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Radiation resistance in glioblastoma (GBM) poses a persistent clinical hurdle, driven in part by hyperactivated EGFR and NF-κB signaling. 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-along with the TCGA database-identified coordinated EGFR and NF-κB (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-κB 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.