Gliomas are the most common primary tumors of the central nervous system; among them, glioblastoma multiforme stands out as the most aggressive and lethal subtype, characterized by high therapeutic resistance and frequent recurrences. Glioblastoma’s complex pathology is driven by biological and molecular factors that compromise conventional therapies, including blood-brain and blood-tumor barriers, angiogenesis, immune evasion, and aberrant signaling pathways, along with genetic drivers of drug resistance. In cancer therapy, mesoporous silica nanoparticles (MSNs) have shown promise as nanocarriers thanks to the unique attributes of their mesostructure, including large surfaces, uniform pore sizes, high loading efficiency, and flexibility of chemical modifications. Several studies have proposed MSNs to address a number of challenges facing drug delivery in gliomas, including limited penetration across the blood-brain barrier, non-specific biodistribution, and systemic adverse reactions. Moreover, MSNs can be functionalized with tumor-targeting ligands so that cancer cells are selectively taken up, while they can also release therapeutic agents in response to internal and external stimuli, enabling controlled drug delivery within tumor microenvironments. Herein, we review the integration of the MSN-based delivery approach with advances in molecular oncology to improve clinical outcomes for glioma therapeutics, while highlighting the concerns around their limited clinical translation and potential toxicity.