PNExo™ Exosome-Grape

Key Bioactive Compounds and Benefits of Grapes

Grapes (Vitis vinifera) are a natural reservoir of diverse polyphenolic compounds, which are primarily found in the skin, seeds, and pulp. These bioactive constituents perform a broad range of biological functions, including antioxidative, anti-inflammatory, and cell-regulatory activities. Their effects on human health at the molecular level are being increasingly investigated in scientific research. The following are the main categories of active ingredients present in grapes, along with their corresponding functional properties:

• Anthocyanins (e.g., cyanidin-3-glucoside): These pigments are responsible for the red to purple color of grapes and have been shown to promote apoptosis in abnormal cells by activating caspase-3 and inducing DNA fragmentation. They also downregulate VEGF pathways, thereby suppressing angiogenesis.
• Flavanols (e.g., catechin, epicatechin, and proanthocyanidins): Known for their strong radical-scavenging capacity, proanthocyanidins also inhibit lipid peroxidation, contributing to membrane integrity. They can arrest the cell cycle in G1 phase and inhibit tumor cell proliferation.
• Resveratrol: A stilbene compound concentrated in grape skin, resveratrol supports endothelial nitric oxide release, enhances vascular function, and modulates SIRT1 signaling involved in cellular homeostasis and aging.
• Flavonols (e.g., quercetin, kaempferol): These compounds are known for downregulating inflammatory mediators such as TNF-α and MCP-1, and for blocking NF-κB signaling, thereby reducing inflammatory cascade reactions.
• Phenolic Acids (e.g., hydroxycinnamic acid, hydroxybenzoic acid): These molecules contribute to antioxidant activity and may support the suppression of oxidative stress-induced cellular damage.

What Are Grape-Derived Exosomes?

Grape-derived exosomes, also known as grape exosome-like nanoparticles (GENs), are nanoscale vesicles naturally secreted by grape cells. These vesicles, typically ranging from 30 to 150 nanometers, are enclosed by a lipid bilayer and act as biological couriers, carrying plant-based biomolecules such as proteins, lipids, RNAs (mRNA, miRNA, lncRNA), and small antioxidants like procyanidins and resveratrol. Increasingly studied as a type of plant-derived extracellular vesicle, GENs show great promise in molecular delivery, intercellular communication, and stability under biological conditions.

Key Advantages of Grape-Derived Exosomes

• Natural Molecular Cargo: GENs contain diverse plant biomolecules including regulatory RNAs and polyphenols, which may influence gene expression and oxidative balance when taken up by mammalian cells.
• Cholesterol-Free Composition: Unlike exosomes from animal sources, GENs contain minimal to no cholesterol, making them structurally unique and potentially less immunogenic in certain research applications.
• Efficient Cellular Uptake: GENs are readily absorbed by various mammalian cells, such as macrophages, lymphocytes, and epithelial cells, primarily through energy-dependent endocytosis.
• High Stability: These vesicles maintain structural integrity under physiological temperatures and can withstand long-term frozen storage and repeated freeze-thaw cycles without degradation.
• Antioxidant Encapsulation: Their bilayer membrane structure protects and delivers active antioxidant compounds, enhancing their bioavailability and potentially amplifying their cellular effects.
• Plant-Based and Biocompatible: As naturally sourced from grapes without synthetic additives or solvents, GENs offer a cleaner, safer alternative for plant nanovesicle research.

Morphological and molecular characterization of grape-derived exosome-like nanoparticles (ENs). (A, B) Scanning electron microscopy (SEM) images and nanoparticle tracking analysis show GCENs (from calluses) and GENs (from juice) have sizes ranging from ~90 to 250 nm with mildly irregular spherical morphology. (C) Western blot analysis confirms the presence of exosomal markers HSP70 and TET8 in both EN samples. (Shkryl Y, et al, 2024)

Potential Applications of Grape Exosome-like Nanoparticles

Intestinal Health and Stem Cell Regulation

Grape exosome-like nanoparticles have been shown to influence intestinal homeostasis. In in vivo models, they promoted the expression of key intestinal stem cell markers such as Lgr5, SOX2, Nanog, and KLF4, supporting epithelial renewal and mucosal barrier function. These findings suggest their potential utility in studies related to gastrointestinal regeneration and inflammation.

Anti-Inflammatory and miRNA Modulation

Grape exosomes are enriched in plant-derived miRNAs, including members of the miR169 family, which have shown sequence similarity with mammalian miRNAs. Some of these molecules have been implicated in downregulating pro-inflammatory genes such as IL-6 and IL-1β, making them relevant in research on immune modulation and inflammation-related signaling.

Antioxidant and Anti-Aging Investigations

Due to their natural content of resveratrol, myricetin, and procyanidins, grape-derived exosomes have demonstrated strong antioxidant properties. Studies suggest their role in scavenging free radicals and mitigating oxidative stress, with applications in models of skin photoaging and epithelial damage. Their vesicular structure enhances compound stability and delivery to target cells.

Targeted Biodistribution and Uptake

Fluorescence-tracking experiments have revealed that grape-derived exosomes can localize to the small intestine, colon, brain, lungs, and liver, depending on the route of administration. This suggests their promise as naturally derived nanocarriers for research on targeted delivery across biological barriers.

Exploratory Cancer Research

Preliminary findings have reported that GENs derived from grape cell cultures, especially those rich in trans-δ-viniferin derivatives, may exhibit cytotoxic effects on tumor cell lines (in vitro). Additionally, studies on breast cancer models have investigated GENs as biocompatible delivery vehicles for drug molecules. These studies pave the way for further exploration of their role in oncology research.

References

1. Ju S, Mu J, Dokland T, et al. Grape exosome-like nanoparticles induce intestinal stem cells and protect mice from DSS-induced colitis. Molecular Therapy. 2013, 21(7): 1345-1357.
2. Record M. Exosome-like nanoparticles from food: Protective nanoshuttles for bioactive cargo. Molecular Therapy. 2013, 21(7): 1294-1296.
3. Pérez-Bermúdez P, Blesa J, Soriano J M, et al. Extracellular vesicles in food: Experimental evidence of their secretion in grape fruits. European Journal of Pharmaceutical Sciences. 2017, 98: 40-50.
4. Ghiasi M R, Rahimi E, Amirkhani Z, et al. Leucine-rich repeat-containing G-protein coupled receptor 5 gene overexpression of the rat small intestinal progenitor cells in response to orally administered grape exosome-like nanovesicles. Advanced Biomedical Research. 2018, 7(1): 125.
5. Teng Y, He J, Zhong Q, et al. Grape exosome-like nanoparticles: A potential therapeutic strategy for vascular calcification. Frontiers in Pharmacology. 2022, 13: 1025768.
6. Farheen J, Iqbal M Z, Lu Y, et al. Vitis vinifera Kyoho-derived exosome-like nanoparticles-based drug delivery and therapeutic modalities for breast cancer therapy. Journal of Drug Delivery Science and Technology. 2024, 92: 105332.
7. Shkryl Y, Tsydeneshieva Z, Menchinskaya E, et al. Exosome-like nanoparticles, high in trans-δ-Viniferin derivatives, produced from grape cell cultures: Preparation, characterization, and anticancer properties. Biomedicines. 2024, 12(9): 2142.
8. Wang M, Chen J, Chen W, et al. Grape-Derived Exosome-Like Nanovesicles Effectively Ameliorate Skin Photoaging by Protecting Epithelial Cells. Journal of Food Science. 2025, 90(6): e70309.