Glioblastoma (GBM) is the most aggressive and treatment-resistant primary brain tumor in adults. Conventional therapies offer limited benefit due to the tumor's heterogeneity, invasive nature, and the presence of the blood-brain barrier, which restricts therapeutic access. Nucleic acid (NA)-based therapies, including small interfering RNA, microRNA, antisense oligonucleotides, splice-switching oligonucleotides, and CRISPR-based systems, have emerged as promising tools to modulate oncogenic pathways and overcome resistance mechanisms at the genetic level. However, effective delivery remains the primary challenge in translating these therapies into clinical success. This review examines the current landscape of NA-based strategies for GBM, with a focus on innovative delivery systems designed to navigate biological barriers and enhance therapeutic precision. We highlight clinical progress made with nanocarrier platforms such as liposomes, lipid nanoparticles, and exosome-based systems, and evaluate their safety, specificity, and delivery efficiency. Additionally, we discuss the most promising preclinical advances, including multifunctional, targeted, and stimuli-responsive carriers, that demonstrate strong potential for clinical translation. Our analysis underscores that the therapeutic efficacy of NA approaches in GBM is inseparable from the sophistication of their delivery platforms. Moving forward, the integration of rationally designed carriers with gene-targeted payloads holds the key to unlocking the full potential of precision medicine in GBM.
