{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T23:11:02Z","timestamp":1792797062536,"version":"4.5.0"},"reference-count":232,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2025,11,22]],"date-time":"2025-11-22T00:00:00Z","timestamp":1763769600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background\/Objectives: Approximately 50% of infertility cases are attributable to male factors; yet conventional semen examination can not identify the molecular abnormalities that hinder sperm functionality. Extracellular vesicles (EVs) derived from sperm, such as testicular EVs, prostasomes, and epididymosomes, have become important modulators of oocyte activation, sperm maturation, capacitation, acrosome stability, motility, and early embryonic development. This study aimed to evaluate the potential diagnostic and translational uses of sperm-associated extracellular vesicles (EVs) in male infertility and assisted reproduction, while also consolidating recent insights on their origins, composition, and functional significance. Methods: A focused narrative search of PubMed (2000\u20132025) was conducted using backward and forward citation tracking. Studies that qualified included human clinical cohorts, functional sperm extracellular vesicle tests, and omics analyses using MISEV-aligned extracellular vesicle isolation and characterisation methodologies. When human mechanistic understanding was constrained, knowledge from animal research was selectively integrated. Results: The cargo signatures specific to the source identified in sperm-derived and seminal EVs encompass proteins, small RNAs, lipids, and enzymatic modules that govern sperm maturation, capacitation, acrosome reaction, redox balance, calcium signalling, zona binding, and DNA integrity. Density-resolved seminal extracellular vesicle subfractions (EV-H\/EV-M\/EV-L) have unique functional and proteomic characteristics linked to progesterone-induced hyperactivation, oxidative stress, and motility. Asthenozoospermia and oligoasthenoteratozoospermia are associated with changes in extracellular vesicle composition, reduced embryonic developmental potential, compromised oocyte activation (related to PLC\u03b6), and increased sperm DNA fragmentation. Numerous EV-related miRNA and protein signatures may predict TESE results, identify functional sperm anomalies not recognised by conventional semen analysis, and differentiate between obstructive and non-obstructive azoospermia. Conclusions: The available findings indicate that sperm-derived extracellular vesicles are significant functional regulators of sperm physiology and may serve as valuable non-invasive indicators for male infertility. The standardisation of EV isolation, characterisation, and clinical validation is essential prior to widespread use; nonetheless, their integration into liquid biopsy methods and assisted reproductive technology processes represents a significant improvement.<\/jats:p>","DOI":"10.3390\/genes16121400","type":"journal-article","created":{"date-parts":[[2025,11,24]],"date-time":"2025-11-24T09:02:07Z","timestamp":1763974927000},"page":"1400","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Sperm-Derived Extracellular Vesicles (Sperm-EVs), Emerging Biomarkers and Functional Modulators in Male Infertility and Assisted Reproduction"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9477-7619","authenticated-orcid":false,"given":"Charalampos","family":"Voros","sequence":"first","affiliation":[{"name":"1st Department of Obstetrics and Gynecology, \u2018Alexandra\u2019 General Hospital, National and Kapodistrian University of Athens, 80 Vasilissis Sofias Avenue, 11528 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fotios","family":"Chatzinikolaou","sequence":"additional","affiliation":[{"name":"Laboratory of Forensic Medicine and Toxicology, School of Medicine, Aristotle University of Thessaloniki, 54124 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georgios","family":"Papadimas","sequence":"additional","affiliation":[{"name":"Athens Medical School, National and Kapodistrian University of Athens, 15772 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Spyridon","family":"Polykalas","sequence":"additional","affiliation":[{"name":"Athens Medical School, National and Kapodistrian University of Athens, 15772 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1220-6594","authenticated-orcid":false,"given":"Despoina","family":"Mavrogianni","sequence":"additional","affiliation":[{"name":"1st Department of Obstetrics and Gynecology, \u2018Alexandra\u2019 General Hospital, National and Kapodistrian University of Athens, 80 Vasilissis Sofias Avenue, 11528 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aristotelis-Marios","family":"Koulakmanidis","sequence":"additional","affiliation":[{"name":"1st Department of Obstetrics and Gynecology, \u2018Alexandra\u2019 General Hospital, National and Kapodistrian University of Athens, 80 Vasilissis Sofias Avenue, 11528 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diamantis","family":"Athanasiou","sequence":"additional","affiliation":[{"name":"IVF Athens Reproduction Center, 15123 Maroussi, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vasiliki","family":"Kanaka","sequence":"additional","affiliation":[{"name":"1st Department of Obstetrics and Gynecology, \u2018Alexandra\u2019 General Hospital, National and Kapodistrian University of Athens, 80 Vasilissis Sofias Avenue, 11528 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Kanaka","sequence":"additional","affiliation":[{"name":"1st Department of Obstetrics and Gynecology, \u2018Alexandra\u2019 General Hospital, National and Kapodistrian University of Athens, 80 Vasilissis Sofias Avenue, 11528 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7563-4305","authenticated-orcid":false,"given":"Kyriakos","family":"Bananis","sequence":"additional","affiliation":[{"name":"King\u2019s College Hospitals NHS Foundation Trust, London SE5 9RS, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonia","family":"Athanasiou","sequence":"additional","affiliation":[{"name":"IVF Athens Reproduction Center, 15123 Maroussi, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aikaterini","family":"Athanasiou","sequence":"additional","affiliation":[{"name":"IVF Athens Reproduction Center, 15123 Maroussi, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9723-5054","authenticated-orcid":false,"given":"Ioannis","family":"Papapanagiotou","sequence":"additional","affiliation":[{"name":"Athens Medical School, National and Kapodistrian University of Athens, 15772 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dimitrios","family":"Vaitsis","sequence":"additional","affiliation":[{"name":"Athens Medical School, National and Kapodistrian University of Athens, 15772 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charalampos","family":"Tsimpoukelis","sequence":"additional","affiliation":[{"name":"1st Department of Obstetrics and Gynecology, \u2018Alexandra\u2019 General Hospital, National and Kapodistrian University of Athens, 80 Vasilissis Sofias Avenue, 11528 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Anastasia","family":"Daskalaki","sequence":"additional","affiliation":[{"name":"1st Department of Obstetrics and Gynecology, \u2018Alexandra\u2019 General Hospital, National and Kapodistrian University of Athens, 80 Vasilissis Sofias Avenue, 11528 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8280-7796","authenticated-orcid":false,"given":"Marianna","family":"Theodora","sequence":"additional","affiliation":[{"name":"1st Department of Obstetrics and Gynecology, \u2018Alexandra\u2019 General Hospital, National and Kapodistrian University of Athens, 80 Vasilissis Sofias Avenue, 11528 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikolaos","family":"Thomakos","sequence":"additional","affiliation":[{"name":"1st Department of Obstetrics and Gynecology, \u2018Alexandra\u2019 General Hospital, National and Kapodistrian University of Athens, 80 Vasilissis Sofias Avenue, 11528 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2106-5922","authenticated-orcid":false,"given":"Panagiotis","family":"Antsaklis","sequence":"additional","affiliation":[{"name":"1st Department of Obstetrics and Gynecology, \u2018Alexandra\u2019 General Hospital, National and Kapodistrian University of Athens, 80 Vasilissis Sofias Avenue, 11528 Athens, 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