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Here, we report the rational design of a multifunctional nanoplatform, Dox[iRGD-GO@AgNP], integrating graphene oxide (GO), silver nanoparticles (AgNPs), and a cyclic iRGD tumor-penetrating peptide to enhance doxorubicin (Dox) transport, tumor penetration, and intracellular delivery. Comprehensive physicochemical characterization confirmed successful synthesis, surface functionalization, colloidal stability, and efficient drug loading. In two-dimensional C6 glioma cell monolayers, cyclic iRGD-functionalized nanohybrids demonstrated significantly enhanced intracellular Dox accumulation compared to free drug and nontargeted controls. These effects were further amplified in three-dimensional glioma spheroids, where Dox[iRGD-GO@AgNP] achieved deep tumor penetration (&amp;gt;80 \u00b5m) and more homogeneous intratumoral distribution. Enhanced delivery translated into superior therapeutic efficacy, as evidenced by reduced cell viability, increased membrane damage, upregulation of apoptosis-related markers (p53 and caspase-3 &amp;9), and pronounced morphological disruption confirmed by fluorescence imaging and electron microscopy. To evaluate endothelial transport, a Transwell-based bEnd.3 BBB model was established and validated by transendothelial electrical resistance measurements and tight junction imaging. Cyclic iRGD-functionalized nanohybrids exhibited significantly enhanced transendothelial transport while preserving BBB integrity, indicating ligand-mediated transport rather than nonspecific barrier disruption. Importantly, improved BBB traversal resulted in increased drug accumulation in downstream glioma cells and spheroids. These composites showed anti-angiogenic properties in ovo CAM model. Overall, this study integrates rational nanocomposite design with a hierarchical in vitro evaluation framework spanning material characterization, tumor-relevant 2D and 3D models, and BBB transport. The Dox[iRGD-GO@AgNP] platform addresses key delivery and efficacy barriers in glioblastoma and provides a translationally relevant strategy for the development of BBB-penetrating nanotherapeutics.<\/jats:p>","DOI":"10.1021\/acsabm.6c00709","type":"journal-article","created":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T10:02:00Z","timestamp":1791799320000},"page":"10129-10151","source":"Crossref","is-referenced-by-count":0,"title":["iRGD-Functionalized Graphene\u2013Silver Nanohybrids for Enhanced Blood\u2013Brain Barrier Transport and Tumor Penetration in Glioma Models"],"prefix":"10.1021","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2389-0814","authenticated-orcid":true,"given":"Vianni","family":"Chopra","sequence":"first","affiliation":[{"name":"Tecnologico de Monterrey , , Av. Eugenio Garza Sada 2501 Sur , , ,","place":["Monterrey, NL, Mexico, 64849"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jocelyn Alexandra G\u00f3mez","family":"Siono","sequence":"additional","affiliation":[{"name":"Tecnologico de Monterrey , , Av. Eugenio Garza Sada 2501 Sur , , ,","place":["Monterrey, NL, Mexico, 64849"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-6007-2338","authenticated-orcid":true,"given":"Carlos Eduardo","family":"Fajardo Barocio","sequence":"additional","affiliation":[{"name":"Tecnologico de Monterrey , , Av. Eugenio Garza Sada 2501 Sur , , ,","place":["Monterrey, NL, Mexico, 64849"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5400-5638","authenticated-orcid":true,"given":"Gaurav","family":"Chauhan","sequence":"additional","affiliation":[{"name":"Tecnologico de Monterrey , , Av. Eugenio Garza Sada 2501 Sur , , ,","place":["Monterrey, NL, Mexico, 64849"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,10,12]]},"reference":[{"issue":"17","key":"2026110201080510600_cit1","doi-asserted-by":"publisher","first-page":"1842","DOI":"10.1001\/jama.2013.280319","article-title":"Glioblastoma and Other Malignant Gliomas: A Clinical Review","volume":"310","author":"Omuro","year":"2013","journal-title":"JAMA"},{"issue":"11","key":"2026110201080510600_cit2","doi-asserted-by":"publisher","first-page":"696","DOI":"10.1038\/s41571-021-00529-6","article-title":"The blood-tumour barrier in cancer biology and therapy","volume":"18","author":"Steeg","year":"2021","journal-title":"Nat. Rev. Clin. 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