Plant-derived exosome-like nanoparticles: from biogenesis to therapeutic applications

doi:10.5246/jcps.2026.06.036

Abstract

Abstract:

Plant-derived exosome-like nanoparticles (PELNs), a specialized subclass of extracellular vesicles originating from plants, are enriched in small RNAs, diverse lipid species, and bioactive metabolites, and uniquely integrate both therapeutic cargo and delivery functions within a single platform. These characteristics have made PELNs an emerging frontier of biomedical investigation. This review provides a comprehensive synthesis of current advances in the field. The biogenesis of PELNs is orchestrated through cellular pathways involving ESCRT complexes, autophagic machinery, and related vesicle trafficking systems, and their morphology typically features a lipid bilayer with diameters ranging from 50 to 200 nm. High-purity isolation requires multistep or combined methodological strategies, and the concurrent application of multiple analytical technologies enables accurate identity verification and purity assessment. Functionally, PELNs exhibit notable capabilities in anti-inflammatory intervention, tumor suppression, and neural tissue repair. PELNs offer several inherent advantages, including excellent biosafety, strong oral tolerance, scalable and low-cost production, absence of ethical concerns, and considerable potential for molecular engineering. Nevertheless, the lack of standardized isolation workflows, rigorous characterization pipelines, and quality control frameworks continues to impede their clinical translation. Future progress will require close interdisciplinary collaboration to establish unified technical standards, decode their in vivo fate, mechanisms of action, and safety profiles, and accelerate their innovative use in precision medicine and related therapeutic domains. Such advances may position PELNs as natural, sustainable, and clinically translatable solutions for designing safer and more effective treatment strategies.

Key words: Plant-derived exosome-like nanoparticles, Biological functions, Separation and characterization, Treatment

Supporting:

Honghua Tan, Shuang Li, Mengsha Cui, Bing Han, Jiameng Liu, Lingxi Yu, Junrong Hao, Chunyan Guo. Plant-derived exosome-like nanoparticles: from biogenesis to therapeutic applications[J]. Journal of Chinese Pharmaceutical Sciences, 2026, 35(6): 509-524.

Figures/Tables 1

References 50

[1]	Chaudhary, P.K.; Kim, S.; Kim, S. Shedding light on the cell biology of platelet-derived extracellular vesicles and their biomedical applications. Life. 2023, 13, 1403.
[2]	Mathieu, M.; Martin-Jaular, L.; Lavieu, G.; Théry, C. Specificities of secretion and uptake of exosomes and other extracellular vesicles for cell-to-cell communication. Nat. Cell Biol. 2019, 21, 9–17.
[3]	Kalluri, R.; LeBleu, V.S. The biology, function, and biomedical applications of exosomes. Science. 2020, 367, eaau6977.
[4]	Toyofuku, M.; Schild, S.; Kaparakis-Liaskos, M.; Eberl, L. Composition and functions of bacterial membrane vesicles. Nat. Rev. Microbiol. 2023, 21, 415–430.
[5]	Cano-Castaño, B.; López-Siles, M.; Nonnoi, F.; Pérez, A.; Corral Lugo, A.; McConnell, M.J. Acinetobacter baumannii as a model for the study and application of gram-negative outer membrane vesicles: a systematic review. Microb. Biotechnol. 2025, 18, e70207.
[6]	Furuyama, N.; Sircili, M.P. Outer membrane vesicles (OMVs) produced by gram-negative bacteria: structure, functions, biogenesis, and vaccine application. BioMed Res. Int. 2021, 2021, 1490732.
[7]	Schwechheimer, C.; Kuehn, M.J. Outer-membrane vesicles from Gram-negative bacteria: biogenesis and functions. Nat. Rev. Microbiol. 2015, 13, 605–619.
[8]	Welsh, J.A.; Goberdhan, D.C.I.; O’Driscoll, L.; Buzas, E.I.; Blenkiron, C.; Bussolati, B.; Cai, H.J.; Di Vizio, D.; Driedonks, T.A.P.; Erdbrügger, U.; Falcon-Perez, J.M.; Fu, Q.L.; Hill, A.F.; Lenassi, M.; Lim, S.K.; Mahoney, M.G.; Mohanty, S.; Möller, A.; Nieuwland, R.; Ochiya, T.; Sahoo, S.; Torrecilhas, A.C.; Zheng, L.; Zijlstra, A.; Abuelreich, S.; Bagabas, R.; Bergese, P.; Bridges, E.M.; Brucale, M.; Burger, D.; Carney, R.P.; Cocucci, E.; Crescitelli, R.; Hanser, E.; Harris, A.L.; Haughey, N.J.; Hendrix, A.; Ivanov, A.R.; Jovanovic-Talisman, T.; Kruh-Garcia, N.A.; Ku’ulei-Lyn Faustino, V.; Kyburz, D.; Lässer, C.; Lennon, K.M.; Lötvall, J.; Maddox, A.L.; Martens-Uzunova, E.S.; Mizenko, R.R.; Newman, L.A.; Ridolfi, A.; Rohde, E.; Rojalin, T.; Rowland, A.; Saftics, A.; Sandau, U.S.; Saugstad, J.A.; Shekari, F.; Swift, S.; Ter-Ovanesyan, D.; Tosar, J.P.; Useckaite, Z.; Valle, F.; Varga, Z.; van der Pol, E.; van Herwijnen, M.J.C.; Wauben, M.H.M.; Wehman, A.M.; Williams, S.; Zendrini, A.; Zimmerman, A.J.; Consortium, M.; Théry, C.; Witwer, K.W. Minimal information for studies of extracellular vesicles (MISEV2023): From basic to advanced approaches. J. Extracell. Vesicles. 2024, 13, e12404.
[9]	Regente, M.; Pinedo, M.; San Clemente, H.; Balliau, T.; Jamet, E.; de la Canal, L. Plant extracellular vesicles are incorporated by a fungal pathogen and inhibit its growth. J. Exp. Bot. 2017, 68, 5485–5495.
[10]	Chi, J.; Wang, X.B.; Song, Y.R.; Wang, J.Z.; Guo, L.; Wang, R.; Wang, G.Z. Emerging plant-derived exosome-like particles reveal key therapeutic benefits. a comprehensive review of evidence. Int. J. Nanomed. 2025, 20, 12393–12411.
[11]	Li, Y.H.; Wang, Y.L.; Zhao, H.R.; Pan, Q.; Chen, G.H. Engineering strategies of plant-derived exosome-like nanovesicles: current knowledge and future perspectives. Int. J. Nanomed. 2024, 19, 12793–12815.
[12]	Muhammad, D.R.; Emmanuela, N.; Iriawati, I.; Wijaya, C.H.; Ana, I.D.; Wungu, T.D.K.; Ratnadewi, D.; Takemori, H.; Barlian, A. Exosome-like nanoparticles from Indonesian Red and Emprit Ginger varieties suppress LPS-induced IL-6 production in RAW_264.7 macrophages. Adv. Pharm. Bull. 2025, 15, 60–69.
[13]	Ning, H.; Huang, X.Y.; Deng, N.; Lin, X.Y.; Zheng, L.; Zhu, Y.; Xu, Y. Plant-derived exosome-like nanovesicles: a novel strategy for targeted oral therapy in ulcerative colitis. Int. J. Nanomed. 2025, 20, 10595–10611.
[14]	Zhang, Z.Y.; Yu, Y.; Zhu, G.X.; Zeng, L.T.; Xu, S.F.; Cheng, H.Y.; Ouyang, Z.; Chen, J.W.; Pathak, J.L.; Wu, L.H.; Yu, L.N. The emerging role of plant-derived exosomes-like nanoparticles in immune regulation and periodontitis treatment. Front. Immunol. 2022, 13, 896745.
[15]	Sha, A.J.; Luo, Y.Y.; Xiao, W.Q.; He, J.; Chen, X.D.; Xiong, Z.; Peng, L.X.; Zou, L.; Liu, B.L.; Li, Q. Plant-derived exosome-like nanoparticles: a comprehensive overview of their composition, biogenesis, isolation, and biological applications. Int. J. Mol. Sci. 2024, 25, 12092.
[16]	Liu, H.H.; Deng, Y.; Li, J.Y.; Lin, W.; Liu, C.Z.; Yang, X.F.; Zhou, Z.Z.; Jiang, Y. Ginger-derived exosome-like nanoparticles: a representative of plant-based natural nanostructured drug delivery system. Front. Bioeng. Biotechnol. 2025, 13, 1569889.
[17]	Jia, S.S.; Yang, Y.; Liu, J.B.; Wang, Z.Y.; Bai, L.H. PPARγ controls ESCRT-dependent fibroblast-like synoviocyte exosome biogenesis and alleviates chondrocyte osteoarthritis mediated by exosomal ANXA1. J. Orthop. Transl. 2025, 53, 187–205.
[18]	Iglesias-Fortes, S.; Lockwood, A.C.; González-Blanco, C.; Lozano, D.; García-Aguilar, A.; Palomino, O.; García, G.; Fernández-Millán, E.; Benito, M.; Guillén, C. Amylin is incorporated into extracellular vesicles in an ESCRT-dependent manner and regulates senescence. Biochim. Biophys. Acta BBA Mol. Basis Dis. 2025, 1871, 167699.
[19]	Hamamoto, K.; Liang, X.W.; Ito, A.; Lanza, M.; Bui, V.; Zhang, J.W.; Opozda, D.M.; Hattori, T.; Chen, L.G.; Haddock, D.; Imamura, F.; Wang, H.-G.; Takahashi, Y. Unveiling the physiological impact of ESCRT-dependent autophagosome closure by targeting the VPS37A ubiquitin E2 variant-like domain. Cell Rep. 2024, 43, 115016.
[20]	Javed, R.; Mari, M.; Trosdal, E.; Duque, T.; Ahmad Paddar, M.; Allers, L.; Mudd, M.H.; Claude-Taupin, A.; Akepati, P.R.; Hendrix, E.; He, Y.; Salemi, M.; Phinney, B.; Uchiyama, Y.; Reggiori, F.; Deretic, V. ATG9A facilitates the closure of mammalian autophagosomes. J. Cell Biol. 2025, 224, e202404047.
[21]	Martin, S.; Scorzoni, S.; Cordone, S.; Mazzagatti, A.; Beznoussenko, G.V.; Gunn, A.L.; Di Bona, M.; Eliezer, Y.; Leor, G.; Ben-Yishay, T.; Loffreda, A.; Cancila, V.; Rainone, M.C.; Ippolito, M.R.; Martis, V.; Bedin, F.; Garrè, M.; Vaites, L.P.; Vasapolli, P.; Polo, S.; Parazzoli, D.; Tripodo, C.; Mironov, A.A.; Cuomo, A.; Ben-David, U.; Bakhoum, S.F.; Hatch, E.M.; Ly, P.; Santaguida, S. A p62-dependent rheostat dictates micronuclei catastrophe and chromosome rearrangements. Science. 2024, 385, eadj7446.
[22]	Chandra, P.; Philips, J.A. USP8 promotes intracellular infection by enhancing ESCRT-mediated membrane repair, limiting xenophagy, and reducing oxidative stress. Autophagy. 2025, 21, 298–314.
[23]	Rasouliha, S.H.; Aguilar, G.; Reinger, C.; Matsuda, S. Shaping and interpretation of Dpp morphogen gradient by endocytic trafficking. PLoS Genet. 2025, 21, e1011766.
[24]	Raimondo, S.; Naselli, F.; Fontana, S.; Monteleone, F.; Lo Dico, A.; Saieva, L.; Zito, G.; Flugy, A.; Manno, M.; Di Bella, M.A.; De Leo, G.; Alessandro, R. Citrus limon-derived nanovesicles inhibit cancer cell proliferation and suppress CML xenograft growth by inducing TRAIL-mediated cell death. Oncotarget. 2015, 6, 19514–19527.
[25]	Teng, Y.; Ren, Y.; Sayed, M.; Hu, X.; Lei, C.; Kumar, A.; Hutchins, E.; Mu, J.Y.; Deng, Z.B.; Luo, C.; Sundaram, K.; Sriwastva, M.K.; Zhang, L.F.; Hsieh, M.; Reiman, R.; Haribabu, B.; Yan, J.; Jala, V.R.; Miller, D.M.; Van Keuren-Jensen, K.; Merchant, M.L.; McClain, C.J.; Park, J.W.; Egilmez, N.K.; Zhang, H.G. Plant-derived exosomal microRNAs shape the gut microbiota. Cell Host Microbe. 2018, 24, 637–652.e8.
[26]	McMillan, H.M.; Kuehn, M.J. Proteomic profiling reveals distinct bacterial extracellular vesicle subpopulations with possibly unique functionality. Appl. Environ. Microbiol. 2023, 89, e01686–e01622.
[27]	Bai, C.M.; liu, J.R.; Zhang, X.M.; Li, Y.; Qin, Q.; Song, H.X.; Yuan, C.X.; Huang, Z.W. Research status and challenges of plant-derived exosome-like nanoparticles. Biomed. Pharmacother. 2024, 174, 116543.
[28]	Yugay, Y.; Tsydeneshieva, Z.; Rusapetova, T.; Grischenko, O.; Mironova, A.; Bulgakov, D.; Silant’ev, V.; Tchernoded, G.; Bulgakov, V.; Shkryl, Y. Isolation and characterization of extracellular vesicles from Arabidopsis thaliana cell culture and investigation of the specificities of their biogenesis. Plants. 2023, 12, 3604.
[29]	Garzo, E.; Sánchez-López, C.M.; Fereres, A.; Soler, C.; Marcilla, A.; Pérez-Bermúdez, P. Isolation of extracellular vesicles from phloem sap by size exclusion chromatography. Curr. Protoc. 2023, 3, e903.
[30]	Nordin, J.Z.; Bostancioglu, R.B.; Corso, G.; EL Andaloussi, S. Tangential flow filtration with or without subsequent bind-elute size exclusion chromatography for purification of extracellular vesicles. Target Identification and Validation in Drug Discovery. New York, NY: Springer New York. 2019, 287–299.
[31]	Lo, K.J.; Wang, M.-H.; Kuo, C.Y.; Pan, M.H. Optimizing isolation methods and exploring the therapeutic potential of lotus-derived extracellular vesicles in modulating inflammation and promoting wound healing. ACS Biomater. Sci. Eng. 2025, 11, 4424–4435.
[32]	Yuan, R.J.; Zhou, Y.J.; Arias, G.F.; Dittmer, D.P. Extracellular vesicle isolation by a tangential-flow filtration-based large-scale purification method. Cell-Secreted Vesicles. New York, NY: Springer US. 2023, 45–55.
[33]	Benedikter, B.J.; Bouwman, F.G.; Vajen, T.; Heinzmann, A.C.A.; Grauls, G.; Mariman, E.C.; Wouters, E.F.M.; Savelkoul, P.H.; Lopez-Iglesias, C.; Koenen, R.R.; Rohde, G.G.U.; Stassen, F.R.M. Ultrafiltration combined with size exclusion chromatography efficiently isolates extracellular vesicles from cell culture media for compositional and functional studies. Sci. Rep. 2017, 7, 15297.
[34]	Visan, K.S.; Lobb, R.J.; Ham, S.; Lima, L.G.; Palma, C.; Edna, C.P.Z.; Wu, L.-Y.; Gowda, H.; Datta, K.K.; Hartel, G.; Salomon, C.; Möller, A. Comparative analysis of tangential flow filtration and ultracentrifugation, both combined with subsequent size exclusion chromatography, for the isolation of small extracellular vesicles. J. Extracell. Vesicles. 2022, 11, 12266.
[35]	Sun, Y.F.; Xu, Y.L.; Yu, H.L.; Song, S.X. Application of nano-flow cytometry for the detection of extracellular vesicles and lipid nanoparticles. J. Chin. Pharm. Sci. 2025, 34, 943–953.
[36]	Kashkanova, A.D.; Blessing, M.; Gemeinhardt, A.; Soulat, D.; Sandoghdar, V. Precision size and refractive index analysis of weakly scattering nanoparticles in polydispersions. Nat. Meth. 2022, 19, 586–593.
[37]	Salem, D.; Abdel Aziz, A.Z. Assessment of the antifungal activity of Actinidia deliciosa derived exosome like nanoparticles. Sci. Rep. 2025, 15, 30160.
[38]	Yin, H.Y.; You, S.H.; Li, X.M.; Li, S.; Guo, C.Y. Progress, challenges, and prospects of small extracellular vesicles isolation and characterization. J. Holist. Integr. Pharm. 2024, 5, 121–130.
[39]	Muhammad, Z.; Muhammad, S.A.; Abbas, A.Y.; Achor, M.; Adeyemi, S.A.; Choonara, Y.E.; Saidu, Y.; Bilbis, L.S. Isolation and characterization of medicinal plant-based extracellular vesicles as nano delivery systems for ascorbic acid. J. Microencapsul. 2025, 42, 120–131.
[40]	Chen, H.C.; Newton, C.J.; Diaz, G.; Zheng, Y.C.; Kong, F.; Yao, Y.; Yang, L.; Kvitko, B.H. Proteomic snapshot of pattern triggered immunity in the Arabidopsis leaf apoplast. Plant J. 2025, 123, e70498.
[41]	Trentini, M.; Zanolla, I.; Tiengo, E.; Zanotti, F.; Sommella, E.; Merciai, F.; Campiglia, P.; Licastro, D.; Degasperi, M.; Lovatti, L.; Bonora, M.; Danese, A.; Pinton, P.; Zavan, B. Link between organic nanovescicles from vegetable Kingdom and human cell physiology: intracellular calcium signalling. J. Nanobiotechnol. 2024, 22, 68.
[42]	Wu, M.; Li, Q.L.; Xia, G.X.; Zhang, Y.S.; Wang, F.X. New insights into defense responses against Verticillium dahliae infection revealed by a quantitative proteomic analysis in Arabidopsis thaliana. Funct. Plant Biol. 2022, 49, 980–994.
[43]	Zhu, M.Z.; Xu, H.M.; Liang, Y.J.; Xu, J.; Yue, N.N.; Zhang, Y.; Tian, C.M.; Yao, J.; Wang, L.S.; Nie, Y.Q.; Li, D.F. Edible exosome-like nanoparticles from portulaca oleracea L mitigate DSS-induced colitis via facilitating double-positive CD4⁺CD8⁺T cells expansion. J. Nanobiotechnol. 2023, 21, 309.
[44]	Huang, R.F.; Jia, B.; Su, D.D.; Li, M.C.; Xu, Z.X.; He, C.; Huang, Y.S.; Fan, H.; Chen, H.B.; Cheng, F. Plant exosomes fused with engineered mesenchymal stem cell-derived nanovesicles for synergistic therapy of autoimmune skin disorders. J. Extracell. Vesicles. 2023, 12, e12361.
[45]	Yang, L.Y.; Liang, G.W.; Cai, B.J.; Xu, K.M.; Zhao, Y.J.; Xie, X.T.; Zhang, Y.L.; Li, C.Q.; Zhang, G.J. Enhanced tumor self-targeting of lemon-derived extracellular vesicles by embedding homotypic cancer cell membranes for efficient drug delivery. J. Nanobiotechnol. 2025, 23, 74.
[46]	Xu, X.H.; Yuan, T.J.; Dad, H.A.; Shi, M.Y.; Huang, Y.Y.; Jiang, Z.H.; Peng, L.H. Plant exosomes as novel nanoplatforms for microRNA transfer stimulate neural differentiation of stem cells in vitro and in vivo. Nano Lett. 2021, 21, 8151–8159.
[47]	Liu, H.L.; He, J.; Xu, L.L.; Chen, Y.X.; Wang, X.N.; Pang, X.N.; Yang, H.H.; Liang, L.H.; Chen, S.W.; Li, S.L. Echinocystic acid in Momordica charantia L. exosome-like nanovesicles attenuates dengue virus-induced vascular leakage associated inflammatory mediators through macrophage metabolic reprogramming and HIF-1α/p300-CBP interaction. Front. Med. 2025, 12, 1653689.
[48]	Wang, D.Z.; Zhang, H.; Liao, X.C.; Li, J.; Zeng, J.; Wang, Y.L.; Zhang, M.J.; Ma, X.Z.; Wang, X.; Ren, F.L.; Wang, Y.Y.; Li, M.; Xu, J.F.; Jin, P.; Sheng, J.Q. Oral administration of Robinia pseudoacacia L. flower exosome-like nanoparticles attenuates gastric and small intestinal mucosal ferroptosis caused by hypoxia through inhibiting HIF-1α- and HIF-2α-mediated lipid peroxidation. J. Nanobiotechnol. 2024, 22, 479.
[49]	Mao, Y.L.; Han, M.Q.; Chen, C.S.; Wang, X.D.; Han, J.N.; Gao, Y.K.; Wang, S.L. A biomimetic nanocomposite made of a ginger-derived exosome and an inorganic framework for high-performance delivery of oral antibodies. Nanoscale. 2021, 13, 20157–20169.
[50]	Atia, G.A.; Abdeen, A.; Taher, E.S.; Alghonemy, W.Y.; El Nashar, E.M.; Al-Zahrani, N.S.; Elmorsy, E.M.; Khanday, S.; Alshambky, A.; Taymour, N.; Atwa, A.M.; Zaghamir, D.E.; Hetta, H.F.; Mohamed, M.E.; Abass, K.S.; Shannour, N.; Elbaghdady, H.A.M.; Haque, M.A.; El-Far, A. From plants to patients: advancing cancer therapy with bioengineered exosomes and AI-driven innovations. Phytother. Res. 2025, 39, 4566–4614.