The article discusses the potential of multimodal neuro-nanotechnology in overcoming the challenges of glioblastoma (GBM) therapy. GBM is a highly aggressive form of brain cancer characterized by poor survival rates and resistance to current treatments. The authors highlight the need for innovative approaches that can enhance the immune system's ability to recognize and eliminate cancer cells while minimizing immune suppression. Key aspects of these therapies include the controlled delivery of structurally defined nanotherapeutics into the GBM tumor microenvironment (TME) and the integration of nanotechnology with existing systemic immunotherapies. The article reviews the physiological barriers to GBM treatment, such as the blood-brain barrier (BBB) and the infiltrative nature of the disease, which limit the efficacy of most systemic therapies. It also discusses the immunosuppressive TME, where the presence of immunosuppressive myeloid cells and the low abundance of effector immune responses pose significant challenges. The authors emphasize the importance of reprogramming myeloid cells to enhance effector T cell activity and the role of emerging targets like the cGAS-STING pathway and PD-1/PD-L1 checkpoints in overcoming these barriers. Recent advances in nanotechnology, such as spherical nucleic acids (SNAs) and poly(beta-amino ester)/dendrimer-based nanoparticles, are highlighted for their potential in delivering immunostimulatory agents and improving therapeutic efficacy. These nanostructures can be designed to activate the cGAS-STING pathway, enhance immune responses, and modulate the TME. The article also explores the use of local hydrogel-mediated delivery systems, such as dextran-dendrimer hydrogels, to deliver therapies directly to the tumor site, enhancing their effectiveness and reducing off-target effects. Additionally, the article discusses the potential of minimally invasive surgical techniques like laser interstitial thermal therapy (LITT) and focused ultrasound (FUS) to ablate tumors and modulate the BBB, thereby improving the delivery of systemic treatments. The authors conclude by calling for collaborative research efforts to develop and translate these advanced technologies into clinical practice, aiming to significantly improve the prognosis and quality of life for GBM patients.The article discusses the potential of multimodal neuro-nanotechnology in overcoming the challenges of glioblastoma (GBM) therapy. GBM is a highly aggressive form of brain cancer characterized by poor survival rates and resistance to current treatments. The authors highlight the need for innovative approaches that can enhance the immune system's ability to recognize and eliminate cancer cells while minimizing immune suppression. Key aspects of these therapies include the controlled delivery of structurally defined nanotherapeutics into the GBM tumor microenvironment (TME) and the integration of nanotechnology with existing systemic immunotherapies. The article reviews the physiological barriers to GBM treatment, such as the blood-brain barrier (BBB) and the infiltrative nature of the disease, which limit the efficacy of most systemic therapies. It also discusses the immunosuppressive TME, where the presence of immunosuppressive myeloid cells and the low abundance of effector immune responses pose significant challenges. The authors emphasize the importance of reprogramming myeloid cells to enhance effector T cell activity and the role of emerging targets like the cGAS-STING pathway and PD-1/PD-L1 checkpoints in overcoming these barriers. Recent advances in nanotechnology, such as spherical nucleic acids (SNAs) and poly(beta-amino ester)/dendrimer-based nanoparticles, are highlighted for their potential in delivering immunostimulatory agents and improving therapeutic efficacy. These nanostructures can be designed to activate the cGAS-STING pathway, enhance immune responses, and modulate the TME. The article also explores the use of local hydrogel-mediated delivery systems, such as dextran-dendrimer hydrogels, to deliver therapies directly to the tumor site, enhancing their effectiveness and reducing off-target effects. Additionally, the article discusses the potential of minimally invasive surgical techniques like laser interstitial thermal therapy (LITT) and focused ultrasound (FUS) to ablate tumors and modulate the BBB, thereby improving the delivery of systemic treatments. The authors conclude by calling for collaborative research efforts to develop and translate these advanced technologies into clinical practice, aiming to significantly improve the prognosis and quality of life for GBM patients.