Plant-derived extracellular vesicles as potential smart nano drug delivery systems for antioxidant vitamins C and E in Alzheimer's disease

 

1. Introduction

Alzheimer’s Disease (AD) is a chronic, progressive neurodegenerative disorder, characterized by memory loss, disorientation, and cognitive decline. It is histopathologically marked by:

• Amyloid-beta (Aβ) plaque accumulation

• Neurofibrillary tangles (tau proteins)

• Oxidative stress and inflammation

Oxidative stress plays a central role in AD pathology, leading to neuronal damage, mitochondrial dysfunction, and apoptosis. Antioxidants like vitamin C and vitamin E counteract ROS, but their therapeutic potential is limited by poor brain bioavailability, rapid degradation, and limited absorption.

2. The Promise of Plant-Derived Extracellular Vesicles (PDEVs)

2.1 What Are PDEVs?

Plant-derived extracellular vesicles are nano- to micro-sized vesicles (50–500 nm) secreted by plant cells for intercellular communication. They are structurally similar to mammalian exosomes but are non-toxic, naturally abundant, and edible.

Sources: Ginger, grapefruit, lemon, broccoli, grape, carrot, and aloe vera.

2.2 Composition

• Lipid Bilayer: Rich in phosphatidic acid, phosphatidylethanolamine—conferring membrane stability.

• Proteins: Enzymes, stress proteins, membrane receptors.

• Nucleic Acids: mRNA, miRNA—can modulate gene expression.

• Phytonutrients: Polyphenols, flavonoids—add intrinsic antioxidant/anti-inflammatory properties.

3. Antioxidants in Alzheimer’s Disease

3.1 Role of Vitamin C

• Water-soluble antioxidant, high concentration in the brain.

• Regenerates vitamin E and scavenges free radicals (ROS, RNS).

• Protects dopamine neurons and enhances neurotransmitter synthesis.

• Deficiency linked with increased Aβ accumulation.

3.2 Role of Vitamin E

• Lipid-soluble antioxidant, protects membranes from lipid peroxidation.

• Reduces inflammatory cytokines.

• Enhances mitochondrial stability and membrane integrity.

• Has shown potential in slowing AD progression in clinical trials.

4. Delivery Challenges with Free Antioxidants

• Degradation in GI tract

• Poor absorption

• Low BBB permeability

• Short plasma half-life

These factors limit their efficacy unless a targeted, stable, and biocompatible delivery platform is used.

5. How PDEVs Act as Smart Drug Delivery Systems

5.1 Encapsulation Techniques

• Passive loading: Antioxidants are mixed with vesicles allowing diffusion.

• Sonication/Electroporation: Uses electrical pulses to enhance loading.

• Freeze-thaw cycles: Repeated cycles allow drug entry via membrane disruption.

5.2 Smart Features

Feature	Mechanism	Benefit
Stability	Protects vitamins from enzymes and pH	Longer circulation
Targeted Delivery	Natural homing to inflamed or damaged tissues	Minimizes off-target effects
BBB Penetration	Nanoparticle size (<200 nm) and lipid membrane allow crossing	Effective brain targeting
Endosomal Escape	Lipid content helps avoid lysosomal degradation	Efficient cytoplasmic delivery

6. Experimental and Preclinical Evidence

6.1 Studies on PDEVs

• Grapefruit-derived EVs showed successful loading of curcumin, with anti-inflammatory effects in brain tissues.

• Ginger-derived EVs protected against colitis, hinting at immunomodulatory potential.

• PDEVs were observed to cross the BBB in mice after oral and intravenous administration.

6.2 Vitamins C & E Delivery in Neurodegeneration

• In vitro models: Neuronal cultures exposed to Aβ showed reduced ROS and apoptosis when treated with antioxidant-loaded PDEVs.

• Animal models: Rodents with AD pathology showed improved spatial memory, reduced amyloid plaques, and decreased microglial activation.

7. Advantages Over Other Delivery Systems

Delivery System	Limitations	PDEVs Advantage
Liposomes	Artificial, costly	Natural, biodegradable
Polymeric NPs	Synthetic polymers may be toxic	Derived from food plants
Micelles	Poor brain targeting	Efficient BBB crossing
Mammalian exosomes	Difficult to mass-produce	Scalable from edible plants

8. Challenges and Considerations

8.1 Technical Hurdles

• Low yield in isolation processes

• Variation in vesicle content depending on plant source

• Standardization of isolation, purification, and storage

8.2 Safety and Immunogenicity

• Generally regarded as safe (GRAS), but immune responses in humans still under investigation.

• Long-term effects of repeated administration unknown.

8.3 Regulatory and Clinical Translation

• No clinical trials yet using PDEVs for brain diseases.

• Need for:

  • Toxicology studies

  • GMP-compliant large-scale production

  • Regulatory approval

9. Future Directions

• Surface modification with targeting ligands for precision delivery.

• Combined therapy: PDEVs carrying vitamins + RNA/peptides.

• Personalized medicine: Plant selection based on patient needs.

• Oral delivery formulations: For non-invasive treatment.

 

10. Conclusion

Plant-derived extracellular vesicles represent a revolutionary drug delivery strategy for neurodegenerative diseases like Alzheimer’s. Their ability to encapsulate, protect, and deliver antioxidants like vitamins C and E across the blood-brain barrier with minimal toxicity positions them as ideal smart nanocarriers. Continued research may soon enable safe, plant-based, non-invasive treatments for combating oxidative stress and cognitive decline in AD patients.