Intranasal Drug Delivery for Glioblastoma Therapy: A Comprehensive Review

Glioblastoma (GBM) is the most aggressive primary brain malignancy, characterized by rapid proliferation, diffuse infiltration, and poor clinical outcomes despite multimodal treatment strategies. A major limitation in GBM therapy is the presence of the blood–brain barrier (BBB) and the blood–brain tumor barrier, which severely restrict the penetration of therapeutic agents into the brain. Intranasal drug delivery has emerged as a promising non-invasive approach that enables direct transport of drugs from the nasal cavity to the central nervous system via olfactory and trigeminal nerve pathways, thereby bypassing the BBB. This route offers several advantages, including rapid onset of action, reduced systemic exposure, and improved brain targeting. Recent advancements in nanotechnology have significantly enhanced the efficiency of intranasal delivery systems. Polymeric nanoparticles, lipid-based carriers, in situ gels, and biomimetic nanocarriers have been developed to improve drug stability, prolong nasal residence time, and facilitate targeted delivery to glioblastoma cells. In addition to conventional chemotherapeutics such as temozolomide, emerging therapeutic modalities including gene therapy, immunotherapy, and stem cell-based approaches are being explored via the intranasal route. These strategies have demonstrated promising results in preclinical studies, with improved tumor targeting and therapeutic efficacy. Clinical translation of intranasal therapies is currently underway, with agents such as intranasal perillyl alcohol (NEO100) showing encouraging safety and efficacy profiles in early-phase trials. However, challenges including mucociliary clearance, limited dosing volume, and anatomical variability remain significant barriers. Overall, intranasal drug delivery represents a transformative strategy for GBM therapy, with the potential to improve patient outcomes through targeted, non-invasive treatment approaches.