Advancing Gene Therapy for Glioblastoma: Cutting-Edge Strategies and Precision Delivery in Neurosurgical Oncology

Abstract Glioblastoma multiforme (GBM) is an aggressive and invasive brain tumor, notorious for its genetic heterogeneity and resistance to conventional therapies, including surgery, chemotherapy, and radiotherapy. Despite aggressive multimodal treatments, survival outcomes remain poor, with a median survival time of only 12 to 15 months, and almost all patients experience tumor recurrence. One of the most significant challenges in treating GBM is its infiltrative nature, which makes complete surgical resection impossible and limits the effectiveness of chemotherapy due to the blood-brain barrier. Gene therapy has emerged as a promising alternative, offering the ability to target GBM at the molecular level by delivering genetic material directly to tumor cells. Among the most promising advancements in gene therapy is the CRISPR-Cas9 technology, which enables precise editing of the genome to target mutations, such as the EGFRvIII mutation, that drive GBM’s malignancy. Preclinical studies have shown that CRISPR can reduce tumor growth and enhance sensitivity to conventional treatments like radiotherapy and chemotherapy. However, a major hurdle remains the delivery of gene therapies to the brain. The blood-brain barrier presents a formidable obstacle, and innovative delivery methods are under exploration, including viral vectors, nanoparticles, and intranasal routes. Adenoviruses and adeno-associated viruses (AAVs) have shown promise in preclinical and early clinical trials, though immune responses and safety concerns, such as off-target effects, remain challenges. Additionally, the combination of gene therapy with other treatments, such as immunotherapy, is being studied to enhance overall treatment efficacy. As research progresses, precision delivery methods and personalized therapeutic strategies offer hope for improving outcomes in GBM, potentially transforming the standard of care for this devastating disease.