{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T13:15:40Z","timestamp":1785417340374,"version":"3.56.0"},"reference-count":56,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2026,5,10]],"date-time":"2026-05-10T00:00:00Z","timestamp":1778371200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"German Research Foundation","doi-asserted-by":"publisher","award":["465409392"],"award-info":[{"award-number":["465409392"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"award":["465409392"],"award-info":[{"award-number":["465409392"]}],"id":[{"id":"https:\/\/ror.org\/018mejw64","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Severe traumatic brain injury (TBI) is a leading cause of mortality and long-term disability in polytrauma (PT) patients, and its clinical outcome remains difficult to predict due to clinical heterogeneity and secondary injury mechanisms. Current diagnostic and prognostic approaches based on clinical assessment and imaging are limited, particularly in PT where neurological evaluation is often impaired. This study aimed to compare plasma- and extracellular vesicle (EV)-associated microRNA (miRNA) signatures in patients with severe TBI and healthy controls to identify their potential as minimally invasive biomarkers and to improve understanding of molecular responses. For profiling circulating miRNAs, blood samples were collected at \u22643 h and at 48 h after admission. In the screening phase, plasma samples of n = 15 patients with severe isolated TBI (Abbreviated Injury Scale [AIS]Head \u2265 4, all other AIS \u2264 1) and n = 15 age- and sex-matched healthy controls were pooled (n = 5\/pool) and subjected to next-generation sequencing (NGS). In the following validation phase, n = 25 severely injured trauma patients (Injury Severity Score [ISS] \u2265 16) were enrolled and stratified into PT without TBI (PT; AISHead = 0; n = 13) and isolated TBI (n = 12). Differentially expressed candidate miRNAs identified in the screening phase were validated in individual plasma and EV samples using reverse transcription droplet digital polymerase chain reaction (RT-ddPCR). Functional enrichment and pathway analyses were performed using miRNet. NGS identified more differentially expressed miRNAs in plasma (ER: 103; 48 h: 65) than in EVs (Emergency Room [ER]: 14; 48 h: 32). Functional enrichment analysis indicated associations with pathways related to cellular stress, senescence, growth factor signaling, transcriptional regulation, and apoptosis. In validation, 12 of 16 plasma and 10 of 15 EV-miRNAs were confirmed as differentially expressed in TBI patients; among these, three plasma and four EV miRNAs differed between TBI and PT. After adjustment, most plasma miRNAs were associated with injury severity rather than group status. EV miRNA profiles showed heterogeneous patterns, with miR-1469 associated with TBI group status in adjusted analysis, while miR-1237-5p was linked to injury severity and other EV miRNAs showed no consistent group-specific effects. Plasma miRNAs mainly correlated with systemic injury markers, whereas EV miR-1469 showed a moderate association with the Glasgow Coma Scale (GCS). Overall, circulating miRNA profiles after injury appear to be predominantly influenced by systemic trauma severity rather than TBI-specific effects. Plasma miRNAs mainly reflected general injury burden, whereas EV-associated miRNAs showed more heterogeneous patterns, with miR-1469 emerging as a candidate associated with TBI after adjustment for clinical covariates. These findings suggest that EV-derived miRNAs, particularly miR-1469, may provide more targeted signals related to brain injury and warrant further investigation.<\/jats:p>","DOI":"10.3390\/ijms27104248","type":"journal-article","created":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T07:49:09Z","timestamp":1778572149000},"page":"4248","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Extracellular Vesicle and Plasma miRNAs as Candidate Biomarkers of Traumatic Brain Injury in the Context of Polytrauma"],"prefix":"10.3390","volume":"27","author":[{"given":"Cora Rebecca","family":"Schindler","sequence":"first","affiliation":[{"name":"Department of Trauma Surgery and Orthopedics, University Hospital of Goethe University Frankfurt, 60323 Frankfurt am Main, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9728-4032","authenticated-orcid":false,"given":"Dirk","family":"Henrich","sequence":"additional","affiliation":[{"name":"Department of Trauma Surgery and Orthopedics, University Hospital of Goethe University Frankfurt, 60323 Frankfurt am Main, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lena","family":"Kr\u00e4mer","sequence":"additional","affiliation":[{"name":"Department of Trauma Surgery and Orthopedics, University Hospital of Goethe University Frankfurt, 60323 Frankfurt am Main, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Inna","family":"Schaible","sequence":"additional","affiliation":[{"name":"Department of Trauma Surgery and Orthopedics, University Hospital of Goethe University Frankfurt, 60323 Frankfurt am Main, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason-Alexander","family":"H\u00f6rauf","sequence":"additional","affiliation":[{"name":"Department of Trauma Surgery and Orthopedics, University Hospital of Goethe University Frankfurt, 60323 Frankfurt am Main, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aileen","family":"Ritter","sequence":"additional","affiliation":[{"name":"Department of Trauma Surgery and Orthopedics, University Hospital of Goethe University Frankfurt, 60323 Frankfurt am Main, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philipp","family":"St\u00f6rmann","sequence":"additional","affiliation":[{"name":"Department of Trauma Surgery and Orthopedics, University Hospital of Goethe University Frankfurt, 60323 Frankfurt am Main, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rald Victor Maria","family":"Groven","sequence":"additional","affiliation":[{"name":"Department of Trauma and Reconstructive Surgery, University Hospital RWTH Aachen, 52074 Aachen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2359-6516","authenticated-orcid":false,"given":"Markus","family":"Huber-Lang","sequence":"additional","affiliation":[{"name":"Institute of Clinical and Experimental Trauma-Immunology, University Hospital of Ulm, 89081 Ulm, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3677-2910","authenticated-orcid":false,"given":"Ingo","family":"Marzi","sequence":"additional","affiliation":[{"name":"Department of Trauma Surgery and Orthopedics, University Hospital of Goethe University Frankfurt, 60323 Frankfurt am Main, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0362-4727","authenticated-orcid":false,"given":"Liudmila","family":"Leppik","sequence":"additional","affiliation":[{"name":"Department of Trauma Surgery and Orthopedics, University Hospital of Goethe University Frankfurt, 60323 Frankfurt am Main, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"154147","DOI":"10.1016\/j.jcrc.2022.154147","article-title":"Predicting mortality in moderate-severe TBI patients without early withdrawal of life-sustaining treatments including ICU complications: The MYSTIC-score","volume":"72","author":"Chang","year":"2022","journal-title":"J. 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