{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T03:46:15Z","timestamp":1773978375525,"version":"3.50.1"},"reference-count":61,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,4,1]],"date-time":"2025-04-01T00:00:00Z","timestamp":1743465600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,4,1]],"date-time":"2025-04-01T00:00:00Z","timestamp":1743465600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"HUN-REN Biological Research Centre, Szeged"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Fluids Barriers CNS"],"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:sec>\n            <jats:title>Background<\/jats:title>\n            <jats:p>Nanocarriers targeting the blood-brain barrier (BBB) are promising drug delivery systems to enhance the penetration of therapeutic molecules into the brain. Immunotherapy, particularly monoclonal antibodies designed to bind amyloid-beta peptides have become a promising strategy for Alzheimer\u2019s disease, but ensuring efficacy and safety is challenging and crucial for these therapies. Our aim was to develop an innovative nanocarriers conjugated with PepH3, a cationic peptide derived from Dengue virus type-2 capsid protein that crosses the BBB and acts as a shuttle peptide for the encapsulated single domain antibody (sdAb) recognizing A\u03b2 oligomers.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>PepH3 peptide enhanced the uptake of the nanoparticles (NPs) into brain endothelial cells, and transcytosis of sdAb, as a potential therapeutic molecule, across both rat and human BBB culture models. The cargo uptake was a temperature dependent active process that was reduced by metabolic and endocytosis inhibitors. The cellular uptake of the cationic PepH3-tagged NPs decreased when the negative surface charge of brain endothelial cells became more positive after treatments with a cationic lipid or with neuraminidase by digesting the glycocalyx. The NPs colocalized mostly with endoplasmic reticulum and Golgi apparatus and not with lysosomes, indicating the cargo may avoid cellular degradation.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>Our results support that combination of NPs with a potential brain shuttle peptide such as PepH3 peptide can improve the delivery of antibody fragments across the BBB.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/s12987-025-00641-0","type":"journal-article","created":{"date-parts":[[2025,4,1]],"date-time":"2025-04-01T13:19:45Z","timestamp":1743513585000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["PepH3-modified nanocarriers for delivery of therapeutics across the blood-brain barrier"],"prefix":"10.1186","volume":"22","author":[{"given":"Anik\u00f3","family":"Szecsk\u00f3","sequence":"first","affiliation":[]},{"given":"M\u00e1ria","family":"M\u00e9sz\u00e1ros","sequence":"additional","affiliation":[]},{"given":"Beatriz","family":"Sim\u00f5es","sequence":"additional","affiliation":[]},{"given":"Marco","family":"Cavaco","sequence":"additional","affiliation":[]},{"given":"Catarina","family":"Chaparro","sequence":"additional","affiliation":[]},{"given":"Gerg\u0151","family":"Porkol\u00e1b","sequence":"additional","affiliation":[]},{"given":"Miguel A.R.B.","family":"Castanho","sequence":"additional","affiliation":[]},{"given":"M\u00e1ria A.","family":"Deli","sequence":"additional","affiliation":[]},{"given":"Vera","family":"Neves","sequence":"additional","affiliation":[]},{"given":"Szilvia","family":"Veszelka","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2025,4,1]]},"reference":[{"issue":"1","key":"641_CR1","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1602\/neurorx.2.1.3","volume":"2","author":"WM Pardridge","year":"2005","unstructured":"Pardridge WM. The blood-brain barrier: bottleneck in brain drug development. NeuroRx. 2005;2(1):3\u201314. https:\/\/doi.org\/10.1602\/neurorx.2.1.3.","journal-title":"NeuroRx"},{"key":"641_CR2","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1016\/j.jconrel.2016.05.044","volume":"235","author":"C Saraiva","year":"2016","unstructured":"Saraiva C, Pra\u00e7a C, Ferreira R, Santos T, Ferreira L, Bernardino L. Nanoparticle-mediated brain drug delivery: overcoming blood-brain barrier to treat neurodegenerative diseases. J Control Release. 2016;235:34\u201347. https:\/\/doi.org\/10.1016\/j.jconrel.2016.05.044.","journal-title":"J Control Release"},{"issue":"1","key":"641_CR3","doi-asserted-by":"publisher","first-page":"38","DOI":"10.3390\/pharmaceutics13010038","volume":"13","author":"GR Topal","year":"2020","unstructured":"Topal GR, M\u00e9sz\u00e1ros M, Porkol\u00e1b G, Szecsk\u00f3 A, Polg\u00e1r TF, Sikl\u00f3s L, Deli MA, Veszelka S, Bozkir A. ApoE-Targeting increases the transfer of solid lipid nanoparticles with donepezil cargo across a culture model of the Blood-Brain barrier. Pharmaceutics. 2020;13(1):38. https:\/\/doi.org\/10.3390\/pharmaceutics13010038.","journal-title":"Pharmaceutics"},{"key":"641_CR4","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1016\/j.jconrel.2015.02.012","volume":"203","author":"M Rotman","year":"2015","unstructured":"Rotman M, Welling MM, Bunschoten A, de Backer ME, Rip J, Nabuurs RJ, Gaillard PJ, van Buchem MA, van der Maarel SM, van der Weerd L. Enhanced glutathione pegylated liposomal brain delivery of an anti-amyloid single domain antibody fragment in a mouse model for Alzheimer\u2019s disease. J Control Release. 2015;203:40\u201350. https:\/\/doi.org\/10.1016\/j.jconrel.2015.02.012.","journal-title":"J Control Release"},{"key":"641_CR5","doi-asserted-by":"publisher","first-page":"6847971","DOI":"10.1155\/2018\/6847971","volume":"2018","author":"M Gharbavi","year":"2018","unstructured":"Gharbavi M, Amani J, Kheiri-Manjili H, Danafar H, Sharafi A. Niosome: A promising nanocarrier for natural drug delivery through Blood-Brain barrier. Adv Pharmacol Sci. 2018;2018:6847971. https:\/\/doi.org\/10.1155\/2018\/6847971.","journal-title":"Adv Pharmacol Sci"},{"key":"641_CR6","doi-asserted-by":"publisher","first-page":"228","DOI":"10.1016\/j.ejps.2018.07.042","volume":"123","author":"M M\u00e9sz\u00e1ros","year":"2018","unstructured":"M\u00e9sz\u00e1ros M, Porkol\u00e1b G, Kiss L, Pilbat AM, K\u00f3ta Z, Kupih\u00e1r Z, K\u00e9ri A, Galb\u00e1cs G, Sikl\u00f3s L, T\u00f3th A, F\u00fcl\u00f6p L, Csete M, Sipos \u00c1, H\u00fclper P, Sipos P, P\u00e1li T, R\u00e1khely G, Szab\u00f3-R\u00e9v\u00e9sz P, Deli MA, Veszelka S. Niosomes decorated with dual ligands targeting brain endothelial transporters increase cargo penetration across the blood-brain barrier. Eur J Pharm Sci. 2018;123:228\u201340. https:\/\/doi.org\/10.1016\/j.ejps.2018.07.042.","journal-title":"Eur J Pharm Sci"},{"issue":"3","key":"641_CR7","doi-asserted-by":"publisher","first-page":"503","DOI":"10.3390\/cells12030503","volume":"12","author":"M M\u00e9sz\u00e1ros","year":"2023","unstructured":"M\u00e9sz\u00e1ros M, Phan THM, Vigh JP, Porkol\u00e1b G, Kocsis A, P\u00e1li EK, Polg\u00e1r TF, Walter FR, Bolognin S, Schwamborn JC, Jan JS, Deli MA, Veszelka S. Targeting human endothelial cells with glutathione and Alanine increases the crossing of a polypeptide nanocarrier through a Blood-Brain barrier model and entry to human brain organoids. Cells. 2023;12(3):503. https:\/\/doi.org\/10.3390\/cells12030503.","journal-title":"Cells"},{"issue":"1","key":"641_CR8","doi-asserted-by":"publisher","first-page":"86","DOI":"10.3390\/pharmaceutics14010086","volume":"14","author":"S Veszelka","year":"2021","unstructured":"Veszelka S, M\u00e9sz\u00e1ros M, Porkol\u00e1b G, Szecsk\u00f3 A, Kondor N, Ferenc G, Polg\u00e1r TF, Katona G, K\u00f3ta Z, Kelemen L, P\u00e1li T, Vigh JP, Walter FR, Bolognin S, Schwamborn JC, Jan JS, Deli MA. A triple combination of targeting ligands increases the penetration of nanoparticles across a Blood-Brain barrier culture model. Pharmaceutics. 2021;14(1):86. https:\/\/doi.org\/10.3390\/pharmaceutics14010086.","journal-title":"Pharmaceutics"},{"issue":"4","key":"641_CR9","doi-asserted-by":"publisher","first-page":"e1695","DOI":"10.1002\/wnan.1695","volume":"13","author":"X Zhou","year":"2021","unstructured":"Zhou X, Smith QR, Liu X. Brain penetrating peptides and peptide-drug conjugates to overcome the blood-brain barrier and target CNS diseases. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2021;13(4):e1695. https:\/\/doi.org\/10.1002\/wnan.1695.","journal-title":"Wiley Interdiscip Rev Nanomed Nanobiotechnol"},{"issue":"6","key":"641_CR10","doi-asserted-by":"publisher","first-page":"583","DOI":"10.1080\/17425247.2019.1614911","volume":"16","author":"B Jafari","year":"2019","unstructured":"Jafari B, Pourseif MM, Barar J, Rafi MA, Omidi Y. Peptide-mediated drug delivery across the blood-brain barrier for targeting brain tumors. Expert Opin Drug Deliv. 2019;16(6):583\u2013605. https:\/\/doi.org\/10.1080\/17425247.2019.1614911.","journal-title":"Expert Opin Drug Deliv"},{"issue":"5","key":"641_CR11","doi-asserted-by":"publisher","first-page":"1257","DOI":"10.1021\/acschembio.7b00087","volume":"12","author":"V Neves","year":"2017","unstructured":"Neves V, Aires-da-Silva F, Morais M, Gano L, Ribeiro E, Pinto A, Aguiar S, Gaspar D, Fernandes C, Correia JDG, Castanho MARB. Novel peptides derived from dengue virus capsid protein translocate reversibly the Blood-Brain barrier through a Receptor-Free mechanism. ACS Chem Biol. 2017;12(5):1257\u201368. https:\/\/doi.org\/10.1021\/acschembio.7b00087.","journal-title":"ACS Chem Biol"},{"issue":"1","key":"641_CR12","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1186\/s12987-024-00545-5","volume":"21","author":"M Cavaco","year":"2024","unstructured":"Cavaco M, Fraga P, Valle J, Silva RDM, Gano L, Correia JDG, Andreu D, Castanho MARB, Neves V. Molecular determinants for brain targeting by peptides: a meta-analysis approach with experimental validation. Fluids Barriers CNS. 2024;21(1):45. https:\/\/doi.org\/10.1186\/s12987-024-00545-5.","journal-title":"Fluids Barriers CNS"},{"key":"641_CR13","doi-asserted-by":"publisher","first-page":"116573","DOI":"10.1016\/j.biopha.2024.116573","volume":"174","author":"M Cavaco","year":"2024","unstructured":"Cavaco M, P\u00e9rez-Peinado C, Valle J, Silva RDM, Gano L, Correia JDG, Andreu D, Castanho MARB, Neves V. The use of a selective, nontoxic dual-acting peptide for breast cancer patients with brain metastasis. Biomed Pharmacother. 2024;174:116573. https:\/\/doi.org\/10.1016\/j.biopha.2024.116573.","journal-title":"Biomed Pharmacother"},{"key":"641_CR14","doi-asserted-by":"publisher","unstructured":"Woods B, Silva RDM, Schmidt C, Wragg D, Cavaco M, Neves V, Ferreira VFC, Gano L, Morais TS, Mendes F, Correia JDG, Casini A. Bioconjugate Supramolecular Pd2+ Metallacages Penetrate the Blood Brain Barrier In Vitro and in vivo. Bioconjug Chem. 2021; 32(7):1399\u20131408. https:\/\/doi.org\/10.1021\/acs.bioconjchem.0c00659","DOI":"10.1021\/acs.bioconjchem.0c00659"},{"issue":"24","key":"641_CR15","doi-asserted-by":"publisher","first-page":"5789","DOI":"10.3390\/molecules25245789","volume":"25","author":"Z Breijyeh","year":"2020","unstructured":"Breijyeh Z, Karaman R. Comprehensive review on Alzheimer\u2019s disease: causes and treatment. Molecules. 2020;25(24):5789. https:\/\/doi.org\/10.3390\/molecules25245789.","journal-title":"Molecules"},{"issue":"1","key":"641_CR16","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1007\/s13311-022-01308-6","volume":"20","author":"L S\u00f6derberg","year":"2023","unstructured":"S\u00f6derberg L, Johannesson M, Nygren P, Laudon H, Eriksson F, Osswald G, M\u00f6ller C, Lannfelt L, Lecanemab. Aducanumab, and Gantenerumab - Binding profiles to different forms of Amyloid-Beta might explain efficacy and side effects in clinical trials for Alzheimer\u2019s disease. Neurotherapeutics. 2023;20(1):195\u2013206. https:\/\/doi.org\/10.1007\/s13311-022-01308-6.","journal-title":"Neurotherapeutics"},{"key":"641_CR17","doi-asserted-by":"publisher","first-page":"870517","DOI":"10.3389\/fnagi.2022.870517","volume":"14","author":"M Shi","year":"2022","unstructured":"Shi M, Chu F, Zhu F, Zhu J. Impact of Anti-amyloid-\u03b2 monoclonal antibodies on the pathology and clinical profile of Alzheimer\u2019s disease: A focus on aducanumab and Lecanemab. Front Aging Neurosci. 2022;14:870517. https:\/\/doi.org\/10.3389\/fnagi.2022.870517.","journal-title":"Front Aging Neurosci"},{"key":"641_CR18","doi-asserted-by":"publisher","first-page":"654611","DOI":"10.3389\/fphar.2021.654611","volume":"12","author":"ZT Sun","year":"2021","unstructured":"Sun ZT, Ma C, Li GJ, Zheng XY, Hao YT, Yang Y, Wang X. Application of antibody fragments against A\u03b2 with emphasis on combined application with nanoparticles in Alzheimer\u2019s disease. Front Pharmacol. 2021;12:654611. https:\/\/doi.org\/10.3389\/fphar.2021.654611.","journal-title":"Front Pharmacol"},{"issue":"12","key":"641_CR19","doi-asserted-by":"publisher","first-page":"2014","DOI":"10.3390\/pharmaceutics13122014","volume":"13","author":"R Bajracharya","year":"2021","unstructured":"Bajracharya R, Caruso AC, Vella LJ, Nisbet RM. Current and emerging strategies for enhancing antibody delivery to the brain. Pharmaceutics. 2021;13(12):2014. https:\/\/doi.org\/10.3390\/pharmaceutics13122014.","journal-title":"Pharmaceutics"},{"key":"641_CR20","unstructured":"Corte-Real S, Neves V, Canh\u00e3o P, Outeiro T, Castanho MARB, Aires da Silva F, Santiago, de Oliveira S. Antibody molecules and peptide delivery systems for use in Alzheimer\u00b4s disease and related disorders. WO2016120843A1, 2016."},{"key":"641_CR21","doi-asserted-by":"publisher","first-page":"6497","DOI":"10.2147\/IJN.S215941","volume":"14","author":"B Dos Santos Rodrigues","year":"2019","unstructured":"Dos Santos Rodrigues B, Lakkadwala S, Kanekiyo T, Singh J. Development and screening of brain-targeted lipid-based nanoparticles with enhanced cell penetration and gene delivery properties. Int J Nanomed. 2019;14:6497\u2013517. https:\/\/doi.org\/10.2147\/IJN.S215941.","journal-title":"Int J Nanomed"},{"issue":"3\u20134","key":"641_CR22","doi-asserted-by":"publisher","first-page":"253","DOI":"10.1016\/j.neuint.2008.12.002","volume":"54","author":"S Nakagawa","year":"2009","unstructured":"Nakagawa S, Deli MA, Kawaguchi H, Shimizudani T, Shimono T, Kittel A, Tanaka K, Niwa M. A new blood-brain barrier model using primary rat brain endothelial cells, pericytes and astrocytes. Neurochem Int. 2009;54(3\u20134):253\u201363. https:\/\/doi.org\/10.1016\/j.neuint.2008.12.002.","journal-title":"Neurochem Int"},{"issue":"2","key":"641_CR23","doi-asserted-by":"publisher","first-page":"279","DOI":"10.1111\/j.1471-4159.2004.03020.x","volume":"93","author":"N Perri\u00e8re","year":"2005","unstructured":"Perri\u00e8re N, Demeuse P, Garcia E, Regina A, Debray M, Andreux JP, Couvreur P, Scherrmann JM, Temsamani J, Couraud PO, Deli MA, Roux F. Puromycin-based purification of rat brain capillary endothelial cell cultures. Effect on the expression of blood-brain barrier-specific properties. J Neurochem. 2005;93(2):279\u201389. https:\/\/doi.org\/10.1111\/j.1471-4159.2004.03020.x.","journal-title":"J Neurochem"},{"issue":"13","key":"641_CR24","doi-asserted-by":"publisher","first-page":"1495","DOI":"10.2174\/1381612826666200213094556","volume":"26","author":"M Cavaco","year":"2020","unstructured":"Cavaco M, Valle J, da Silva R, Correia JDG, Castanho MARB, Andreu D, Neves V. DPepH3, an improved peptide shuttle for Receptor-independent transport across the Blood-Brain barrier. Curr Pharm Des. 2020;26(13):1495\u2013506. https:\/\/doi.org\/10.2174\/1381612826666200213094556.","journal-title":"Curr Pharm Des"},{"issue":"1","key":"641_CR25","doi-asserted-by":"publisher","first-page":"1600332","DOI":"10.1002\/biot.201600332","volume":"12","author":"B Moser","year":"2017","unstructured":"Moser B, Hochreiter B, Herbst R, Schmid JA. Fluorescence colocalization microscopy analysis can be improved by combining object-recognition with pixel-intensity-correlation. Biotechnol J. 2017;12(1):1600332. https:\/\/doi.org\/10.1002\/biot.201600332.","journal-title":"Biotechnol J"},{"key":"641_CR26","doi-asserted-by":"publisher","first-page":"166","DOI":"10.3389\/fnmol.2018.00166","volume":"11","author":"S Veszelka","year":"2018","unstructured":"Veszelka S, T\u00f3th A, Walter FR, T\u00f3th AE, Gr\u00f3f I, M\u00e9sz\u00e1ros M, Bocsik A, Hellinger \u00c9, Vastag M, R\u00e1khely G, Deli MA. Comparison of a rat primary cell-Based Blood-Brain barrier model with epithelial and brain endothelial cell lines: gene expression and drug transport. Front Mol Neurosci. 2018;11:166. https:\/\/doi.org\/10.3389\/fnmol.2018.00166.","journal-title":"Front Mol Neurosci"},{"issue":"1","key":"641_CR27","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1007\/s10571-004-1377-8","volume":"25","author":"MA Deli","year":"2005","unstructured":"Deli MA, Abrah\u00e1m CS, Kataoka Y, Niwa M. Permeability studies on in vitro blood-brain barrier models: physiology, pathology, and Pharmacology. Cell Mol Neurobiol. 2005;25(1):59\u2013127. https:\/\/doi.org\/10.1007\/s10571-004-1377-8.","journal-title":"Cell Mol Neurobiol"},{"key":"641_CR28","doi-asserted-by":"publisher","first-page":"552035","DOI":"10.3389\/fbioe.2020.552035","volume":"8","author":"M Cavaco","year":"2020","unstructured":"Cavaco M, P\u00e9rez-Peinado C, Valle J, Silva RDM, Correia JDG, Andreu D, Castanho MARB, Neves V. To what extent do fluorophores bias the biological activity of peptides?? A practical approach using Membrane-Active peptides? as models. Front Bioeng Biotechnol. 2020;8:552035. https:\/\/doi.org\/10.3389\/fbioe.2020.552035.","journal-title":"Front Bioeng Biotechnol"},{"issue":"11","key":"641_CR29","doi-asserted-by":"publisher","first-page":"1663","DOI":"10.1021\/acsmedchemlett.1c00225","volume":"12","author":"M Cavaco","year":"2021","unstructured":"Cavaco M, Frutos S, Oliete P, Valle J, Andreu D, Castanho MARB, Vila-Perell\u00f3 M, Neves V. Conjugation of a blood brain barrier peptide shuttle to an Fc domain for brain delivery of therapeutic biomolecules. ACS Med Chem Lett. 2021;12(11):1663\u20138. https:\/\/doi.org\/10.1021\/acsmedchemlett.1c00225.","journal-title":"ACS Med Chem Lett"},{"issue":"3","key":"641_CR30","doi-asserted-by":"publisher","first-page":"437","DOI":"10.1007\/s10545-013-9608-0","volume":"36","author":"NJ Abbott","year":"2013","unstructured":"Abbott NJ. Blood-brain barrier structure and function and the challenges for CNS drug delivery. J Inherit Metab Dis. 2013;36(3):437\u201349. https:\/\/doi.org\/10.1007\/s10545-013-9608-0.","journal-title":"J Inherit Metab Dis"},{"issue":"6","key":"641_CR31","doi-asserted-by":"publisher","first-page":"679","DOI":"10.1002\/med.20034","volume":"25","author":"F Hudecz","year":"2005","unstructured":"Hudecz F, B\u00e1n\u00f3czi Z, Cs\u00edk G. Medium-sized peptides as built in carriers for biologically active compounds. Med Res Rev. 2005;25(6):679\u2013736. https:\/\/doi.org\/10.1002\/med.20034.","journal-title":"Med Res Rev"},{"issue":"17","key":"641_CR32","doi-asserted-by":"publisher","first-page":"4690","DOI":"10.1039\/c6cs00076b","volume":"45","author":"B Oller-Salvia","year":"2016","unstructured":"Oller-Salvia B, S\u00e1nchez-Navarro M, Giralt E, Teixid\u00f3 M. Blood-brain barrier shuttle peptides: an emerging paradigm for brain delivery. Chem Soc Rev. 2016;45(17):4690\u2013707. https:\/\/doi.org\/10.1039\/c6cs00076b.","journal-title":"Chem Soc Rev"},{"issue":"5","key":"641_CR33","doi-asserted-by":"publisher","first-page":"460","DOI":"10.3109\/1061186X.2014.888070","volume":"22","author":"J Rip","year":"2014","unstructured":"Rip J, Chen L, Hartman R, van den Heuvel A, Reijerkerk A, van Kregten J, van der Boom B, Appeldoorn C, de Boer M, Maussang D, de Lange EC, Gaillard PJ. Glutathione pegylated liposomes: pharmacokinetics and delivery of cargo across the blood-brain barrier in rats. J Drug Target. 2014;22(5):460\u20137. https:\/\/doi.org\/10.3109\/1061186X.2014.888070.","journal-title":"J Drug Target"},{"key":"641_CR34","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.ddtec.2016.11.002","volume":"20","author":"PJ Gaillard","year":"2016","unstructured":"Gaillard PJ. BBB crossing assessment and BBB crossing technologies in CNS drug discovery. Drug Discov Today Technol. 2016;20:1\u20133. https:\/\/doi.org\/10.1016\/j.ddtec.2016.11.002.","journal-title":"Drug Discov Today Technol"},{"issue":"7","key":"641_CR35","doi-asserted-by":"publisher","first-page":"635","DOI":"10.3390\/pharmaceutics12070635","volume":"12","author":"G Porkol\u00e1b","year":"2020","unstructured":"Porkol\u00e1b G, M\u00e9sz\u00e1ros M, T\u00f3th A, Szecsk\u00f3 A, Harazin A, Szegletes Z, Ferenc G, Blasty\u00e1k A, M\u00e1t\u00e9s L, R\u00e1khely G, Deli MA, Veszelka S. Combination of Alanine and glutathione as targeting ligands of nanoparticles enhances cargo delivery into the cells of the neurovascular unit. Pharmaceutics. 2020;12(7):635. https:\/\/doi.org\/10.3390\/pharmaceutics12070635.","journal-title":"Pharmaceutics"},{"issue":"4","key":"641_CR36","doi-asserted-by":"publisher","first-page":"1153","DOI":"10.1039\/d0bm01755h","volume":"9","author":"K Desale","year":"2021","unstructured":"Desale K, Kuche K, Jain S. Cell-penetrating peptides (CPPs): an overview of applications for improving the potential of nanotherapeutics. Biomater Sci. 2021;9(4):1153\u201388. https:\/\/doi.org\/10.1039\/d0bm01755h.","journal-title":"Biomater Sci"},{"key":"641_CR37","doi-asserted-by":"publisher","first-page":"8507","DOI":"10.2147\/IJN.S183117","volume":"13","author":"C Ross","year":"2018","unstructured":"Ross C, Taylor M, Fullwood N, Allsop D. Liposome delivery systems for the treatment of Alzheimer\u2019s disease. Int J Nanomed. 2018;13:8507\u201322. https:\/\/doi.org\/10.2147\/IJN.S183117.","journal-title":"Int J Nanomed"},{"issue":"13","key":"641_CR38","doi-asserted-by":"publisher","first-page":"1366","DOI":"10.2174\/1381612824666171201115126","volume":"24","author":"M McCully","year":"2018","unstructured":"McCully M, Sanchez-Navarro M, Teixido M, Giralt E. Peptide mediated brain delivery of Nano- and submicroparticles: A synergistic approach. Curr Pharm Des. 2018;24(13):1366\u201376. https:\/\/doi.org\/10.2174\/1381612824666171201115126.","journal-title":"Curr Pharm Des"},{"issue":"10","key":"641_CR39","doi-asserted-by":"publisher","first-page":"1753","DOI":"10.3390\/molecules22101753","volume":"22","author":"S Neves-Coelho","year":"2017","unstructured":"Neves-Coelho S, Eleut\u00e9rio RP, Enguita FJ, Neves V, Castanho MARB. A new noncanonical anionic peptide that translocates a cellular Blood-Brain barrier model. Molecules. 2017;22(10):1753. https:\/\/doi.org\/10.3390\/molecules22101753.","journal-title":"Molecules"},{"key":"641_CR40","doi-asserted-by":"publisher","first-page":"580","DOI":"10.1016\/j.ijbiomac.2021.07.056","volume":"186","author":"P Salahuddin","year":"2021","unstructured":"Salahuddin P, Khan RH, Furkan M, Uversky VN, Islam Z, Fatima MT. Mechanisms of amyloid proteins aggregation and their Inhibition by antibodies, small molecule inhibitors, nano-particles and nano-bodies. Int J Biol Macromol. 2021;186:580\u201390. https:\/\/doi.org\/10.1016\/j.ijbiomac.2021.07.056.","journal-title":"Int J Biol Macromol"},{"key":"641_CR41","doi-asserted-by":"publisher","first-page":"238428","DOI":"10.1155\/2013\/238428","volume":"2013","author":"M Masserini","year":"2013","unstructured":"Masserini M. Nanoparticles for brain drug delivery. ISRN Biochem. 2013;2013:238428. https:\/\/doi.org\/10.1155\/2013\/238428.","journal-title":"ISRN Biochem"},{"key":"641_CR42","doi-asserted-by":"publisher","first-page":"120571","DOI":"10.1016\/j.ijpharm.2021.120571","volume":"601","author":"D Guimar\u00e3es","year":"2021","unstructured":"Guimar\u00e3es D, Cavaco-Paulo A, Nogueira E. Design of liposomes as drug delivery system for therapeutic applications. Int J Pharm. 2021;601:120571. https:\/\/doi.org\/10.1016\/j.ijpharm.2021.120571.","journal-title":"Int J Pharm"},{"key":"641_CR43","doi-asserted-by":"publisher","first-page":"120321","DOI":"10.1016\/j.ijpharm.2021.120321","volume":"596","author":"A Gordillo-Galeano","year":"2021","unstructured":"Gordillo-Galeano A, Ospina-Giraldo LF, Mora-Huertas CE. Lipid nanoparticles with improved biopharmaceutical attributes for tuberculosis treatment. Int J Pharm. 2021;596:120321. https:\/\/doi.org\/10.1016\/j.ijpharm.2021.120321.","journal-title":"Int J Pharm"},{"issue":"2","key":"641_CR44","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1016\/j.jconrel.2007.12.018","volume":"127","author":"IP Kaur","year":"2008","unstructured":"Kaur IP, Bhandari R, Bhandari S, Kakkar V. Potential of solid lipid nanoparticles in brain targeting. J Control Release. 2008;127(2):97\u2013109. https:\/\/doi.org\/10.1016\/j.jconrel.2007.12.018.","journal-title":"J Control Release"},{"key":"641_CR45","doi-asserted-by":"publisher","first-page":"44","DOI":"10.3389\/fncel.2012.00044","volume":"6","author":"MM Ribeiro","year":"2012","unstructured":"Ribeiro MM, Domingues MM, Freire JM, Santos NC, Castanho MA. Translocating the blood-brain barrier using electrostatics. Front Cell Neurosci. 2012;6:44. https:\/\/doi.org\/10.3389\/fncel.2012.00044.","journal-title":"Front Cell Neurosci"},{"issue":"3","key":"641_CR46","doi-asserted-by":"publisher","first-page":"1904773","DOI":"10.1080\/21688370.2021.1904773","volume":"9","author":"FR Walter","year":"2021","unstructured":"Walter FR, Santa-Maria AR, M\u00e9sz\u00e1ros M, Veszelka S, D\u00e9r A, Deli MA. Surface charge, glycocalyx, and blood-brain barrier function. Tissue Barriers. 2021;9(3):1904773. https:\/\/doi.org\/10.1080\/21688370.2021.1904773.","journal-title":"Tissue Barriers"},{"key":"641_CR47","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1186\/1472-6750-2-9","volume":"2","author":"JP Colletier","year":"2002","unstructured":"Colletier JP, Chaize B, Winterhalter M, Fournier D. Protein encapsulation in liposomes: efficiency depends on interactions between protein and phospholipid bilayer. BMC Biotechnol. 2002;2:9. https:\/\/doi.org\/10.1186\/1472-6750-2-9.","journal-title":"BMC Biotechnol"},{"issue":"7","key":"641_CR48","doi-asserted-by":"publisher","first-page":"947","DOI":"10.1016\/j.addr.2003.10.038","volume":"56","author":"S Sim\u00f5es","year":"2004","unstructured":"Sim\u00f5es S, Moreira JN, Fonseca C, D\u00fczg\u00fcne\u015f N, de Lima MC. On the formulation of pH-sensitive liposomes with long circulation times. Adv Drug Deliv Rev. 2004;56(7):947\u201365. https:\/\/doi.org\/10.1016\/j.addr.2003.10.038.","journal-title":"Adv Drug Deliv Rev"},{"issue":"7","key":"641_CR49","doi-asserted-by":"publisher","first-page":"2780","DOI":"10.1039\/c1cs15233e","volume":"41","author":"CD Walkey","year":"2012","unstructured":"Walkey CD, Chan WC. Understanding and controlling the interaction of nanomaterials with proteins in a physiological environment. Chem Soc Rev. 2012;41(7):2780\u201399. https:\/\/doi.org\/10.1039\/c1cs15233e.","journal-title":"Chem Soc Rev"},{"issue":"12","key":"641_CR50","doi-asserted-by":"publisher","first-page":"3166","DOI":"10.1021\/acschemneuro.8b00339","volume":"9","author":"A Arcella","year":"2018","unstructured":"Arcella A, Palchetti S, Digiacomo L, Pozzi D, Capriotti AL, Frati L, Oliva MA, Tsaouli G, Rota R, Screpanti I, Mahmoudi M, Caracciolo G. Brain targeting by Liposome-Biomolecular Corona boosts anticancer efficacy of Temozolomide in glioblastoma cells. ACS Chem Neurosci. 2018;9(12):3166\u201374. https:\/\/doi.org\/10.1021\/acschemneuro.8b00339.","journal-title":"ACS Chem Neurosci"},{"key":"641_CR51","doi-asserted-by":"publisher","first-page":"115114","DOI":"10.1016\/j.addr.2023.115114","volume":"202","author":"K Jiang","year":"2023","unstructured":"Jiang K, Yu Y, Qiu W, Tian K, Guo Z, Qian J, Lu H, Zhan C. Protein Corona on brain targeted nanocarriers: challenges and prospects. Adv Drug Deliv Rev. 2023;202:115114. https:\/\/doi.org\/10.1016\/j.addr.2023.115114.","journal-title":"Adv Drug Deliv Rev"},{"issue":"26","key":"641_CR52","doi-asserted-by":"publisher","first-page":"12386","DOI":"10.1039\/c8nr02393j","volume":"10","author":"YT Ho","year":"2018","unstructured":"Ho YT, Kamm RD, Kah JCY. Influence of protein Corona and caveolae-mediated endocytosis on nanoparticle uptake and transcytosis. Nanoscale. 2018;10(26):12386\u201397. https:\/\/doi.org\/10.1039\/c8nr02393j.","journal-title":"Nanoscale"},{"issue":"2","key":"641_CR53","doi-asserted-by":"publisher","first-page":"116","DOI":"10.1016\/j.tips.2010.11.005","volume":"32","author":"WP Verdurmen","year":"2011","unstructured":"Verdurmen WP, Brock R. Biological responses towards cationic peptides and drug carriers. Trends Pharmacol Sci. 2011;32(2):116\u201324. https:\/\/doi.org\/10.1016\/j.tips.2010.11.005.","journal-title":"Trends Pharmacol Sci"},{"issue":"17","key":"641_CR54","doi-asserted-by":"publisher","first-page":"2873","DOI":"10.1007\/s00018-009-0053-z","volume":"66","author":"H Hillaireau","year":"2009","unstructured":"Hillaireau H, Couvreur P. Nanocarriers\u2019 entry into the cell: relevance to drug delivery. Cell Mol Life Sci. 2009;66(17):2873\u201396. https:\/\/doi.org\/10.1007\/s00018-009-0053-z.","journal-title":"Cell Mol Life Sci"},{"issue":"3","key":"641_CR55","doi-asserted-by":"publisher","first-page":"266","DOI":"10.1038\/s41565-021-00858-8","volume":"16","author":"JJ Rennick","year":"2021","unstructured":"Rennick JJ, Johnston APR, Parton RG. Key principles and methods for studying the endocytosis of biological and nanoparticle therapeutics. Nat Nanotechnol. 2021;16(3):266\u201376. https:\/\/doi.org\/10.1038\/s41565-021-00858-8.","journal-title":"Nat Nanotechnol"},{"key":"641_CR56","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1007\/978-1-59745-178-9_2","volume":"440","author":"AI Ivanov","year":"2008","unstructured":"Ivanov AI. Pharmacological Inhibition of endocytic pathways: is it specific enough to be useful? Methods Mol Biol. 2008;440:15\u201333. https:\/\/doi.org\/10.1007\/978-1-59745-178-9_2.","journal-title":"Methods Mol Biol"},{"issue":"3","key":"641_CR57","doi-asserted-by":"publisher","first-page":"455","DOI":"10.1208\/s12248-008-9055-2","volume":"10","author":"F Herv\u00e9","year":"2008","unstructured":"Herv\u00e9 F, Ghinea N, Scherrmann JM. CNS delivery via adsorptive transcytosis. AAPS J. 2008;10(3):455\u201372. https:\/\/doi.org\/10.1208\/s12248-008-9055-2.","journal-title":"AAPS J"},{"issue":"6","key":"641_CR58","doi-asserted-by":"publisher","first-page":"1081","DOI":"10.1007\/s00018-018-2982-x","volume":"76","author":"R Villase\u00f1or","year":"2019","unstructured":"Villase\u00f1or R, Lampe J, Schwaninger M, Collin L. Intracellular transport and regulation of transcytosis across the blood-brain barrier. Cell Mol Life Sci. 2019;76(6):1081\u201392. https:\/\/doi.org\/10.1007\/s00018-018-2982-x.","journal-title":"Cell Mol Life Sci"},{"issue":"13","key":"641_CR59","doi-asserted-by":"publisher","first-page":"1405","DOI":"10.2174\/1381612826666200212113421","volume":"26","author":"AE Toth","year":"2020","unstructured":"Toth AE, Holst MR, Nielsen MS. Vesicular transport machinery in brain endothelial cells: what we know and what we do not. Curr Pharm Des. 2020;26(13):1405\u201316. https:\/\/doi.org\/10.2174\/1381612826666200212113421.","journal-title":"Curr Pharm Des"},{"issue":"5\u20136","key":"641_CR60","doi-asserted-by":"publisher","first-page":"254","DOI":"10.1080\/10623320802487759","volume":"15","author":"P Candela","year":"2008","unstructured":"Candela P, Gosselet F, Miller F, Buee-Scherrer V, Torpier G, Cecchelli R, Fenart L. Physiological pathway for low-density lipoproteins across the blood-brain barrier: transcytosis through brain capillary endothelial cells in vitro. Endothelium. 2008;15(5\u20136):254\u201364. https:\/\/doi.org\/10.1080\/10623320802487759.","journal-title":"Endothelium"},{"issue":"1","key":"641_CR61","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1016\/j.nbd.2009.07.030","volume":"37","author":"NJ Abbott","year":"2010","unstructured":"Abbott NJ, Patabendige AA, Dolman DE, Yusof SR, Begley DJ. Structure and function of the blood-brain barrier. Neurobiol Dis. 2010;37(1):13\u201325. https:\/\/doi.org\/10.1016\/j.nbd.2009.07.030.","journal-title":"Neurobiol Dis"}],"container-title":["Fluids and Barriers of the CNS"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12987-025-00641-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12987-025-00641-0\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12987-025-00641-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,4,3]],"date-time":"2025-04-03T09:39:16Z","timestamp":1743673156000},"score":1,"resource":{"primary":{"URL":"https:\/\/fluidsbarrierscns.biomedcentral.com\/articles\/10.1186\/s12987-025-00641-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,1]]},"references-count":61,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["641"],"URL":"https:\/\/doi.org\/10.1186\/s12987-025-00641-0","relation":{},"ISSN":["2045-8118"],"issn-type":[{"value":"2045-8118","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,1]]},"assertion":[{"value":"30 August 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 March 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 April 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The procedure of organ harvesting required to obtain primary cells from brain is exempt of animal experimentation permission based on the Directive 2010\/63\/EU of the European Parliament and of the Council on the protection of animals used for scientific purposes.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"Technophage, Investiga\u00e7\u00e3o E Desenvolvimento Em Biotecnologia, Sa owns a patent (WO2016120843A1) related to antibody molecules and peptide delivery systems for use in Alzheimer\u2019s disease; V.N. and M.A.R.B.C. are named inventors. This patent was granted in the territories AU, CA, CN, EP, IN, JP, US. Additionally divisional\/continuation patent applications covering peptides crossing brain endothelial cell layer are being pursued in the European and US regions and both are currently pending. Other authors declare no competing interest.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"31"}}