Multimodal neuro-nanotechnology offers a promising approach to overcome the challenges in glioblastoma (GBM) therapy. GBM is a highly aggressive brain cancer with poor survival rates due to the immunosuppressive tumor microenvironment (TME), the blood-brain barrier (BBB), and the presence of immunosuppressive myeloid cells. Current therapies, including surgery, chemotherapy, and radiation, have limited efficacy due to the heterogeneity and resistance of GBM. Immunotherapy, which can stimulate tumor-specific immune responses, is a promising modality but faces challenges in delivering therapies to the TME and overcoming immunosuppressive mechanisms. Multimodal neuro-nanotechnology combines nanotechnology with immunotherapy to enhance the delivery of nanotherapeutics to the GBM TME, enabling precise and controlled drug release. Nanostructures such as spherical nucleic acids (SNAs) and poly(beta-amino ester)/dendrimer-based nanoparticles have shown promise in preclinical models due to their ability to activate antigen-presenting cells and prime T cells. These nanostructures can be tailored to optimize their distribution, TME accumulation, and immunostimulatory effects. The integration of nanotechnology with emerging surgical techniques, such as laser interstitial thermal therapy (LITT), and systemic immunotherapies, including checkpoint inhibitors, can enhance the efficacy of GBM treatment. LITT can increase BBB permeability, allowing for better delivery of immunotherapies and enhancing immune cell infiltration into the TME. Additionally, the use of hydrogels for localized drug delivery can improve therapeutic efficacy by concentrating treatments in the target area and enabling sustained delivery. The cGAS-STING pathway and STAT3 signaling are critical targets for immunotherapy in GBM. Activating the cGAS-STING pathway can enhance immune responses, while inhibiting STAT3 can reduce immunosuppressive myeloid cells. SNAs and other nanotherapeutics can be designed to target these pathways, enhancing the immune response against GBM. Future research should focus on developing multimodal, neuro-nanotechnology-enabled immunotherapies that combine systemic and localized treatments. These therapies, along with advances in nanotechnology and immunotherapy, hold the potential to significantly improve GBM treatment outcomes. The development of clinical-grade STING agonists and the optimization of nanotherapeutic delivery systems are key steps in translating these advancements into effective clinical treatments for GBM.Multimodal neuro-nanotechnology offers a promising approach to overcome the challenges in glioblastoma (GBM) therapy. GBM is a highly aggressive brain cancer with poor survival rates due to the immunosuppressive tumor microenvironment (TME), the blood-brain barrier (BBB), and the presence of immunosuppressive myeloid cells. Current therapies, including surgery, chemotherapy, and radiation, have limited efficacy due to the heterogeneity and resistance of GBM. Immunotherapy, which can stimulate tumor-specific immune responses, is a promising modality but faces challenges in delivering therapies to the TME and overcoming immunosuppressive mechanisms. Multimodal neuro-nanotechnology combines nanotechnology with immunotherapy to enhance the delivery of nanotherapeutics to the GBM TME, enabling precise and controlled drug release. Nanostructures such as spherical nucleic acids (SNAs) and poly(beta-amino ester)/dendrimer-based nanoparticles have shown promise in preclinical models due to their ability to activate antigen-presenting cells and prime T cells. These nanostructures can be tailored to optimize their distribution, TME accumulation, and immunostimulatory effects. The integration of nanotechnology with emerging surgical techniques, such as laser interstitial thermal therapy (LITT), and systemic immunotherapies, including checkpoint inhibitors, can enhance the efficacy of GBM treatment. LITT can increase BBB permeability, allowing for better delivery of immunotherapies and enhancing immune cell infiltration into the TME. Additionally, the use of hydrogels for localized drug delivery can improve therapeutic efficacy by concentrating treatments in the target area and enabling sustained delivery. The cGAS-STING pathway and STAT3 signaling are critical targets for immunotherapy in GBM. Activating the cGAS-STING pathway can enhance immune responses, while inhibiting STAT3 can reduce immunosuppressive myeloid cells. SNAs and other nanotherapeutics can be designed to target these pathways, enhancing the immune response against GBM. Future research should focus on developing multimodal, neuro-nanotechnology-enabled immunotherapies that combine systemic and localized treatments. These therapies, along with advances in nanotechnology and immunotherapy, hold the potential to significantly improve GBM treatment outcomes. The development of clinical-grade STING agonists and the optimization of nanotherapeutic delivery systems are key steps in translating these advancements into effective clinical treatments for GBM.