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To recapitulate post-radiation tumor recurrence, we engineered radioresistant glioblastoma stem cells (GSCs) from U87-derived GSCs via 13 cycles of 5Gy irradiation (IR), yielding differentiated radioresistant progeny cells (Diff) that mimic the aggressive phenotype of recurrent GBM. Integrative analysis of RNA sequencing data from parental U87 cells, GSCs, and Diff cells\u2014along with the TCGA database\u2014identified coordinated EGFR and NF-\u03baB (RelA\/p65) signaling as central mediators of therapeutic resistance. Leveraging this insight, we designed iRGD-modified liposomes (iRGD-OB-LP) for targeted co-delivery of Osimertinib (EGFR inhibitor) and Bortezomib (NF-\u03baB suppressor). These liposomes exhibited enhanced tumor penetration, sustained release kinetics, and dual pathway inhibition, which collectively prolonged radiation-induced DNA damage, attenuated cancer stemness, and amplified apoptotic cell death. In vivo, iRGD-OB-LP achieved tumor-specific biodistribution, synergized with radiotherapy to suppress tumor progression, and extended survival without systemic toxicity. By bridging a radioresistant GBM model with mechanism-driven nanotherapy, this work provides a translatable blueprint for dismantling therapeutic resistance in GBM through precision multi-targeting.<\/jats:p>","DOI":"10.1038\/s41419-025-08083-0","type":"journal-article","created":{"date-parts":[[2025,10,21]],"date-time":"2025-10-21T13:01:54Z","timestamp":1761051714000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["GSCs differentiation model-informed nanotherapy: dual-functional brain-targeting liposomes with iRGD modification for co-delivery of osimertinib and bortezomib to combat radioresistant glioblastoma"],"prefix":"10.1038","volume":"16","author":[{"given":"Cuiying","family":"Xie","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jieyi","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Han","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ancheng","family":"Gu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wanwen","family":"Cao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangcao","family":"Yao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiyong","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuchun","family":"Niu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-3310-8716","authenticated-orcid":false,"given":"Jianlong","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4604-8355","authenticated-orcid":false,"given":"Zhongyuan","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4879-6987","authenticated-orcid":false,"given":"Bohong","family":"Cen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,10,21]]},"reference":[{"key":"8083_CR1","first-page":"299","volume":"70","author":"AC Tan","year":"2020","unstructured":"Tan AC, Ashley DM, L\u00f3pez GY, Malinzak M, Friedman HS, Khasraw M. 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