Engineering extracellular vesicles to transiently permeabilize the blood–brain barrier
Abstract Background Drug delivery to the brain is challenging due to the restrict permeability of the blood brain barrier (BBB). Recent studies indicate that BBB permeability increases over time during physiological aging likely due to factors (including extracellular vesicles (EVs)) that exist in t...
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BMC
2024-12-01
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| Series: | Journal of Nanobiotechnology |
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| Online Access: | https://doi.org/10.1186/s12951-024-03019-w |
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| author | Francesca Tomatis Susana Rosa Susana Simões Marta Barão Carlos Jesus João Novo Emanuel Barth Manja Marz Lino Ferreira |
| author_facet | Francesca Tomatis Susana Rosa Susana Simões Marta Barão Carlos Jesus João Novo Emanuel Barth Manja Marz Lino Ferreira |
| author_sort | Francesca Tomatis |
| collection | DOAJ |
| description | Abstract Background Drug delivery to the brain is challenging due to the restrict permeability of the blood brain barrier (BBB). Recent studies indicate that BBB permeability increases over time during physiological aging likely due to factors (including extracellular vesicles (EVs)) that exist in the bloodstream. Therefore, inspiration can be taken from aging to develop new strategies for the transient opening of the BBB for drug delivery to the brain. Results Here, we evaluated the impact of small EVs (sEVs) enriched with microRNAs (miRNAs) overexpressed during aging, with the capacity to interfere transiently with the BBB. Initially, we investigated whether the miRNAs were overexpressed in sEVs collected from plasma of aged individuals. Next, we evaluated the opening properties of the miRNA-enriched sEVs in a static or dynamic (under flow) human in vitro BBB model. Our results showed that miR-383-3p-enriched sEVs significantly increased BBB permeability in a reversible manner by decreasing the expression of claudin 5, an important tight junction protein of brain endothelial cells (BECs) of the BBB, mediated in part by the knockdown of activating transcription factor 4 (ATF4). Conclusions Our findings suggest that engineered sEVs have potential as a strategy for the temporary BBB opening, making it easier for drugs to reach the brain when injected into the bloodstream. Graphical abstract |
| format | Article |
| id | doaj-art-2e5459f13ce94ce4bcb3fbe77447b78c |
| institution | Kabale University |
| issn | 1477-3155 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Nanobiotechnology |
| spelling | doaj-art-2e5459f13ce94ce4bcb3fbe77447b78c2024-12-08T12:45:17ZengBMCJournal of Nanobiotechnology1477-31552024-12-0122112110.1186/s12951-024-03019-wEngineering extracellular vesicles to transiently permeabilize the blood–brain barrierFrancesca Tomatis0Susana Rosa1Susana Simões2Marta Barão3Carlos Jesus4João Novo5Emanuel Barth6Manja Marz7Lino Ferreira8CNC-UC - Center for Neuroscience and Cell Biology, University of Coimbra, UC—Biotech Parque Tecnológico de CantanhedeCNC-UC - Center for Neuroscience and Cell Biology, University of Coimbra, UC—Biotech Parque Tecnológico de CantanhedeCNC-UC - Center for Neuroscience and Cell Biology, University of Coimbra, UC—Biotech Parque Tecnológico de CantanhedeCNC-UC - Center for Neuroscience and Cell Biology, University of Coimbra, UC—Biotech Parque Tecnológico de CantanhedeCNC-UC - Center for Neuroscience and Cell Biology, University of Coimbra, UC—Biotech Parque Tecnológico de CantanhedeCNC-UC - Center for Neuroscience and Cell Biology, University of Coimbra, UC—Biotech Parque Tecnológico de CantanhedeBioinformatics Core Facility, Faculty of Mathematics and Computer Science, Friedrich Schiller University JenaBioinformatics/High Throughput Analysis, Faculty of Mathematics and Computer Science, Friedrich Schiller University JenaCNC-UC - Center for Neuroscience and Cell Biology, University of Coimbra, UC—Biotech Parque Tecnológico de CantanhedeAbstract Background Drug delivery to the brain is challenging due to the restrict permeability of the blood brain barrier (BBB). Recent studies indicate that BBB permeability increases over time during physiological aging likely due to factors (including extracellular vesicles (EVs)) that exist in the bloodstream. Therefore, inspiration can be taken from aging to develop new strategies for the transient opening of the BBB for drug delivery to the brain. Results Here, we evaluated the impact of small EVs (sEVs) enriched with microRNAs (miRNAs) overexpressed during aging, with the capacity to interfere transiently with the BBB. Initially, we investigated whether the miRNAs were overexpressed in sEVs collected from plasma of aged individuals. Next, we evaluated the opening properties of the miRNA-enriched sEVs in a static or dynamic (under flow) human in vitro BBB model. Our results showed that miR-383-3p-enriched sEVs significantly increased BBB permeability in a reversible manner by decreasing the expression of claudin 5, an important tight junction protein of brain endothelial cells (BECs) of the BBB, mediated in part by the knockdown of activating transcription factor 4 (ATF4). Conclusions Our findings suggest that engineered sEVs have potential as a strategy for the temporary BBB opening, making it easier for drugs to reach the brain when injected into the bloodstream. Graphical abstracthttps://doi.org/10.1186/s12951-024-03019-wExtracellular vesiclesModulationMicroRNABlood–brain barrierMicrofluidic systemClaudin 5 |
| spellingShingle | Francesca Tomatis Susana Rosa Susana Simões Marta Barão Carlos Jesus João Novo Emanuel Barth Manja Marz Lino Ferreira Engineering extracellular vesicles to transiently permeabilize the blood–brain barrier Journal of Nanobiotechnology Extracellular vesicles Modulation MicroRNA Blood–brain barrier Microfluidic system Claudin 5 |
| title | Engineering extracellular vesicles to transiently permeabilize the blood–brain barrier |
| title_full | Engineering extracellular vesicles to transiently permeabilize the blood–brain barrier |
| title_fullStr | Engineering extracellular vesicles to transiently permeabilize the blood–brain barrier |
| title_full_unstemmed | Engineering extracellular vesicles to transiently permeabilize the blood–brain barrier |
| title_short | Engineering extracellular vesicles to transiently permeabilize the blood–brain barrier |
| title_sort | engineering extracellular vesicles to transiently permeabilize the blood brain barrier |
| topic | Extracellular vesicles Modulation MicroRNA Blood–brain barrier Microfluidic system Claudin 5 |
| url | https://doi.org/10.1186/s12951-024-03019-w |
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