The blood-brain barrier (BBB) and blood-tumor barrier (BTB) pose significant challenges to effective drug delivery for glioblastoma multiforme (GBM), a highly aggressive primary brain tumor. Nanoparticle (NP)-based combinational strategies have emerged as promising approaches to overcome these barriers and enhance drug penetration into the brain parenchyma. This review discusses various NP-based combinatorial approaches, including cell-based drug delivery, viral drug delivery, focused ultrasound, magnetic fields, and intranasal drug delivery. Cell-based drug delivery uses engineered cells as carriers for NPs, leveraging their migratory and homing capabilities. Viral drug delivery employs engineered viral vectors to deliver therapeutic genes or payloads to specific cells within the GBM microenvironment. Focused ultrasound, combined with microbubbles or NPs, temporarily disrupts the BBB to increase drug permeability. Magnetic field-guided drug delivery uses magnetic NPs to facilitate targeted drug delivery under an external magnetic field. Intranasal drug delivery offers a minimally invasive route to bypass the BBB and deliver therapeutic agents directly to the brain via the olfactory and trigeminal pathways. By combining these strategies, synergistic effects can enhance drug delivery efficiency, improve therapeutic efficacy, and reduce off-target effects. Future research should focus on optimizing NP design, exploring new combination strategies, and advancing preclinical and clinical investigations to translate NP-based combination therapies for GBM.The blood-brain barrier (BBB) and blood-tumor barrier (BTB) pose significant challenges to effective drug delivery for glioblastoma multiforme (GBM), a highly aggressive primary brain tumor. Nanoparticle (NP)-based combinational strategies have emerged as promising approaches to overcome these barriers and enhance drug penetration into the brain parenchyma. This review discusses various NP-based combinatorial approaches, including cell-based drug delivery, viral drug delivery, focused ultrasound, magnetic fields, and intranasal drug delivery. Cell-based drug delivery uses engineered cells as carriers for NPs, leveraging their migratory and homing capabilities. Viral drug delivery employs engineered viral vectors to deliver therapeutic genes or payloads to specific cells within the GBM microenvironment. Focused ultrasound, combined with microbubbles or NPs, temporarily disrupts the BBB to increase drug permeability. Magnetic field-guided drug delivery uses magnetic NPs to facilitate targeted drug delivery under an external magnetic field. Intranasal drug delivery offers a minimally invasive route to bypass the BBB and deliver therapeutic agents directly to the brain via the olfactory and trigeminal pathways. By combining these strategies, synergistic effects can enhance drug delivery efficiency, improve therapeutic efficacy, and reduce off-target effects. Future research should focus on optimizing NP design, exploring new combination strategies, and advancing preclinical and clinical investigations to translate NP-based combination therapies for GBM.