inflammation. Nat Commun. 2019;10(1):5816. doi: 10.1038/s41467-019-13812-z EDN: AYBYSU</mixed-citation></ref><ref id="B25"><label>25.</label><mixed-citation>Senatorov VV Jr, Friedman AR, Milikovsky DZ, et al. Blood-brain barrier dysfunction in aging induces hyperactivation of TGFβ signaling and chronic yet reversible neural dysfunction. Sci Transl Med. 2019;11(521):eaaw8283. doi: 10.1126/scitranslmed.aaw8283</mixed-citation></ref><ref id="B26"><label>26.</label><mixed-citation>Banks WA, Greig NH. Small molecules as central nervous system therapeutics: old challenges, new directions, and a philosophic divide. Future Med Chem. 2019;11(6):489–493. doi: 10.4155/fmc-2018-0436</mixed-citation></ref><ref id="B27"><label>27.</label><mixed-citation>Moura RP, Martins C, Pinto S, et al. Blood-brain barrier receptors and transporters: an insight on their function and how to exploit them through nanotechnology. Expert Opin Drug Deliv. 2019;16(3):271–285. doi: 10.1080/17425247.2019.1583205 EDN: SSZMGP</mixed-citation></ref><ref id="B28"><label>28.</label><mixed-citation>Fong CW. Permeability of the Blood-Brain Barrier: Molecular Mechanism of Transport of Drugs and Physiologically Important Compounds. J Membr Biol. 2015;248(4):651–669. doi: 10.1007/s00232-015-9778-9 EDN: WZBXNM</mixed-citation></ref><ref id="B29"><label>29.</label><mixed-citation>Han L. Modulation of the Blood-Brain Barrier for Drug Delivery to Brain. Pharmaceutics. 2021;13(12):2024. doi: 10.3390/pharmaceutics13122024</mixed-citation></ref><ref id="B30"><label>30.</label><mixed-citation>Chelyshev YuA, Kabdesh IM, Mukhamedshina YaO. Blood-spinal cord barrier in spinal cord injury: a scientific review based on own experimental trial. Spine surgery. 2024;21(3):25–35. doi: 10.14531/ss2024.3.25-35 EDN: PEGQGE</mixed-citation></ref><ref id="B31"><label>31.</label><mixed-citation>Katada S, S Rodrigues K, Nakashima K. The influence of the choroid plexus on brain function: beyond its role in cerebrospinal fluid production. Inflamm Regen. 2025;45(1):20. doi: 10.1186/s41232-025-00386-1 EDN: MUUGOD</mixed-citation></ref><ref id="B32"><label>32.</label><mixed-citation>Terenteva OA, Vainshtein VA, Tikhonova VV, et al. Development of a mafedine lyophilizate for parenteral use. Drug development &amp; registration. 2021;10(4):88–94. doi: 10.33380/2305-2066-2021-10-4(1)-88-94 EDN: FOELYA</mixed-citation></ref><ref id="B33"><label>33.</label><mixed-citation>Lebedev IA, Levitina EV, Akimzhanova AK, et al. Intrathecal administration of drugs. S.S. Korsakov journal of neurology and psychiatry. 2016;116(10):89–92. doi: 10.17116/jnevro201611610189-92 EDN: WYHWGN</mixed-citation></ref><ref id="B34"><label>34.</label><mixed-citation>Azarmi M, Maleki H, Nikkam N, Malekinejad H. Transcellular brain drug delivery: A review on recent advancements. Int J Pharm. 2020;586:119582. doi: 10.1016/j.ijpharm.2020.119582 EDN: WUHKYU</mixed-citation></ref><ref id="B35"><label>35.</label><mixed-citation>Zhu X, Jin K, Huang Y, Pang Z. Brain drug delivery by adsorption-mediated transcytosis. In: Brain Targeted Drug Delivery System. A Focus on Nanotechnology and Nanoparticulate. Gao H, Gao X, editors. Academic Press; 2018. P. 159–183. ISBN-13: 978-0128140024</mixed-citation></ref><ref id="B36"><label>36.</label><mixed-citation>Slominsky PA, Shadrina MI. Peptide pharmaceuticals: opportunities, prospects, and limitations. Molecular Genetics, Microbiology and Virology. 2018;1(1):8–14. doi: 10.18821/0208-0613 EDN: LXRJQD</mixed-citation></ref><ref id="B37"><label>37.</label><mixed-citation>Komin A, Russell LM, Hristova KA, Searson PC. Peptide-based strategies for enhanced cell uptake, transcellular transport, and circulation: Mechanisms and challenges. Adv Drug Deliv Rev. 2017;110–111:52–64. doi: 10.1016/j.addr.2016.06.002 EDN: YDNTWJ</mixed-citation></ref><ref id="B38"><label>38.</label><mixed-citation>Yamaguchi S, Ito S, Masuda T, et al. Novel cyclic peptides facilitating transcellular blood-brain barrier transport of macromolecules in vitro and in vivo. J Control release Off J Control Release Soc. 2020;321:744–755. doi: 10.1016/j.jconrel.2020.03.001 EDN: XBTZFR</mixed-citation></ref><ref id="B39"><label>39.</label><mixed-citation>Zhang L, Zhang Y, Tai L, et al. Functionalized cell nucleus-penetrating peptide combined with doxorubicin for synergistic treatment of glioma. Acta Biomater. 2016;42:90–101. doi: 10.1016/j.actbio.2016.06.031 EDN: WSXQJB</mixed-citation></ref><ref id="B40"><label>40.</label><mixed-citation>Ronaldson PT, Davis TP. Regulation of blood-brain barrier integrity by microglia in health and disease: A therapeutic opportunity. J Cereb blood flow Metab Off J Int Soc Cereb Blood Flow Metab. 2020;40(1_suppl):S6–S24. doi: 10.1177/0271678X20951995 EDN: FLGHEB</mixed-citation></ref><ref id="B41"><label>41.</label><mixed-citation>Tashima T. Smart Strategies for Therapeutic Agent Delivery into Brain across the Blood-Brain Barrier Using Receptor-Mediated Transcytosis. Chem Pharm Bull. 2020;68(4):316–325. doi: 10.1248/cpb.c19-00854 EDN: XVNGWN</mixed-citation></ref><ref id="B42"><label>42.</label><mixed-citation>Zhang W, Chen H, Ding L, et al. Trojan Horse Delivery of 4,4'-Dimethoxychalcone for Parkinsonian Neuroprotection. Adv Sci. 2021;8(9):2004555. doi: 10.1002/advs.202004555 EDN: OABYMR</mixed-citation></ref><ref id="B43"><label>43.</label><mixed-citation>Pardridge WM. Blood-brain barrier endogenous transporters as therapeutic targets: a new model for small molecule CNS drug discovery. Expert Opin Ther Targets. 2015;19(8):1059–1072. doi: 10.1517/14728222.2015.1042364</mixed-citation></ref><ref id="B44"><label>44.</label><mixed-citation>Helms HC, Abbott NJ, Burek M, et al. In vitro models of the blood-brain barrier: an overview of commonly used brain endothelial cell culture models and guidelines for their use. J Cereb Blood Flow Metab. 2016;36(5):862–890. doi: 10.1177/0271678X16630991</mixed-citation></ref><ref id="B45"><label>45.</label><mixed-citation>Yan R, Li Y, Müller J, et al. Mechanism of substrate transport and inhibition of the human LAT1-4F2hc amino acid transporter. Cell Discov. 2021;7(1):16. doi: 10.1038/s41421-021-00247-4 EDN: CBWVZC</mixed-citation></ref><ref id="B46"><label>46.</label><mixed-citation>Pardridge WM. A Historical Review of Brain Drug Delivery. Pharmaceutics. 2022;14(6). doi: 10.3390/pharmaceutics14061283</mixed-citation></ref><ref id="B47"><label>47.</label><mixed-citation>Zenaro E, Piacentino G, Constantin G. The blood-brain barrier in Alzheimer's disease. Neurobiol Dis. 2017;107:41–56. doi: 10.1016/j.nbd.2016.07.007</mixed-citation></ref><ref id="B48"><label>48.</label><mixed-citation>Li X, Ding W, Zhang X, et al. Caveolin-1-mediated blood-brain barrier disruption via MMP2/9 contributes to postoperative cognitive dysfunction. Neurochem Res. 2025;50(4):210. doi: 10.1007/s11064-025-04458-z EDN: QJASST</mixed-citation></ref><ref id="B49"><label>49.</label><mixed-citation>Wang Z, Zheng Y, Wang F, et al. Mfsd2a and Spns2 are essential for sphingosine-1-phosphate transport in the formation and maintenance of the blood-brain barrier. Sci Adv. 2020;6(22):eaay8627. doi: 10.1126/sciadv.aay8627 EDN: IOKUGG</mixed-citation></ref><ref id="B50"><label>50.</label><mixed-citation>Lorin V, Danckaert A, Porrot F, et al. Antibody Neutralization of HIV-1 Crossing the Blood-Brain Barrier. MBio. 2020;11(5). doi: 10.1128/mBio.02424-20 EDN: AAQCRO</mixed-citation></ref><ref id="B51"><label>51.</label><mixed-citation>Islamov R, Bashirov F, Izmailov A, et al. New therapy for Spinal Cord Injury: Autologous Genetically-Enriched Leucoconcentrate Integrated with Epidural Electrical Stimulation. Cells. 2022;11(1):1–26. doi: 10.3390/cells11010144 EDN: FXRTHB</mixed-citation></ref><ref id="B52"><label>52.</label><mixed-citation>Safiullov Z, Izmailov A, Sokolov M, et al. Autologous Genetically Enriched Leucoconcentrate in the Preventive and Acute Phases of Stroke Treatment in a Mini-Pig Model. Pharmaceutics. 2022;14(10):2209. doi: 10.3390/PHARMACEUTICS14102209 EDN: YMUITU</mixed-citation></ref><ref id="B53"><label>53.</label><mixed-citation>Ayer M, Klok HA. Cell-mediated delivery of synthetic nano- and microparticles. J Control release Off J Control Release Soc. 2017;259:92–104. doi: 10.1016/j.jconrel.2017.01.048 EDN: YEWFWE</mixed-citation></ref><ref id="B54"><label>54.</label><mixed-citation>Wang YT, Lu XM, Chen KT, et al. Immunotherapy strategies for spinal cord injury. Curr Pharm Biotechnol. 2015;16(6):492–505. doi: 10.2174/138920101606150407112646</mixed-citation></ref><ref id="B55"><label>55.</label><mixed-citation>Xu D, Wu D, Qin M, et al. Efficient Delivery of Nerve Growth Factors to the Central Nervous System for Neural Regeneration. Adv Mater. 2019;31(33). doi: 10.1002/adma.201900727</mixed-citation></ref><ref id="B56"><label>56.</label><mixed-citation>Li TF, Li K, Wang C, et al. Harnessing the cross-talk between tumor cells and tumor-associated macrophages with a nano-drug for modulation of glioblastoma immune microenvironment. J Control release Off J Control Release Soc. 2017;268:128–146. doi: 10.1016/j.jconrel.2017.10.024</mixed-citation></ref><ref id="B57"><label>57.</label><mixed-citation>Wang C, Li K, Li T, et al. Monocyte-mediated chemotherapy drug delivery in glioblastoma. Nanomedicine. 2018;13(2):157–178. doi: 10.2217/nnm-2017-0266 EDN: YJPGLR</mixed-citation></ref><ref id="B58"><label>58.</label><mixed-citation>Li TF, Li K, Zhang Q, et al. Dendritic cell-mediated delivery of doxorubicin-polyglycerol-nanodiamond composites elicits enhanced anti-cancer immune response in glioblastoma. Biomaterials. 2018;181:35–52. doi: 10.1016/j.biomaterials.2018.07.035</mixed-citation></ref><ref id="B59"><label>59.</label><mixed-citation>Salmina AB, Komleva YK, Malinovskaya NA, et al. Blood–brain barrier breakdown in stress and neurodegeneration: biochemical mechanisms and new models for translational research. Biochemistr. 2021;86(6):917–932. doi: 10.31857/S0320972521060130 EDN: QSCMFB</mixed-citation></ref><ref id="B60"><label>60.</label><mixed-citation>Davleeva MA, Garifulin RR, Bashirov FV, et al. Molecular and cellular changes in the post-traumatic spinal cord remodeling after autoinfusion of a genetically-enriched leucoconcentrate in a mini-pig model. Neural Regen Res. 2023;18(7):1505–1511. doi: 10.4103/1673-5374.360241 EDN: EIGCPB</mixed-citation></ref><ref id="B61"><label>61.</label><mixed-citation>Garifulin R, Davleeva M, Izmailov A, et al. Evaluation of the Autologous Genetically Enriched Leucoconcentrate on the Lumbar Spinal Cord Morpho-Functional Recovery in a Mini Pig with Thoracic Spine Contusion Injury. Biomedicines. 2023;11(5):1–18. doi: 10.3390/biomedicines11051331 EDN: HVVKRQ</mixed-citation></ref><ref id="B62"><label>62.</label><mixed-citation>Gomez Limia C, Baird M, Schwartz M, et al. Emerging Perspectives on Gene Therapy Delivery for Neurodegenerative and Neuromuscular Disorders. J Pers Med. 2022;12(12). doi: 10.3390/jpm12121979 EDN: QORKUJ</mixed-citation></ref><ref id="B63"><label>63.</label><mixed-citation>Lysogorskaia EV, Abramycheva NYu, Vetchinova AS, et al. Current cell and molecular approaches in studies of motor neuron diseases. Nevrologicheskii zhurnal. 2018;23(4):160-165. doi: 10.18821/1560-9545-2018-23-4-160-165 EDN: YPHMFN</mixed-citation></ref><ref id="B64"><label>64.</label><mixed-citation>Mingozzi F, High KA. Overcoming the Host Immune Response to Adeno-Associated Virus Gene Delivery Vectors: The Race Between Clearance, Tolerance, Neutralization, and Escape. Annu Rev Virol. 2017;4(1):511–534. doi: 10.1146/annurev-virology-101416-041936</mixed-citation></ref><ref id="B65"><label>65.</label><mixed-citation>Vagner T, Dvorzhak A, Wójtowicz AM, et al. Systemic application of AAV vectors targeting GFAP-expressing astrocytes in Z-Q175-KI Huntington's disease mice. Mol Cell Neurosci. 2016;77:76–86. doi: 10.1016/j.mcn.2016.10.007 EDN: XUOHKZ</mixed-citation></ref><ref id="B66"><label>66.</label><mixed-citation>Mullagulova A, Shaimardanova A, Solovyeva V, et al. Safety and Efficacy of Intravenous and Intrathecal Delivery of AAV9-Mediated ARSA in Minipigs. Int J Mol Sci. 2023;24(11). doi: 10.3390/ijms24119204 EDN: GIICIN</mixed-citation></ref><ref id="B67"><label>67.</label><mixed-citation>Mendell JR, Al-Zaidy SA, Rodino-Klapac LR, et al. Current Clinical Applications of In Vivo Gene Therapy with AAVs. Mol Ther. 2021;29(2):464–488. doi: 10.1016/j.ymthe.2020.12.007 EDN: BZNBVQ</mixed-citation></ref><ref id="B68"><label>68.</label><mixed-citation>Schroth MK, Deans J, Bharucha Goebel DX, et al. Spinal Muscular Atrophy Update in Best Practices: Recommendations for Treatment Considerations. Neurol Clin Pract. 2025;15(1):e200374. doi: 10.1212/CPJ.0000000000200374 EDN: DIDTKW</mixed-citation></ref><ref id="B69"><label>69.</label><mixed-citation>Cheng GG, Liu Y, Ma R, et al. Anti-Parkinsonian Therapy: Strategies for Crossing the Blood-Brain Barrier and Nano-Biological Effects of Nanomaterials. Nano-micro Lett. 2022;14(1):105. doi: 10.1007/s40820-022-00847-z EDN: LEOXKY</mixed-citation></ref><ref id="B70"><label>70.</label><mixed-citation>Antimisiaris SG, Marazioti A, Kannavou M, et al. Overcoming barriers by local drug delivery with liposomes. Adv Drug Deliv Rev. 2021;174:53–86. doi: 10.1016/j.addr.2021.01.019 EDN: AJCCQK</mixed-citation></ref><ref id="B71"><label>71.</label><mixed-citation>Hersh AM, Alomari S, Tyler BM. Crossing the Blood-Brain Barrier: Advances in Nanoparticle Technology for Drug Delivery in Neuro-Oncology. Int J Mol Sci. 2022;23(8). doi: 10.3390/ijms23084153 EDN: RITVXR</mixed-citation></ref><ref id="B72"><label>72.</label><mixed-citation>Sun K, Zheng X, Jin H, et al. Exosomes as CNS Drug Delivery Tools and Their Applications. Pharmaceutics. 2022;14(10). doi: 10.3390/pharmaceutics14102252 EDN: OJUETH</mixed-citation></ref><ref id="B73"><label>73.</label><mixed-citation>Han X, Gong C, Yang Q, et al. Biomimetic nano-drug delivery system: an emerging platform for promoting tumor treatment. Int J Nanomedicine. 2024;19:571–608. doi: 10.2147/ijn.s442877 EDN: FQQYAJ</mixed-citation></ref><ref id="B74"><label>74.</label><mixed-citation>Li J, Song J, Jia L, et al. Exosomes in Central Nervous System Diseases: A Comprehensive Review of Emerging Research and Clinical Frontiers. Biomolecules. 2024;14(12). doi: 10.3390/biom14121519 EDN: QPTPJT</mixed-citation></ref><ref id="B75"><label>75.</label><mixed-citation>Nouri Z, Barfar A, Perseh S, et al. Exosomes as therapeutic and drug delivery vehicle for neurodegenerative diseases. J Nanobiotechnology. 2024;22(1):463. doi: 10.1186/s12951-024-02681-4 EDN: VSYVQG</mixed-citation></ref><ref id="B76"><label>76.</label><mixed-citation>Liu WZ, Ma ZJ, Li JR, Kang XW. Mesenchymal stem cell-derived exosomes: therapeutic opportunities and challenges for spinal cord injury. Stem Cell Res Ther. 2021;12(1):102. doi: 10.1186/s13287-021-02153-8 EDN: MLCCUK</mixed-citation></ref><ref id="B77"><label>77.</label><mixed-citation>Tian T, Zhang HX, He CP, et al. Surface functionalized exosomes as targeted drug delivery vehicles for cerebral ischemia therapy. Biomaterials. 2018;150:137–149. doi: 10.1016/j.biomaterials.2017.10.012 EDN: YHYHMJ</mixed-citation></ref><ref id="B78"><label>78.</label><mixed-citation>Israel LL, Galstyan A, Holler E, Ljubimova JY. Magnetic iron oxide nanoparticles for imaging, targeting and treatment of primary and metastatic tumors of the brain. J Control release Off J Control Release Soc. 2020;320:45–62. doi: 10.1016/j.jconrel.2020.01.009 EDN: ZXNKPS</mixed-citation></ref><ref id="B79"><label>79.</label><mixed-citation>Huang Y, Zhang B, Xie S, et al. Superparamagnetic Iron Oxide Nanoparticles Modified with Tween 80 Pass through the Intact Blood-Brain Barrier in Rats under Magnetic Field. ACS Appl Mater Interfaces. 2016;8(18):11336–11341. doi: 10.1021/acsami.6b02838 EDN: WUSHPR</mixed-citation></ref><ref id="B80"><label>80.</label><mixed-citation>Kim HY, Kim TJ, Kang L, et al. Mesenchymal stem cell-derived magnetic extracellular nanovesicles for targeting and treatment of ischemic stroke. Biomaterials. 2020;243:119942. doi: 10.1016/j.biomaterials.2020.119942 EDN: OLAFZF</mixed-citation></ref><ref id="B81"><label>81.</label><mixed-citation>Howaili F, Özliseli E, Küçüktürkmen B, et al. Stimuli-Responsive, Plasmonic Nanogel for Dual Delivery of Curcumin and Photothermal Therapy for Cancer Treatment. Front Chem. 2020;8:602941. doi: 10.3389/fchem.2020.602941 EDN: BVUJMW</mixed-citation></ref><ref id="B82"><label>82.</label><mixed-citation>Zhou H, Gong Y, Liu Y, et al. Intelligently thermoresponsive flower-like hollow nano-ruthenium system for sustained release of nerve growth factor to inhibit hyperphosphorylation of tau and neuronal damage for the treatment of Alzheimer's disease. Biomaterials. 2020;237:119822. doi: 10.1016/j.biomaterials.2020.119822 EDN: ZLJKBA</mixed-citation></ref><ref id="B83"><label>83.</label><mixed-citation>McMahon D, Poon C, Hynynen K. Evaluating the safety profile of focused ultrasound and microbubble-mediated treatments to increase blood-brain barrier permeability. Expert Opin Drug Deliv. 2019;16(2):129–142. doi: 10.1080/17425247.2019.1567490</mixed-citation></ref><ref id="B84"><label>84.</label><mixed-citation>Wang J, Li Z, Pan M, et al. Ultrasound-mediated blood-brain barrier opening: an effective drug delivery system for theranostics of brain diseases. Adv Drug Deliv Rev. 2022;190:114539. doi: 10.1016/j.addr.2022.114539</mixed-citation></ref><ref id="B85"><label>85.</label><mixed-citation>Drath I, Richter F, Feja M. Nose-to-brain drug delivery: from bench to bedside. Transl Neurodegener. 2025;14(1):23. doi: 10.1186/s40035-025-00481-w EDN: TJUVVV</mixed-citation></ref><ref id="B86"><label>86.</label><mixed-citation>Craft S, Raman R, Chow TW, et al. Safety, Efficacy, and Feasibility of Intranasal Insulin for the Treatment of Mild Cognitive Impairment and Alzheimer Disease Dementia: A Randomized Clinical Trial. JAMA Neurol. 2020;77(9):1099–1109. doi: 10.1001/jamaneurol.2020.1840 EDN: VTVFZZ</mixed-citation></ref></ref-list></back></article>
