Plant-Derived Exosome-Like Nanoparticles: Advances in Therapeutic Applications and Drug Delivery
Abstract
Background: Plant-derived exosome-like nanoparticles (PELNs) are nanoscale vesicles secreted by plant cells that contain lipids, proteins, RNAs, and secondary metabolites. Increasing evidence indicates that these vesicles can deliver plant-derived molecules into mammalian cells and modulate biological processes, including inflammation, oxidative stress, and immune responses.
Scope of the Review: This review summarizes current knowledge of PELNs, including their biogenesis, molecular composition, isolation and characterization strategies, cellular uptake mechanisms, and reported therapeutic applications. Representative examples from medicinal plants, such as ginger (Zingiber officinale), turmeric (Curcuma longa), and tea (Camellia sinensis), are discussed to illustrate their biological activity and their potential as natural nanocarriers. Their physicochemical stability, biocompatibility, and low immunogenicity support ongoing investigation for both oral and systemic delivery.
Challenges and Future Prospects: Despite growing interest, several challenges remain, including the lack of standardized isolation and purification protocols, variability in vesicle composition, and limited regulatory frameworks. Advances in omics-based analyses and functional validation will be essential to clarify mechanisms of action and improve reproducibility.
Conclusion: PELNs represent a rapidly developing research area at the interface of natural products and nanomedicine. Although current evidence is largely preclinical, these vesicles may contribute to the development of safe and effective therapeutic strategies with further validation.
How to Cite
References
- Wani MC, Taylor HL, Wall ME, Coggon P, McPhail AT. Taxol: a novel antileukemic and antitumor agent from Taxus brevifolia. J Am Chem Soc. 1971;93:2325-2327.
- Tu Y. The discovery of artemisinin (qinghaosu) and gifts from Chinese medicine. Nat Med. 2011;17:1217-1220.
- Newman DJ, Cragg GM. Natural products as sources of new drugs from 1981 to 2019. J Nat Prod. 2020;83:770-803.
- Wagner H, Ulrich-Merzenich G. Synergy research: approaching a new generation of phytopharmaceuticals. Phytomedicine. 2009;16:97-110.
- Atanasov AG, Waltenberger B, Pferschy-Wenzig EM, et al. Discovery and resupply of pharmacologically active plant-derived natural products. Biotechnol Adv. 2015;33:1582-1614.
- Efferth T, Koch E. Complex interactions between phytochemicals: the multi-target therapeutic concept. Planta Med. 2011;77:1086-1094.
- McClements DJ. Enhancing nutraceutical bioavailability through food matrix design. Adv Colloid Interface Sci. 2015;219:27-53.
- Zhang M, Viennois E, Prasad M, et al. Edible ginger-derived nanoparticles: a novel therapeutic approach for colitis. Biomaterials. 2016;101:321-340.
- Ju S, Mu J, Dokland T, et al. Grape exosome-like nanoparticles induce intestinal stem cells. Mol Ther. 2013;21:1345-1357.
- Wang B, Zhuang X, Deng ZB, et al. Targeted drug delivery using grapefruit-derived nanovesicles. Mol Ther. 2014;22:522-534.
- Teng Y, Ren Y, Sayed M, et al. Plant-derived exosomal microRNAs shape the gut microbiota. Cell Host Microbe. 2018;24:637-652.
- Xiao J, Feng S, Wang X, et al. Identification of plant-derived microRNAs in human plasma. PeerJ. 2018;6:e5186.
- Théry C, Witwer KW, Aikawa E, et al. MISEV2018 guidelines. J Extracell Vesicles. 2018;7:1535750.
- Colombo M, Raposo G, Théry C. Biogenesis, secretion, and intercellular interactions of exosomes. Annu Rev Cell Dev Biol. 2014;30:255-289.
- van Niel G, D’Angelo G, Raposo G. Shedding light on the cell biology of extracellular vesicles. Nat Rev Mol Cell Biol. 2018;19:213-228.
- Raposo G, Stoorvogel W. Extracellular vesicles: exosomes, microvesicles, and friends. J Cell Biol. 2013;200:373-383.
- Henne WM, Stenmark H, Emr SD. Molecular mechanisms of the ESCRT pathway. Dev Cell. 2011;21:77-91.
- Théry C, Zitvogel L, Amigorena S. Exosomes: composition, biogenesis and function. Nat Rev Immunol. 2002;2:569-579.
- Pan BT, Teng K, Wu C, et al. Transferrin receptor externalization via vesicles. J Cell Biol. 1985;101:942-948.
- Harding C, Heuser J, Stahl P. Receptor-mediated endocytosis and vesicle trafficking. J Cell Biol. 1983;97:329-339.
- Cai Q, Qiao L, Wang M, et al. Plants send small RNAs via extracellular vesicles. Science. 2018;360:1126-1129.
- He B, Cai Q, Qiao L, et al. RNA-binding proteins mediate RNA loading into plant EVs. Nat Plants. 2021;7:342-352.
- Robinson DG, Ding Y, Jiang L. Unconventional protein secretion in plants: a critical assessment. Protoplasma. 2016;253:31-43.
- Pinedo M, de la Canal L, de Marcos Lousa C. Standardization in plant EV research. J Extracell Vesicles. 2021;10:e12048.
- Regente M, et al. Plant EVs inhibit fungal growth. J Exp Bot. 2017;68:5485-5495.
- Liu B, Benning C. Lipids in plant membranes. Annu Rev Plant Biol. 2013;64:645-670.
- Cai Q, et al. Tetraspanin-positive vesicles in plant defense. Science. 2018;360:1126-1129.
- He B, et al. TET8-associated vesicles. Nat Plants. 2021;7:342-352.
- Robinson DG, et al. Golgi and TGN function. Protoplasma. 2016;253:31-43.
- Yu X, Harris SL, Levine AJ. The regulation of exosome secretion: a novel function of the p53 protein. Cancer Res. 2006;66:4795-4801.
- Baldrich P, Rutter BD, Karimi HZ, et al. Plant extracellular vesicles contain diverse small RNA species. Plant J. 2018;93:544-558.
- Schlemmer T, Barth M, Weipoltshammer K, et al. Lipid composition of extracellular vesicles. Biochim Biophys Acta. 2019;1862:183-194.
- Rutter BD, Innes RW. Extracellular vesicles isolated from the leaf apoplast carry stress-response proteins. Plant Physiol. 2017;173:728-741.
- De Palma M, Biziato D, Petrova TV. Microenvironmental regulation of tumour angiogenesis. Nat Rev Cancer. 2017;17:457-474.
- Valadi H, Ekström K, Bossios A, et al. Exosome-mediated transfer of mRNAs and microRNAs. Nat Cell Biol. 2007;9:654-659.
- Mittelbrunn M, Sánchez-Madrid F. Intercellular communication via exosomes. Nat Rev Mol Cell Biol. 2012;13:328-335.
- Villarroya-Beltri C, et al. Sorting of RNA into exosomes. Nat Commun. 2013;4:2987.
- Théry C, Amigorena S, Raposo G, Clayton A. Isolation and characterization of exosomes. Curr Protoc Cell Biol. 2006;30:3.22.1-3.22.29.
- Lobb RJ, Becker M, Wen SW, et al. Optimized exosome isolation protocol. J Extracell Vesicles. 2015;4:27031.
- Böing AN, van der Pol E, Grootemaat AE, et al. Single-step isolation of extracellular vesicles by size-exclusion chromatography. J Extracell Vesicles. 2014;3:23430.
- Nordin JZ, Lee Y, Vader P, et al. Ultrafiltration with size-exclusion chromatography for EV isolation. Sci Rep. 2015;5:17333.
- Li P, Kaslan M, Lee SH, et al. Progress in exosome isolation techniques. Theranostics. 2017;7:789-804.
- Busatto S, Vilanilam G, Ticer T, et al. Tangential flow filtration for EV purification. J Extracell Vesicles. 2018;7:1535750.
- Théry C. Exosomes: secreted vesicles and intercellular communications. F1000 Biol Rep. 2011;3:15.
- Gardiner C, Di Vizio D, Sahoo S, et al. Techniques used for EV characterization. J Extracell Vesicles. 2016;5:32945.
- Mulcahy LA, Pink RC, Carter DRF. Routes and mechanisms of extracellular vesicle uptake. J Extracell Vesicles. 2014;3:24641.
- Tian T, Zhu YL, Hu FH, et al. Dynamics of exosome internalization. Biomaterials. 2013;34:9395-9407.
- Svensson KJ, Christianson HC, Wittrup A, et al. Macropinocytosis of exosomes. J Biol Chem. 2013;288:17713-17724.
- Feng D, Zhao WL, Ye YY, et al. Cellular internalization of exosomes occurs via lipid raft–mediated pathways. J Biol Chem. 2010;285:4357-4369.
- Huotari J, Helenius A. Endosome maturation. EMBO J. 2011;30:3481-3500.
- Gruenberg J, van der Goot FG. Mechanisms of endosomal membrane fusion. Nat Rev Mol Cell Biol. 2006;7:495-504.
- Simons K, Sampaio JL. Membrane organization and lipid rafts. Cold Spring Harb Perspect Biol. 2011;3:a004697.
- Zhang L, Hou D, Chen X, et al. Exogenous plant MIR168a regulates LDLRAP1. Cell Res. 2012;22:107-126.
- Snow JW, Hale AE, Isaacs SK, et al. Ineffective delivery of diet-derived microRNAs. RNA Biol. 2013;10:1107-1116.
- Dickinson B, Zhang Y, Petrick JS, et al. Lack of detectable oral bioavailability of plant microRNAs. Nat Biotechnol. 2013;31:965-967.
- Witwer KW. Dietary microRNAs: uptake remains controversial. J Extracell Vesicles. 2015;4:28586.
- Record M, Carayon K, Poirot M, Silvente-Poirot S. Exosomes as intercellular signalosomes. Biochim Biophys Acta. 2014;1841:108-120.
- Yáñez-Mó M, Siljander PR, Andreu Z, et al. Biological properties of extracellular vesicles. J Extracell Vesicles. 2015;4:27066.
- Kalluri R, LeBleu VS. The biology, function, and biomedical applications of exosomes. Science. 2020;367:eaau6977.
- Tkach M, Théry C. Communication by extracellular vesicles. Nat Rev Mol Cell Biol. 2016;17:160-174.
- Zhuang X, Deng ZB, Mu J, et al. Ginger-derived nanoparticles protect against alcohol-induced liver damage. J Extracell Vesicles. 2015;4:28713.
- Mu J, Zhuang X, Wang Q, et al. Interspecies communication via plant nanoparticles. Mol Nutr Food Res. 2014;58:1561-1573.
- Kim DK, et al. Antioxidant effects of plant-derived vesicles. Antioxidants. 2021;10:1286.
- Chen Q, et al. Tea-derived extracellular vesicles suppress tumor growth. Acta Pharm Sin B. 2022;12:907-923.
- Raimondo S, Naselli F, Fontana S, et al. Citrus limon-derived nanovesicles inhibit tumor growth. Oncotarget. 2015;6:19514-19527.
- Wang Q, Ren Y, Mu J, et al. Grapefruit-derived nanoparticles for targeted therapy. Mol Ther. 2013;21:1345-1357.
- Wang Q, et al. Grapefruit-derived lipid nanoparticles for drug delivery. Nat Commun. 2013;4:1867.
- Zhuang X, et al. Grapefruit-derived nanovectors for therapy. Mol Ther. 2015;23:1422-1432.
- Wang B, et al. Targeted delivery via plant vesicles. Mol Ther. 2014;22:522-534.
- Liu B, et al. Plant-derived vesicles in tissue repair. Front Pharmacol. 2020;11:586000.
- Teng Y, et al. Plant exosomal RNAs shape microbiota. Cell Host Microbe. 2018;24:637-652.
- Woith E, Fuhrmann G, Melzig MF. Extracellular vesicles—connecting kingdoms. Int J Mol Sci. 2019;20:5695.
- Zhuang X, et al. Drug delivery using plant vesicles. Mol Ther. 2015;23:1422-1432.
- Wang Q, et al. Therapeutic nanoparticle delivery system. Nat Commun. 2013;4:1867.
- Woith E, Fuhrmann G, Melzig MF. Extracellular vesicles—connecting kingdoms. Int J Mol Sci. 2019;20:5695.
- Liu H, Chen X, Hu X. Plant exosome-like nanoparticles: emerging mediators. Front Pharmacol. 2020;11:586000.
- Raimondo S, et al. Plant vesicles in cancer therapy. Oncotarget. 2015;6:19514-19527.
- Wang B, et al. Nanovesicle-based delivery systems. Mol Ther. 2014;22:522-534.
- Zhuang X, et al. Nanoparticle-mediated delivery strategies. Mol Ther. 2015;23:1422-1432.
- Witwer KW, et al. Defining EVs for clinical applications. J Extracell Vesicles. 2019;8:1596016.
- Lener T, et al. Applying EVs in clinical trials. J Extracell Vesicles. 2015;4:30087.
- Reiner AT, et al. EV-based therapeutics. Stem Cells Transl Med. 2017;6:1730-1739.
- Pinedo M, et al. Challenges in plant EV standardization. J Extracell Vesicles. 2021;10:e12048.
- U.S. Food and Drug Administration. Botanical Drug Development: Guidance for Industry. FDA, Silver Spring, MD. 2016. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/botanical-drug-development-guidance-industry.
- European Medicines Agency. Guideline on quality of herbal medicinal products/traditional herbal medicinal products. EMA/HMPC/201116/2005 Rev. 2. 2011.