Grapefruit-derived Nanovectors Delivering Therapeutic miR17 Through an Intranasal Route Inhibit Brain Tumor Progression
Open accessAbstract
The lack of access to the brain is a major obstacle for central nervous system drug development. In this study, we demonstrate the capability of a grapefruit-derived nanovector (GNV) to carry miR17 for therapeutic treatment of mouse brain tumor. We show that GNVs coated with folic acid (FA-GNVs) are enhanced for targeting the GNVs to a folate receptor-positive GL-26 brain tumor. Additionally, FA-GNV-coated polyethylenimine (FA-pGNVs) not only enhance the capacity to carry RNA, but the toxicity of the polyethylenimine is eliminated by the GNVs. Intranasal administration of miR17 carried by FA-pGNVs led to rapid delivery of miR17 to the brain that was selectively taken up by GL-26 tumor cells. Mice treated intranasally with FA-pGNV/miR17 had delayed brain tumor growth. Our results demonstrate that this strategy may provide a noninvasive therapeutic approach for treating brain-related disease through intranasal delivery.
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GNV reduces toxicity of polyethylenimine used for RNA loading.
“They found GNV reduces the toxicity of the polyethylenimine, which was used for the load of RNA”
From The blood–brain barrier: Structure, regulation and drug delivery (2023) · cites this paper as [186]
FA-GNVs show better targeting than GNVs and rapidly move into brain within 1.5 h.
“FA-GNVs show better targeting behavior than GNVs with rapid movement into the brain within 1.5 h.”
From The blood–brain barrier: Structure, regulation and drug delivery (2023) · cites this paper as [186]
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“This strategy may provide a noninvasive treatment for brain-related diseases through nasal administration [91].”
BackgroundGinger: a representative material of herb-derived exosome-like nanoparticles
Zhu, H., & He, W. (2023) · Frontiers in Nutrition · doi:10.3389/fnut.2023.1223349 · Cited by 95 · see citing works
Li, Y., Wang, Y., Zhao, H., Pan, Q., & Chen, G. (2024) · International Journal of Nanomedicine · doi:10.2147/ijn.s496664 · Cited by 97 · see citing works
“114 Similar paradigm has been reported where enhanced biomedical effects were observed in drug-loaded PELNs comparing with free drug.”
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“Thus, they are of particular interest as vehicles for drug delivery [10,14,15].”
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Şahin, T. Ö., Yılmaz, B., Yeşilyurt, N., Cicia, D., Szymanowska, A., Amero, P., Ağagündüz, D., & Capasso, R. (2023) · Phytotherapy Research · doi:10.1002/ptr.7937 · Cited by 87 · see citing works
Plant and mammalian-derived extracellular vesicles: a new therapeutic approach for the future
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“It was reported that grapefruit-derived nanovesicles were labeled with a lipophilic carbocyanine dye that permitted their in vivo tracking by fluorescence (Zhuang et al., 2016).”
BackgroundResultExtracellular Vesicles as Biological Shuttles for Targeted Therapies
Raimondo, S., Giavaresi, G., Lorico, A., & Alessandro, R. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20081848 · Cited by 82 · see citing works
The Multiple Facets of Plant–Fungal Interactions Revealed Through Plant and Fungal Secretomics
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“In particular, fruit-derived exosomes have been isolated, characterized and tested as beneficial products (Wang et al., 2014; Raimondo et al., 2015; Zhuang et al., 2016; GarciaManrique et al., 2018).”
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Logozzi, M., Raimo, R. D., Mizzoni, D., & Fais, S. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23094919 · Cited by 79 · see citing works
“Non-specified Intranasally administrated grapefruit nanovesicles deliver miR17 to mice brain tumors [48]”
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Orefice, N. S., Raimo, R. D., Mizzoni, D., Logozzi, M., & Fais, S. (2023) · Expert Opinion on Therapeutic Patents · doi:10.1080/13543776.2023.2195093 · Cited by 81 · see citing works
“miR-17 Intranasally administrated grapefruit nanovesicles deliver miR17 to mice brain tumors [83]”
BackgroundAdvances in plant-derived extracellular vesicles: isolation, composition, and biological functions
Zeng, Y., Deng, X., Shen, L., Yang, Y. M., Zhou, X., Ye, L., Chen, S., Da-jian, Y., & Chen, G. (2024) · Food & Function · doi:10.1039/d4fo04321a · Cited by 80 · see citing works
Uptake of MicroRNAs from Exosome-Like Nanovesicles of Edible Plant Juice by Rat Enterocytes
Ito, Y., Taniguchi, K., Kuranaga, Y., Eid, N. A. S., Inomata, Y., Lee, S., & Uchiyama, K. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22073749 · Cited by 79 · see citing works
Application of plant-derived exosome-like nanoparticles in drug delivery
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“For example, Zhuang et al. (2016) revealed that grapefruit-derived nanovectors could carry exogenous miRNA, such as miR17, to mouse brain tumors via the intranasal route with high biocompatibility.”
BackgroundThe Nasal–Brain Drug Delivery Route: Mechanisms and Applications to Central Nervous System Diseases
Qiu, Y., Huang, S., Peng, L., Yang, L., Zhang, G., Liu, T., Yan, F., & Peng, X. (2025) · MedComm · doi:10.1002/mco2.70213 · Cited by 90 · see citing works
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Plant-derived exosomes: a green approach for cancer drug delivery
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Nanotherapeutics Overcoming the Blood-Brain Barrier for Glioblastoma Treatment
Tang, L., Feng, Y., Gao, S., Mu, Q., & Liu, C. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.786700 · Cited by 73 · see citing works
“In a recent study, GNV was coated with folic acid to achieve precise targeting of folate receptor-positive GL-26 brain tumors (Zhuang et al., 2016).”
MethodExosomes on the border of species and kingdom intercommunication
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“The mechanism of GNVs displacement from nasal cavity to the brain, and ultimately all the nervous system is not completely recognized, and further studies are accordingly needed (Zhuang et al. 2016).”
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Song, Y., Feng, N., Yu, Q. B., Li, Y., Meng, M., Yang, X. W., Gan, Z., Xu, T., Tang, C., & Zhang, Y. (2025) · International Journal of Nanomedicine · doi:10.2147/ijn.s540094 · Cited by 65 · see citing works
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Nose-to-brain delivery: exploring newer domains for glioblastoma multiforme management
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“These nanocarriers rapidly delivered miR17 to the brain upon intranasal administration, significantly prolonged the survival, and delayed the tumor growth inGL26 tumor-inducedmice [70].”
BackgroundBeta vulgaris juice contains biologically active exosome-like nanoparticles
Mahdipour, E. (2022) · Tissue and Cell · doi:10.1016/j.tice.2022.101800 · Cited by 62 · see citing works
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“In particular, EVs have superior cellular uptake ability and intrinsic transcytosis effect, enabling them to efficiently traverse physiological barriers and penetrate dense tumor tissue22,23.”
BackgroundNanoencapsulation of nutraceuticals: enhancing stability and bioavailability in functional foods
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Ishida, T., Kawada, K., Jobu, K., Morisawa, S., Kawazoe, T., Nishimura, S., Akagaki, K., Yoshioka, S., & Miyamura, M. (2023) · Journal of Pharmacy and Pharmacology · doi:10.1093/jpp/rgad062 · Cited by 60 · see citing works
Edible plant-derived extracellular vesicles serve as promising therapeutic systems
Yang, C., Zhang, W., Bai, M., Luo, Q., Zheng, Q., Xu, Y., Li, X., Jiang, C., Cho, W. C. S., & Fan, Z. (2023) · Nano TransMed · doi:10.1016/j.ntm.2023.100004 · Cited by 60 · see citing works
Plant-derived nanovesicles and therapeutic application
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“As for plant ELNs, they are typically isolated from freshly squeezed fruit [18] and vegetable juices, such as grape [4] , grapefruit [14] , and ginger [19] , whose production has undergone anthropogenic intervention.”
InfluentialSelf-citationBahri, F., Mansoori, M., Vafaei, S., Fooladi, S., Mir, Y., Mehrabani, M., Hozhabri, Y., Nematollahi, M. H., & Iravani, S. (2024) · Materials Advances · doi:10.1039/d3ma00856h · Cited by 59 · see citing works
Using aptamers for targeted delivery of RNA therapies
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“8,22,99,106,110 Milk-derived nanovesicles (MNVs) have also been shown to be potent targeted delivery vehicles for cancer therapeutics.”
Karabay, A. Z., Barar, J., Hekmatshoar, Y., & Saadat, Y. R. (2025) · Biomolecules · doi:10.3390/biom15030394 · Cited by 58 · see citing works
“It has been reported that the use of PDEVs for the application of peptides, which are inherently unstable and exhibit limited absorption from the skin, exhibits advantages, such as much more effective passage through the skin barrier compared to free peptides [150].”
Plant Exosomal Vesicles: Perspective Information Nanocarriers in Biomedicine
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“Encap-sulation can be optimized to respond to specific stimuli in the microenvironment, such as pH or enzymatic activity, further enhancing site-specific delivery [225, 270, 273].”
Exosome-like Nanoparticles: A New Type of Nanocarrier
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Carrier-free nanoplatforms from natural plants for enhanced bioactivity
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“Grapefruit derived NVs loaded with miR-17 modified by folic acid (FA) can also be rapidly delivered to the brain by intranasal administration and selectively endocytosed by GL-26 tumor cells.(84) Moreover, when grapefruitderived NVs were used as drug delivery vehicles to inject pregnant mice through the tail vein, the…”
BackgroundMethodInfluentialPlant-Derived Vesicles: A New Era for Anti-Cancer Drug Delivery and Cancer Treatment
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“92 Notably, although PDVEs could cross biological barriers, they could not penetrate the placental barrier when injected intravenously into pregnant mice, suggesting the high safety of PDVEs in pregnant women.”
BackgroundPlant-derived exosome-like nanoparticles for microRNA delivery in cancer treatment
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“Nanovesicles derived from ginger, strawberries, grapefruit, cucumbers, yams, and ginseng all exhibit lower in vivo cytotoxicity [ 25, 91, 93, 144–146].”
InfluentialSusa, F., Arpicco, S., Pirri, C. F., & Limongi, T. (2024) · Pharmaceutics · doi:10.3390/pharmaceutics16070849 · Cited by 50 · see citing works
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“Plant ELNs also serve as efficient carriers for nucleic acid medications (miRNA) for cancer treatment, as demonstrated by cabbage and grapefruit ELNs (You, Kang, and Rhee 2021; Zhuang et al. 2016).”
Fang, X., Feng, J., Zhu, X., Feng, D., & Zheng, L. (2024) · Molecular Therapy · doi:10.1016/j.ymthe.2024.02.021 · Cited by 46 · see citing works
Yang, L., Li, C.-Q., Zhang, Y.-L., et al. (2024) · International Journal of Nanomedicine · doi:10.2147/ijn.s454794 · Cited by 45 · see citing works
- Authors
- Zhuang, X., Teng, Y., Samykutty, A., Mu, J., Deng, Z., Zhang, L., Cao, P., Rong, Y., Yan, J., Miller, D., & Zhang, H.-G.
- Affiliations
- University of Louisville (US)
- Corresponding author
- Zhang, Huang-Ge
- ORCID
- Venue
- Molecular Therapy
- Publisher
- Elsevier BV
- Published
- 2016-01
- Volume
- 24
- Issue
- 1
- Pages
- 96-105
- ISSN
- 1525-0016 (ISSN-L)
- PMC
- PMC4754550
- OpenAlex
- W2223281187
- Semantic Scholar
- 7b82ce56643cc8f742baa0594e76a940e23d05a1
- Cited by
- 294
- References
- 35
- Citations by year
- 2026: 57 · 2025: 54 · 2024: 51 · 2023: 39 · 2022: 29 · 2021: 19 · 2020: 14 · 2019: 15 · 2018: 6 · 2017: 4 · 2016: 6
- FWCI
- 2.31
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Molecular Therapy (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Veterans Affairs (I01 BX000962)
- National Institutes of Health (UH3TR000875, UH2TR000875)
- National Center for Advancing Translational Sciences
- National Center for Complementary and Integrative Health (R01AT004294, R01AT008617)
- 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 › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Advanced Drug Delivery Systems
- Keywords
- intranasal drug delivery, brain tumors, glioblastoma, folic acid targeting, folate receptor, polyethyleneimine, RNA delivery, brain drug delivery, tumor growth inhibition
- MeSH terms
- Administration, Intranasal, Animals, Brain Neoplasms, Folic Acid, Organ Specificity, Plant Extracts, Polyethyleneimine, Genetic Therapy, Treatment Outcome, Disease Progression, Xenograft Model Antitumor Assays, Citrus paradisi, MicroRNAs, Cell Line, Tumor, Mice, Nanoparticles
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