{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T01:52:22Z","timestamp":1781488342129,"version":"3.54.1"},"reference-count":125,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2026,6,14]],"date-time":"2026-06-14T00:00:00Z","timestamp":1781395200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Glioblastoma (GBM) is one of the most aggressive human cancers, with therapeutic failure driven by pronounced intratumoral heterogeneity, microenvironmental plasticity, immune suppression, blood\u2013brain barrier (BBB)-related pharmacological constraints, and adaptive resistance mechanisms. A major limitation in GBM research is the lack of a human-relevant experimental system able to reproduce these dynamic features while generating interpretable, multimodal datasets. In this context, we propose a testable organ-on-chip (OoC)-extracellular vesicle (EV)-deep learning (DL) framework in which patient-derived GBM cells, endothelial cells, astrocytes, pericytes, stromal cells, and immune components are organized within perfused microphysiological systems. EVs are selectively and temporally harvested from defined compartments, and imaging, barrier-function, sensor, and EV-cargo data are integrated through modality-specific and multimodal DL architectures. This framework is intended not as an immediately validated clinical tool but as an experimental roadmap for linking EV-mediated communication to measurable phenotypes such as BBB disruption, invasion, immune reprogramming, and drug response. We critically discuss the technical requirements of BBB-on-chip systems, EV source attribution, immune-component integration, DL model selection, data scarcity, overfitting, batch effects, domain shift, regulatory barriers, cost, throughput, and reproducibility. By repositioning OoC-EV-DL integration as a staged translational strategy rather than a clinically established solution, this work aims to define a realistic and biologically grounded route for advancing precision oncology in GBM.<\/jats:p>","DOI":"10.3390\/cells15121080","type":"journal-article","created":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T00:44:58Z","timestamp":1781484298000},"page":"1080","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Decoding Glioblastoma Complexity Through Extracellular Vesicles, Organ-on-Chip Models, and Deep Learning"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4004-9338","authenticated-orcid":false,"given":"Domenico","family":"Amato","sequence":"first","affiliation":[{"name":"Department of Mathematics and Computer Science, University of Palermo, Via Archirafi 34, 90123 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2131-563X","authenticated-orcid":false,"given":"Giuseppa","family":"D\u2019Amico","sequence":"additional","affiliation":[{"name":"Section of Human Anatomy and Histology, Department of Biomedicine, Neuroscience and Advanced Diagnostics (BIND), University of Palermo, Via del Vespro 129, 90127 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0999-6345","authenticated-orcid":false,"given":"Salvatore","family":"Calderaro","sequence":"additional","affiliation":[{"name":"Department of Mathematics and Computer Science, University of Palermo, Via Archirafi 34, 90123 Palermo, Italy"},{"name":"Department of Physics and Chemistry, University of Palermo, Via Archirafi 36, 90123 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7566-4309","authenticated-orcid":false,"given":"Alessandra Maria","family":"Vitale","sequence":"additional","affiliation":[{"name":"Section of Human Anatomy and Histology, Department of Biomedicine, Neuroscience and Advanced Diagnostics (BIND), University of Palermo, Via del Vespro 129, 90127 Palermo, Italy"},{"name":"Euro-Mediterranean Institute of Science and Technology (IEMEST), Via Michele Miraglia, 90139 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0960-8712","authenticated-orcid":false,"given":"Pierlorenzo","family":"Veiceschi","sequence":"additional","affiliation":[{"name":"Section of Human Anatomy and Histology, Department of Biomedicine, Neuroscience and Advanced Diagnostics (BIND), University of Palermo, Via del Vespro 129, 90127 Palermo, Italy"},{"name":"Department of Neurosurgery, National Relevance and High 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Italy"},{"name":"Euro-Mediterranean Institute of Science and Technology (IEMEST), Via Michele Miraglia, 90139 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1602-0693","authenticated-orcid":false,"given":"Giosu\u00e8","family":"Lo Bosco","sequence":"additional","affiliation":[{"name":"Department of Mathematics and Computer Science, University of Palermo, Via Archirafi 34, 90123 Palermo, Italy"},{"name":"Euro-Mediterranean Institute of Science and Technology (IEMEST), Via Michele Miraglia, 90139 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1231","DOI":"10.1093\/neuonc\/noab106","article-title":"The 2021 WHO Classification of Tumors of the Central Nervous System: A 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