Delivery of RNA to the Blood-Brain Barrier Endothelium Using Cationic Bicelles

Joan Cheng; Lushan Wang; Vineetha Guttha; Greg Haugstad; Karunya k. Kandimalla

doi:10.3390/pharmaceutics15082086

Delivery of RNA to the Blood-Brain Barrier Endothelium Using Cationic Bicelles

Joan Cheng, Lushan Wang, Vineetha Guttha, Greg Haugstad, Karunya k. Kandimalla

Research output: Contribution to journal › Article › peer-review

Abstract

Blood-brain barrier (BBB) dysfunction is prevalent in Alzheimer’s disease and other neurological disorders. Restoring normal BBB function through RNA therapy is a potential avenue for addressing cerebrovascular changes in these disorders that may lead to cognitive decline. Although lipid nanoparticles have been traditionally used as drug carriers for RNA, bicelles have been emerging as a better alternative because of their higher cellular uptake and superior transfection capabilities. Cationic bicelles composed of DPPC/DC₇PC/DOTAP at molar ratios of 63.8/25.0/11.2 were evaluated for the delivery of RNA in polarized hCMEC/D3 monolayers, a widely used BBB cell culture model. RNA-bicelle complexes were formed at five N/P ratios (1:1 to 5:1) by a thin-film hydration method. The RNA-bicelle complexes at N/P ratios of 3:1 and 4:1 exhibited optimal particle characteristics for cellular delivery. The cellular uptake of cationic bicelles laced with 1 mol% DiI-C18 was confirmed by flow cytometry and confocal microscopy. The ability of cationic bicelles (N/P ratio 4:1) to transfect polarized hCMEC/D3 with FITC-labeled control siRNA was tested vis-a-vis commercially available Lipofectamine RNAiMAX. These studies demonstrated the higher transfection efficiency and greater potential of cationic bicelles for RNA delivery to the BBB endothelium.

Original language	English (US)
Article number	2086
Journal	Pharmaceutics
Volume	15
Issue number	8
DOIs	https://doi.org/10.3390/pharmaceutics15082086 https://doi.org/10.3390/pharmaceutics15082086
State	Published - Aug 2023

Bibliographical note

Funding Information:
Portions of this work were conducted in the Minnesota Nano Center, which is supported by the National Science Foundation through the National Nanotechnology Coordinated Infrastructure (NNCI) under Award Number ECCS-2025124. Portions of this work were carried out in the Characterization Facility, University of Minnesota, which receives partial support from the NSF through the MRSEC (Award Number DMR-2011401) and the NNCI (Award Number ECCS-2025124) programs.

Funding Information:
This research was funded by the National Institutes of Health/National Institute of Neurological Disorders and Stroke, grant number R01NS125437.

Publisher Copyright:
© 2023 by the authors.

Keywords

Alzheimer’s disease
blood-brain barrier
cationic bicelles
drug delivery
inflammation
lipid nanodiscs
nitrogen-to-phosphate ratio
RNA

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title = "Delivery of RNA to the Blood-Brain Barrier Endothelium Using Cationic Bicelles",

abstract = "Blood-brain barrier (BBB) dysfunction is prevalent in Alzheimer{\textquoteright}s disease and other neurological disorders. Restoring normal BBB function through RNA therapy is a potential avenue for addressing cerebrovascular changes in these disorders that may lead to cognitive decline. Although lipid nanoparticles have been traditionally used as drug carriers for RNA, bicelles have been emerging as a better alternative because of their higher cellular uptake and superior transfection capabilities. Cationic bicelles composed of DPPC/DC7PC/DOTAP at molar ratios of 63.8/25.0/11.2 were evaluated for the delivery of RNA in polarized hCMEC/D3 monolayers, a widely used BBB cell culture model. RNA-bicelle complexes were formed at five N/P ratios (1:1 to 5:1) by a thin-film hydration method. The RNA-bicelle complexes at N/P ratios of 3:1 and 4:1 exhibited optimal particle characteristics for cellular delivery. The cellular uptake of cationic bicelles laced with 1 mol% DiI-C18 was confirmed by flow cytometry and confocal microscopy. The ability of cationic bicelles (N/P ratio 4:1) to transfect polarized hCMEC/D3 with FITC-labeled control siRNA was tested vis-a-vis commercially available Lipofectamine RNAiMAX. These studies demonstrated the higher transfection efficiency and greater potential of cationic bicelles for RNA delivery to the BBB endothelium.",

keywords = "Alzheimer{\textquoteright}s disease, blood-brain barrier, cationic bicelles, drug delivery, inflammation, lipid nanodiscs, nitrogen-to-phosphate ratio, RNA",

author = "Joan Cheng and Lushan Wang and Vineetha Guttha and Greg Haugstad and Kandimalla, {Karunya k.}",

note = "Funding Information: Portions of this work were conducted in the Minnesota Nano Center, which is supported by the National Science Foundation through the National Nanotechnology Coordinated Infrastructure (NNCI) under Award Number ECCS-2025124. Portions of this work were carried out in the Characterization Facility, University of Minnesota, which receives partial support from the NSF through the MRSEC (Award Number DMR-2011401) and the NNCI (Award Number ECCS-2025124) programs. Funding Information: This research was funded by the National Institutes of Health/National Institute of Neurological Disorders and Stroke, grant number R01NS125437. Publisher Copyright: {\textcopyright} 2023 by the authors.",

year = "2023",

month = aug,

doi = "10.3390/pharmaceutics15082086",

language = "English (US)",

volume = "15",

journal = "Pharmaceutics",

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AU - Kandimalla, Karunya k.

N1 - Funding Information: Portions of this work were conducted in the Minnesota Nano Center, which is supported by the National Science Foundation through the National Nanotechnology Coordinated Infrastructure (NNCI) under Award Number ECCS-2025124. Portions of this work were carried out in the Characterization Facility, University of Minnesota, which receives partial support from the NSF through the MRSEC (Award Number DMR-2011401) and the NNCI (Award Number ECCS-2025124) programs. Funding Information: This research was funded by the National Institutes of Health/National Institute of Neurological Disorders and Stroke, grant number R01NS125437. Publisher Copyright: © 2023 by the authors.

PY - 2023/8

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N2 - Blood-brain barrier (BBB) dysfunction is prevalent in Alzheimer’s disease and other neurological disorders. Restoring normal BBB function through RNA therapy is a potential avenue for addressing cerebrovascular changes in these disorders that may lead to cognitive decline. Although lipid nanoparticles have been traditionally used as drug carriers for RNA, bicelles have been emerging as a better alternative because of their higher cellular uptake and superior transfection capabilities. Cationic bicelles composed of DPPC/DC7PC/DOTAP at molar ratios of 63.8/25.0/11.2 were evaluated for the delivery of RNA in polarized hCMEC/D3 monolayers, a widely used BBB cell culture model. RNA-bicelle complexes were formed at five N/P ratios (1:1 to 5:1) by a thin-film hydration method. The RNA-bicelle complexes at N/P ratios of 3:1 and 4:1 exhibited optimal particle characteristics for cellular delivery. The cellular uptake of cationic bicelles laced with 1 mol% DiI-C18 was confirmed by flow cytometry and confocal microscopy. The ability of cationic bicelles (N/P ratio 4:1) to transfect polarized hCMEC/D3 with FITC-labeled control siRNA was tested vis-a-vis commercially available Lipofectamine RNAiMAX. These studies demonstrated the higher transfection efficiency and greater potential of cationic bicelles for RNA delivery to the BBB endothelium.

AB - Blood-brain barrier (BBB) dysfunction is prevalent in Alzheimer’s disease and other neurological disorders. Restoring normal BBB function through RNA therapy is a potential avenue for addressing cerebrovascular changes in these disorders that may lead to cognitive decline. Although lipid nanoparticles have been traditionally used as drug carriers for RNA, bicelles have been emerging as a better alternative because of their higher cellular uptake and superior transfection capabilities. Cationic bicelles composed of DPPC/DC7PC/DOTAP at molar ratios of 63.8/25.0/11.2 were evaluated for the delivery of RNA in polarized hCMEC/D3 monolayers, a widely used BBB cell culture model. RNA-bicelle complexes were formed at five N/P ratios (1:1 to 5:1) by a thin-film hydration method. The RNA-bicelle complexes at N/P ratios of 3:1 and 4:1 exhibited optimal particle characteristics for cellular delivery. The cellular uptake of cationic bicelles laced with 1 mol% DiI-C18 was confirmed by flow cytometry and confocal microscopy. The ability of cationic bicelles (N/P ratio 4:1) to transfect polarized hCMEC/D3 with FITC-labeled control siRNA was tested vis-a-vis commercially available Lipofectamine RNAiMAX. These studies demonstrated the higher transfection efficiency and greater potential of cationic bicelles for RNA delivery to the BBB endothelium.

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KW - blood-brain barrier

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KW - drug delivery

KW - inflammation

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KW - nitrogen-to-phosphate ratio

KW - RNA

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SN - 1999-4923

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JO - Pharmaceutics

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ER -

Delivery of RNA to the Blood-Brain Barrier Endothelium Using Cationic Bicelles

Abstract

Bibliographical note

Keywords

MRSEC Support

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University of Minnesota Materials Research Science and Engineering Center (DMR-2011401)

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Delivery of RNA to the Blood-Brain Barrier Endothelium Using Cationic Bicelles

Abstract

Bibliographical note

Keywords

MRSEC Support

PubMed: MeSH publication types

Publisher link

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University of Minnesota Materials Research Science and Engineering Center (DMR-2011401)

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