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Design and Validation of Liposomal ApoE2 Gene Delivery System to Evade Blood–Brain Barrier for Effective Treatment of Alzheimer’s Disease
Open accessAbstract
Targeting gene-based therapeutics to the brain is a strategy actively sought to treat Alzheimer’s disease (AD). Recent findings discovered the role of apolipoprotein E (ApoE) isoforms in the clearance of toxic amyloid beta proteins from the brain. ApoE2 isoform is beneficial for preventing AD development, whereas ApoE4 is a major contributing factor to the disease. In this paper, we demonstrated efficient brain-targeted delivery of ApoE2 encoding plasmid DNA (pApoE2) using glucose transporter-1 (glut-1) targeted liposomes. Liposomes were surface-functionalized with a glut-1 targeting ligand mannose (MAN) and a cell-penetrating peptide (CPP) to enhance brain-targeting and cellular internalization, respectively. Among various CPPs, rabies virus glycoprotein peptide (RVG) or penetratin (Pen) was selected as a cell-penetration enhancer. Dual (RVGMAN and PenMAN)-functionalized liposomes were cytocompatible at 100 nM phospholipid concentration and demonstrated significantly higher expression of ApoE2 in bEnd.3 cells, primary neurons, and astrocytes compared to monofunctionalized and unmodified (plain) liposomes. Dual-modified liposomes also showed ∼2 times higher protein expression than other formulation controls in neurons cultured below the in vitro BBB model. These results translated well to in vivo efficacy study with significantly higher transfection of pApoE2 in the C57BL/6 mice brain following single tail vein administration of RVGMAN and PenMAN functionalized liposomes without any noticeable signs of toxicity. These results illustrate the potential of surface-modified liposomes for safe and brain-targeted delivery of the pApoE2 gene for effective AD therapy.
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“However, while ApoE2 is beneficial for preventing AD development, ApoE4 is a contributing factor to AD progression [101].”
From Advances in Strategies to Transport Nanoparticles Across the Blood–Brain Barrier for Drug Delivery into the Brain for the Treatment of Alzheimer’s Disease (2026) · cites this paper as [101]
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“The results showed that dual-modified liposomes resulted in ∼2 times higher ApoE2 protein expression in the brain of mice compared to endogenous ApoE levels.”
From Advances in Strategies to Transport Nanoparticles Across the Blood–Brain Barrier for Drug Delivery into the Brain for the Treatment of Alzheimer’s Disease (2026) · cites this paper as [101]
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“Plain or monofunctionalized liposomes resulted in ∼1.25 times higher expression than the endogenous one.”
From Advances in Strategies to Transport Nanoparticles Across the Blood–Brain Barrier for Drug Delivery into the Brain for the Treatment of Alzheimer’s Disease (2026) · cites this paper as [101]
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“Arora et al. [101] demonstrated efficient brain-targeted delivery of pApoE2 using GLUT-1-targeted, dual-functionalized liposomes, in in vitro (Transwell BBB model) and in vivo (C57BL/6 mice) studies.”
From Advances in Strategies to Transport Nanoparticles Across the Blood–Brain Barrier for Drug Delivery into the Brain for the Treatment of Alzheimer’s Disease (2026) · cites this paper as [101]
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“Results in vitro showed that dual-functionalized liposomes had 2 times greater transfection efficiency than plain and monofunctionalized liposomes.”
From Advances in Strategies to Transport Nanoparticles Across the Blood–Brain Barrier for Drug Delivery into the Brain for the Treatment of Alzheimer’s Disease (2026) · cites this paper as [101]
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“Following single-tail vein administration, the use of these liposomes to encapsulate the ApoE2/chitosan complex proved to significantly enhance the transport and transfection of the ApoE2 gene across the BBB in in vivo models, without any noticeable signs of toxicity.”
From Advances in Strategies to Transport Nanoparticles Across the Blood–Brain Barrier for Drug Delivery into the Brain for the Treatment of Alzheimer’s Disease (2026) · cites this paper as [101]
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Lamptey, R. N. L., Chaulagain, B., Trivedi, R., Gothwal, A., Layek, B., & Singh, J. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23031851 · Cited by 1,010
Self-citationA Comprehensive Review of Nanoparticles: From Classification to Application and Toxicity
Eker, F., Duman, H., Akdaşçi, E., Bolat, E., Sarıtaş, S., Karav, S., & Witkowska, A. M. (2024) · Molecules · doi:10.3390/molecules29153482 · Cited by 303
Nanomedicine: How nanomaterials are transforming drug delivery, bio-imaging, and diagnosis
Kurul, F., Turkmen, H., Çetin, A. E., & Topkaya, S. N. (2025) · Next Nanotechnology · doi:10.1016/j.nxnano.2024.100129 · Cited by 280
Pires, M., & Rego, A. C. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24010778 · Cited by 157
Juhairiyah, F., & de Lange, E. C. M. (2021) · The AAPS Journal · doi:10.1208/s12248-021-00648-z · Cited by 164
Metadata
- Authors
- Arora, S., Layek, B., & Singh, J.
- Affiliations
- North Dakota State University (US)
- Corresponding author
- Singh, Jagdish
- Venue
- Molecular Pharmaceutics
- Publisher
- American Chemical Society (ACS)
- Published
- 2020-08-11
- Volume
- 18
- Issue
- 2
- Pages
- 714-725
- ISSN
- 1543-8384 (ISSN-L)
- 1543-8392
- PMC
- PMC10292003
- OpenAlex
- W3048402510
- Cited by
- 149
- References
- 86
- Citations by year
- 2026: 18 · 2025: 31 · 2024: 36 · 2023: 25 · 2022: 25 · 2021: 14
- FWCI
- 5.19
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Molecular Pharmaceutics (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Aging (R01AG051574)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Keywords
- Alzheimer's disease, apolipoprotein E2, gene delivery, liposomes, blood-brain barrier, glucose transporter 1, cell-penetrating peptides, penetratin, plasmid transfection, brain-targeted delivery, amyloid-beta clearance, bEnd.3 cells, astrocytes, in vitro BBB model, in vivo transfection
- MeSH terms
- Alzheimer Disease, Animals, Astrocytes, Blood-Brain Barrier, Brain, Cell Line, Drug Compounding, Female, Humans, Liposomes, Male, Neurons, Gene Transfer Techniques, Models, Animal, Glucose Transporter Type 1, Mice, Rats, Apolipoprotein E2, Cell-Penetrating Peptides, Primary Cell Culture
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