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Despite shared structural features, EVs derived from bacteria, plants, and mammalian cells differ substantially in their biogenesis, molecular composition, and immunological functions. EV formation pathways generate vesicles with distinct cargo profiles, including pathogen-associated molecular patterns (PAMPs) in bacterial EVs, regulatory small RNAs in plant-derived vesicles, and cytokines, microRNAs, and antigen-presenting complexes in mammalian EVs. Differences in cargo result in divergent immune outcomes. Bacterial EVs predominantly activate innate immunity via pattern recognition receptors such as Toll-like receptors, whereas plant-derived EVs exhibit low immunogenicity and mediate cross-kingdom RNA interference. In contrast, mammalian EVs primarily regulate immune responses by modulating antigen presentation and cytokine signaling. These findings support a framework in which EV origin determines immunological function and therapeutic applicability. This perspective highlights the importance of selecting appropriate EV sources for vaccine development, regenerative medicine, and targeted delivery strategies, while addressing current challenges related to heterogeneity, standardization, and safety.<\/jats:p>","DOI":"10.3390\/biom16060919","type":"journal-article","created":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T10:01:17Z","timestamp":1782813677000},"page":"919","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Choosing the Right Extracellular Vesicle: Cross-Kingdom Immunological Functions Linking Molecular Mechanisms to Therapeutic Applications"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0548-1416","authenticated-orcid":false,"given":"Bogl\u00e1rka","family":"Schilling-T\u00f3th","sequence":"first","affiliation":[{"name":"Department of Physiology and Biochemistry, University of Veterinary Medicine Budapest, Istv\u00e1n u. 2., H-1078 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daiana","family":"Alymbaeva","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biochemistry, University of Veterinary Medicine Budapest, Istv\u00e1n u. 2., H-1078 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-2470-4792","authenticated-orcid":false,"given":"Kriszti\u00e1n","family":"N\u00e9meth","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biochemistry, University of Veterinary Medicine Budapest, Istv\u00e1n u. 2., H-1078 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1555-8766","authenticated-orcid":false,"given":"D\u00e1vid S\u00e1ndor","family":"Kiss","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biochemistry, University of Veterinary Medicine Budapest, Istv\u00e1n u. 2., H-1078 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0168-4753","authenticated-orcid":false,"given":"Istv\u00e1n","family":"T\u00f3th","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biochemistry, University of Veterinary Medicine Budapest, Istv\u00e1n u. 2., H-1078 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G\u00e1bor","family":"And\u00f3cs","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Infectious Diseases, University of Veterinary Medicine Budapest, Hung\u00e1ria krt. 23-25., H-1143 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ondra\u0161ovi\u010dov\u00e1","family":"Silvia","sequence":"additional","affiliation":[{"name":"Department of Biology and Physiology, University of Veterinary Medicine and Pharmacy in Ko\u0161ice, Komensk\u00e9ho 73, 04181 Ko\u0161ice, Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brigitta","family":"Tagscherer-Micska","sequence":"additional","affiliation":[{"name":"Department of Immunology, Institute of Biology, E\u00f6tv\u00f6s L\u00f3r\u00e1nd University, P\u00e1zm\u00e1ny P\u00e9ter s\u00e9t\u00e1ny 1\/a, H-1117 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-8842-1798","authenticated-orcid":false,"given":"Gergely","family":"J\u00f3cs\u00e1k","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biochemistry, University of Veterinary Medicine Budapest, Istv\u00e1n u. 2., H-1078 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tibor","family":"Bartha","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biochemistry, University of Veterinary Medicine Budapest, Istv\u00e1n u. 2., H-1078 Budapest, Hungary"},{"name":"National Laboratory of Infectious Animal Diseases, Antimicrobial Resistance, Veterinary Public Health and Food Chain Safety, University of Veterinary Medicine, H-1078 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e12404","DOI":"10.1002\/jev2.12404","article-title":"Minimal information for studies of extracellular vesicles (MISEV2023): From basic to advanced approaches","volume":"13","author":"Welsh","year":"2024","journal-title":"J. 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