Delivery of Small Interfering RNA to Inhibit Vascular Endothelial Growth Factor in Zebrafish Using Natural Brain Endothelia Cell-Secreted Exosome Nanovesicles for the Treatment of Brain Cancer
Abstract
Although small interfering RNA (siRNA) holds great therapeutic promise, its delivery to the disease site remains a paramount obstacle. In this study, we tested whether brain endothelial cell-derived exosomes could deliver siRNA across the blood-brain barrier (BBB) in zebrafish. Natural exosomes were isolated from brain endothelial bEND.3 cell culture media and vascular endothelial growth factor (VEGF) siRNA was loaded in exosomes with the assistance of a transfection reagent. While fluorescence-activated cell flow cytometry and immunocytochemistry staining studies indicated that wild-type exosomes significantly increased the uptake of fluorescence-labeled siRNA in the autologous brain endothelial cells, decreased fluorescence intensity was observed in the cells treated with the tetraspanin CD63 antibody-blocked exosome-delivered formulation (p < 0.05). In the transport study, exosomes also enhanced the permeability of rhodamine 123 in a co-cultured monolayer of brain endothelial bEND.3 cell and astrocyte. Inhibition at the expression of VEGF RNA and protein levels was observed in glioblastoma-astrocytoma U-87 MG cells treated with exosome-delivered siRNAs. Imaging results showed that exosome delivered more siRNAs across the BBB in Tg(fli1:GFP) zebrafish. In a xenotransplanted brain tumor model, exosome-delivered VEGF siRNAs decreased the fluorescence intensity of labeled cancer cells in the brain of zebrafish. Brain endothelial cell-derived exosomes could be potentially used as a natural carrier for the brain delivery of exogenous siRNA.
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Some natural cell membranes such as exosomes without any functionalization have the ability to cross the BBB.
“Some natural cell membranes such as exosomes without any functionalization have ability to cross the BBB.”
From The blood–brain barrier: Structure, regulation and drug delivery (2023) · cites this paper as [361]
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- Authors
- Yang, T., Fogarty, B., LaForge, B., Aziz, S., Pham, T., Lai, L., & Bai, S.
- Affiliations
- Husson University (US)
- Nova Southeastern University (US)
- Corresponding author
- Bai, Shuhua
- Venue
- The AAPS Journal
- Published
- 2016-11-23
- Volume
- 19
- Issue
- 2
- Pages
- 475-486
- ISSN
- 1550-7416 (ISSN-L)
- OpenAlex
- W2552099798
- Cited by
- 204
- References
- 52
- Citations by year
- 2026: 13 · 2025: 17 · 2024: 24 · 2023: 27 · 2022: 29 · 2021: 40 · 2020: 22 · 2019: 16 · 2018: 11 · 2017: 5
- FWCI
- 5.55
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The AAPS Journal (publishedVersion)
- PubMed (publishedVersion)
- NSUWorks (Nova Southeastern University) (submittedVersion)
- Funders
- Husson University
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Keywords
- exosomes, siRNA delivery, vascular endothelial growth factor, blood-brain barrier, brain endothelial cells, glioblastoma, brain cancer, CD63, bEnd.3 cells, zebrafish xenograft, U87 cells, astrocytes, tetraspanins
- MeSH terms
- Animals, Astrocytes, Blood-Brain Barrier, Brain, Brain Neoplasms, Humans, Transfection, Zebrafish, Gene Transfer Techniques, Coculture Techniques, RNA, Small Interfering, Vascular Endothelial Growth Factor A, Endothelial Cells, Cell Line, Tumor, Exosomes
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