Onion Peel-Derived Exosome-Like Nanovesicles as a Novel Therapeutic Approach for Inflammatory Bowel Disease

Authors

  • Fabrizia Sepe Research Institute on Terrestrial Ecosystems (IRET)-CNR, Via Pietro Castellino 111, 80131 Naples, Italy
  • Anna Valentino Research Institute on Terrestrial Ecosystems (IRET)-CNR, Via Pietro Castellino 111, 80131 Naples, Italy
  • Youssra Lefrioui Laboratory of Biotechnology Environment Agrofood and Health (LBEAS), Faculty of Sciences Dhar El Mahraz, Sidi Mohamed Ben Abdellah University, Fez 30000, Morocco
  • Sabrina Margarucci Research Institute on Terrestrial Ecosystems (IRET)-CNR, Via Pietro Castellino 111, 80131 Naples, Italy
  • Orsolina Petillo Research Institute on Terrestrial Ecosystems (IRET)-CNR, Via Pietro Castellino 111, 80131 Naples, Italy
  • Loredana Marcolongo Research Institute on Terrestrial Ecosystems (IRET)-CNR, Via Pietro Castellino 111, 80131 Naples, Italy
  • Dalila Bousta Laboratory of Biotechnology Environment Agrofood and Health (LBEAS), Faculty of Sciences Dhar El Mahraz, Sidi Mohamed Ben Abdellah University, Fez 30000, Morocco and National Agency of Medicinal and Aromatic Plants, 34025 Taounate, Morocco
  • Anna Calarco Research Institute on Terrestrial Ecosystems (IRET)-CNR, Via Pietro Castellino 111, 80131 Naples, Italy
  • Raffaele Conte Research Institute on Terrestrial Ecosystems (IRET)-CNR, Via Pietro Castellino 111, 80131 Naples, Italy

DOI:

https://doi.org/10.29169/1927-5951.2026.16.04

Keywords:

Allium cepa, Plant-derived exosome-like nanoparticles, Inflammatory Bowel Disease (IBD), Intestinal epithelial barrier, Waste valorization

Abstract

Chronic inflammation of the intestinal mucosa and impaired intestinal epithelial barrier integrity are two hallmarks of inflammatory bowel disease (IBD). Given the limitations and side effects of conventional biological therapies, the isolation of plant-derived exosome-like nanoparticles (PDEN) from agri-food byproducts represents a sustainable and biocompatible therapeutic option for the development of novel bioactive platforms. In this study, we successfully extracted nanovesicles from industrial onion (Allium cepa) waste peels (OP-EVs) using a protocol combining enzymatic digestion, differential centrifugation, and ultracentrifugation. Their stable nanoscale size (94.1 ± 1.7 nm mode; 63.0 nm), negative surface charge (-16.3 mV), plant-specific markers (Hsp70, TET8, PEN1), and high encapsulation of bioactive flavonoids and polyphenols were confirmed by NTA, DLS, Western blot and LC-MS/MS analysis. In human colonic epithelial cells (HCECs), OP-EVs were non-cytotoxic and efficiently internalized. OP-EVs significantly reduced pro-inflammatory cytokine production (IL-8, IL-6, and TNF-α) under LPS-induced acute inflammatory stress by reducing MAPK/ERK activation and NF-κB (p65). Additionally, OP-EVs restored E-cadherin expression, suppressed N-cadherin overexpression, and markedly accelerated scratch wound closure to protect mucosal barrier integrity in chronic inflammatory conditions. Collectively, these findings suggest that OP-EVs may represent a potential zero-waste nutraceutical platform capable of sustaining epithelial barrier integrity while lowering mucosal inflammation.

References

[1] Heydari K, Rahnavard M, Ghahramani S, Hoseini A, Alizadeh-Navaei R, Rafati S, Raei M, Vahidipour M, Salehi F, Motafeghi F, Neshat S, Moosazadeh M, Yousefi M, Pourali A, Rasouli K, Shokrirad S, Lotfi P, Beladi SA, Hadizadeh Neisanghalb M, Sheydaee F, Moghadam S. Global preva-lence and incidence of inflammatory bowel disease: a syste--matic review and meta-analysis of population-based studies. Gastroenterol Hepatol Bed Bench 2025; 18(2): 132-146.

[2] Yang X, Guo H, Zou M. Inflammatory bowel diseases: pathological mechanisms and therapeutic perspectives. Mol Biomed 2026; 7(1): 2.

[3] Ramos GP, Papadakis KA. Mechanisms of Disease: Inflammatory Bowel Diseases. Mayo Clin Proc 2019; 94(1): 155-165.

[4] Gieryńska M, Szulc-Dąbrowska L, Struzik J, Mielcarska MB, Gregorczyk-Zboroch KP. Integrity of the Intestinal Barrier: The Involvement of Epithelial Cells and Microbiota-A Mutual Relationship. Animals (Basel) 2022; 12(2): 145.

[5] Ghosh S, Whitley CS, Haribabu B, Jala VR. Regulation of Intestinal Barrier Function by Microbial Metabolites. Cellular and Molecular Gastroenterology and Hepatology 2021; 11(5): 1463-1482.

[6] Shabani M, Ghoshehy A, Mottaghi AM, Chegini Z, Kerami A, Shariati A, Taati Moghadam M. The relationship between gut microbiome and human diseases: mechanisms, predisposing factors and potential intervention. Front Cell Infect Microbiol 2025; 15: 1516010.

[7] Saez A, Herrero-Fernandez B, Gomez-Bris R, Sánchez-Martinez H, Gonzalez-Granado JM. Pathophysiology of Inflammatory Bowel Disease: Innate Immune System. Int J Mol Sci 2023; 24(2): 1526.

[8] Cai Z, Wang S, Li J. Treatment of Inflammatory Bowel Disease: A Comprehensive Review. Front Med (Lausanne) 2021; 8: 765474.

[9] Liu CY, Cham CM, Chang EB. Epithelial wound healing in inflammatory bowel diseases: the next therapeutic frontier. Transl Res 2021; 236: 35-51.

[10] Zhang Y, Liu Y, Liang X, Wen Y, Zhao J, He Y, Xie Q, Xie C. Intestinal barrier in chronic gut and liver diseases: Pathogenesis and therapeutic targets. Acta Pharm Sin B 2025; 15(11): 5515-5536.

[11] Salomon C, Das S, Erdbrügger U, Kalluri R, Kiang Lim S, Olefsky JM, Rice GE, Sahoo S, Andy Tao W, Vader P, Wang Q, Weaver AM. Extracellular Vesicles and Their Emerging Roles as Cellular Messengers in Endocrinology: An Endocrine Society Scientific Statement. Endocr Rev 2022; 43(3): 441-468.

[12] Xiang H, Bao C, Chen Q, Gao Q, Wang N, Gao Q, Mao L. Extracellular vesicles (EVs)' journey in recipient cells: from recognition to cargo release. J Zhejiang Univ Sci B 2024; 25(8): 633-655.

[13] Di Liu, Jingxian Gao, Xueling Wu, Lu Han, Plant-derived exosome-like nanoparticles as promising biotherapeutic tools: recent advances and challenges. Smart Materials in Medicine 2025; 6(2): 285-304.

[14] Li DF, Tang Q, Yang MF, Xu HM, Zhu MZ, Zhang Y, Tian CM, Nie YQ, Wang JY, Liang YJ, Wang LS, Yao J. Plant-derived exosomal nanoparticles: potential therapeutic for inflammatory bowel disease. Nanoscale Adv 2023; 5(14): 3575-3588.

[15] Bouqbis L, Elomri A, Zair T. Allium cepaL. Peels: Phytochemical Characterization and Bioactive Potential in Infectious and Metabolic Contexts (In vitro, In vivo, and In Silico). Pharmaceutics 2026; 18(4): 476.

[16] Chen Y, Xu L, Yu Y, Xu Z, Xiao S, Mai H. Protocol for isolating plant-derived extracellular vesicles. STAR Protoc 2026; 7(1): 104379.

[17] Yamasaki M, Yamasaki Y, Furusho R, Kimura H, Kamei I, Sonoda H, Ikeda M, Oshima T, Ogawa K, Nishiyama K. Onion (Allium cepa L.)-Derived Nanoparticles Inhibited LPS-Induced Nitrate Production, However, Their Intracellular Incorporation by Endocytosis Was Not Involved in This Effect on RAW264 Cells. Molecules 2021; 26(9): 2763.

[18] Özkan İ, Koçak P, Yıldırım M, Ünsal N, Yılmaz H, Telci D, Şahin F. Garlic (Allium sativum)-derived SEVs inhibit cancer cell proliferation and induce caspase mediated apoptosis. Sci Rep 2021; 11(1): 14773.

[19] Qi W, Yang L, Pan Y, Lv K, Zhao L, Zhang Y, Kai G, Sun Y, Pan H, Wang D. Chinese leek-derived extracellular vesicles ameliorate sarcopenia by regulating mitochondrial biogenesis and autophagy via AMPK and maintaining myosin homeostasis. J Nanobiotechnology 2025; 23(1): 721.

[20] Seo N, Ichiki T. Negative Surface Charge and Membrane Lipid Composition Underlying Extracellular Vesicle Function. ACS Nano Med 2026; 1(4): 791-805.

[21] Jacob S, Kather FS, Boddu SHS, Rao R, Nair AB. Vesicular Carriers for Phytochemical Delivery: A Comprehensive Review of Techniques and Applications. Pharmaceutics 2025; 17(4): 464.

[22] Yousefi A, Shadnoush M. Encapsulation Systems for Delivery of Flavonoids: A Review. Biointerface Research in Applied Chemistry 2021; 11(6): 13934-13951.

[23] Goh YX, Jalil J, Lam KW, Husain K, Premakumar CM. Genistein: A Review on its Anti-Inflammatory Properties. Front Pharmacol 2022; 13: 820969.

[24] Manikyam HK, Joshi SK. Network Pharmacology of Baicalein Targeting TNF Signaling in Inflammation [J]. Diseases & Research 2025; 5(4): 172-180.

[25] Mueller M, Hobiger S, Jungbauer A, Anti-inflammatory activity of extracts from fruits, herbs and spices, Food Chemistry 2010; 122(4): 987-996.

[26] Piva M, Martelossi-Cebinelli G, Mendes-Pierotti S, Chinen WH, Cardines PHF, Martinez RM, Georgetti SR, Baracat MM, Vicentini FTMC, Verri WA, et al. Flavonoids as Nutraceuticals to Treat Inflammatory Diseases: Focusing on Quercetin, Kaempferol, Luteolin, Apigenin, Epicatechin and Their Effects on Hepatic, Nervous, and Pulmonary Systems. Foods 2026; 15: 2159.

[27] Liu J, Guan Y, Yang L, Fang H, Sun H, Sun Y, Yan G, Kong L, Wang X. Ferulic Acid as an Anti-Inflammatory Agent: Insights into Molecular Mechanisms, Pharmacokinetics and Applications. Pharmaceuticals (Basel) 2025; 18(6): 912.

[28] Koch BL, Gardner D, Smith H, Bracewell R, Awdey L, Foster J, Borniego ML, Munch DH, Nielsen ME, Pasupuleti R, Trinidad J, Rutter B, Thordal-Christensen H, Innes RW. Molecular insights into the production of extracellular vesicles by plants, Plant Physiology 2026; 200(2): kiag011.

[29] Zuppini F, Renzullo L, Tornatore F, Poggio P, Brancaccio M. Heat shock proteins at the crossroads of endosomal trafficking pathways. Cell Biol Toxicol 2025 Dec 11; 41(1): 162.

[30] Tan XH, Fang D, Xu YD, Nan TG, Song WP, Gu YY, Gu SJ, Yuan YM, Xin ZC, Zhou LQ, Guan RL, Li XS. Skimmed Bovine Milk-Derived Extracellular Vesicles Isolated via "Salting-Out": Characterizations and Potential Functions as Nanocarriers. Front Nutr 2021; 8: 769223.

[31] Chen L, Chen W, Chen H, Guo M, Du W, Wang S, Lao T, Lin H, Shi Y, Pan G, Tian J, Fan Z, Chen F, Liu C. Edible Plant-Derived Extracellular Vesicles: Emerging Nanocarriers for Regenerative Medicine. Journal of Future Foods 2026.

[32] Sánchez-López CM, Manzaneque-López MC, Pérez-Bermúdez P, Soler C, Marcilla A. Characterization and bioactivity of extracellular vesicles isolated from pomegranate. Food Funct 2022; 13(24): 12870-12882.

[33] You JY, Kang SJ, Rhee WJ. Isolation of cabbage exosome-like nanovesicles and investigation of their biological activi-ties in human cells. Bioact Mater 2021; 6(12): 4321-4332.

[34] Valentino A, Conte R, Bousta D, Bekkari H, Di Salle A, Calarco A, Peluso G. Extracellular Vesicles Derived from Opuntia ficus-indica Fruit (OFI-EVs) Speed Up the Normal Wound Healing Processes by Modulating Cellular Responses. Int J Mol Sci 2024; 25(13): 7103.

[35] Neurath MF. Cytokines in inflammatory bowel disease. Nat Rev Immunol 2014; 14(5): 329-42.

[36] Zhong R, Miao L, Zhang H, Tan L, Zhao Y, Tu Y, Angel Prieto M, Simal-Gandara J, Chen L, He C, Cao H. Anti-inflammatory activity of flavonols viainhibiting MAPK and NF-κB signaling pathways in RAW264.7 macrophages. Curr Res Food Sci 2022; 5: 1176-1184.

[37] Alhelwani S, Degirmenci NS, Altıntaş CM, et al. Comparative Analysis of Red Onion-Derived Exosome-Like Nanovesicles and Extract Reveals Sustained Immunomodulatory Effects in LPS/IFN-γ-Stimulated Microglia. Mol Neurobiol 2026; 63: 533.

[38] Ivanov AI, Parkos CA, Nusrat A. Cytoskeletal regulation of epithelial barrier function during inflammation. Am J Pathol 2010; 177(2): 512-24.

[39] Zulkefli N, Che Zahari CNM, Sayuti NH, Kamarudin AA, Saad N, Hamezah HS, Bunawan H, Baharum SN, Mediani A, Ahmed QU, Ismail AFH, Sarian MN. Flavonoids as Potential Wound-Healing Molecules: Emphasis on Pathways Perspective. Int J Mol Sci 2023; 24(5): 4607.

[40] Jergens AE, Parvinroo S, Kopper J, Wannemuehler MJ. Rules of Engagement: Epithelial-Microbe Interactions and Inflammatory Bowel Disease. Front Med (Lausanne) 2021; 8: 669913.

[41] Page MJ, Kell DB, Pretorius E. The Role of Lipopolysaccharide-Induced Cell Signalling in Chronic Inflammation. Chronic Stress (Thousand Oaks) 2022; 6: 24705470221076390.

[42] Gao J, Cao B, Zhao R, Li H, Xu Q, Wei B. Critical Signaling Transduction Pathways and Intestinal Barrier: Implications for Pathophysiology and Therapeutics. Pharmaceuticals (Basel) 2023; 16(9): 1216.

[43] Curson JEB, Liu L, Luo L, Muusse TW, Lucas RM, Gunther KS, Vajjhala PR, Abrol R, Jones A, Kapetanovic R, Stacey KJ, Stow JL, Sweet MJ. TLR4 phosphorylation at tyrosine 672 activates the ERK/c-FOS signaling module for LPS-induced cytokine responses in macrophages. Eur J Immunol 2023; 53(7): e2250056.

[44] Tan F, Liu W, Li T, et al. Plant-derived extracellular vesicles as tools and targets for inflammatory diseases. J Nanobiotechnol 2026; 24: 397.

[45] Samson SC, Khan AM, Mendoza MC. ERK signaling for cell migration and invasion. Front Mol Biosci 2022; 9: 998475.

[46] Huang D, Chen J, Zhao M, Shen H, Jin Q, Xiao D, Peng Z, Chen T, Zhang Y, Rao D, Liu M. Plant-derived extracellular vesicles: composition, function and clinical potential. J Transl Med 2025; 23(1): 1065.

[47] Lialios P, Alimperti S. Role of E-cadherin in epithelial barrier dysfunction: implications for bacterial infection, inflammation, and disease pathogenesis. Front Cell Infect Microbiol 2025; 15: 1506636.

[48] Ju S, Mu J, Dokland T, Zhuang X, Wang Q, Jiang H, Xiang X, Deng ZB, Wang B, Zhang L, Roth M, Zhang HG. Grape exosome-like vesicles induce intestinal stem cells and protect mice from DSS-induced colitis. Molecular Therapy 2013; 21(7): 1345-1357.

[49] Zhang M, Viennois E, Prasad M, Zhang Y, Wang L, Zhang Z, Si TY, Xiao B, Merlin D. Edible Ginger-Derived Nanoparticles Protect Against Intestinal Inflammation and Colitis-Associated Cancer. Cell Host & Microbe 2016; 20(2): 212-227.

Downloads

Published

2026-08-21

Issue

Section

Articles

How to Cite

Onion Peel-Derived Exosome-Like Nanovesicles as a Novel Therapeutic Approach for Inflammatory Bowel Disease. (2026). Journal of Pharmacy and Nutrition Sciences , 16, 29-45. https://doi.org/10.29169/1927-5951.2026.16.04

Similar Articles

61-70 of 147

You may also start an advanced similarity search for this article.