Jul 2026· International Journal of Medical Science and Pharmaceutical Research· 0 citations
TL;DR
A narrative review comprehensively summarizes the advances achieved between 2016 and 2026 in GBM-directed gene therapy, focusing on the engineering principles, biological characteristics, and translational applications of viral vectors including retroviral, adenoviral, and adeno-associated viral systems.
Abstract
Glioblastoma (GBM) remains the most aggressive primary malignant brain tumor in adults, characterized by extensive intratumoral heterogeneity, diffuse infiltration, profound immunosuppression, and an invariably poor prognosis despite multimodal treatment strategies. Although maximal safe surgical resection followed by radiotherapy and temozolomide constitutes the current standard of care, therapeutic resistance and tumor recurrence remain nearly universal, underscoring the urgent need for innovative treatment modalities. In this context, gene therapy has emerged as a promising therapeutic paradigm capable of addressing several biological limitations associated with conventional therapies through targeted genetic modulation and immune microenvironment reprogramming. This narrative review comprehensively summarizes the advances achieved between 2016 and 2026 in GBM-directed gene therapy. Particular emphasis is placed on the engineering principles, biological characteristics, and translational applications of viral vectors including retroviral, adenoviral, and adeno-associated viral systems as well as emerging non-viral delivery platforms such as lipid nanoparticles, polymeric nanocarriers, electroporation, engineered exosomes, messenger RNA technologies, and CRISPR/Cas-based genome editing. Furthermore, the review discusses recent developments in oncolytic virotherapy, suicide gene systems, RNA interference strategies, immune-stimulatory gene delivery, and adoptive cellular gene therapies. Beyond vector technology, this review highlights the critical role of immune microenvironment remodeling in improving therapeutic efficacy. Current evidence suggests that successful gene therapy should not solely focus on tumor cell eradication but should also promote durable antitumor immunity through enhanced antigen presentation, increased lymphocyte infiltration, reversal of myeloid-mediated immunosuppression, and rational integration with immune checkpoint blockade, dendritic cell vaccines, CAR-T cell therapy, and other multimodal immunotherapeutic approaches. Finally, ongoing clinical trials, translational challenges, manufacturing considerations, biomarker-guided patient selection, and future perspectives are critically discussed to provide a comprehensive overview of the evolving landscape of gene therapy for glioblastoma.
This review discusses the most recent progress in genetic therapies for gliomas, with a focus on clinical platforms and those nearing clinical translation.
Alexander F. Haddad, Rithvik Ramesh, J. Agudelo et al.· JAMA Neurology· 0 citations
Glioblastoma (GBM) remains one of the most lethal brain malignancies, characterized by aggressive invasion, therapeutic resistance and poor prognosis. Conventional treatment approaches are limited by systemic toxicity, poor blood–brain barrier (BBB) penetration and lack of tumor specificity. Nanoparticle-based therapeutics offer a transformative paradigm redefining drug delivery, diagnostics and multimodal strategies in GBM. In this review, we critically explore a diverse variety of advanced nanocarrier platforms designed for anti-proliferative, radiosensitizing and immunomodulatory interventions. These systems enhance BBB penetration, tumor localization and enable co-delivery of chemotherapeutics, gene therapies and imaging agents with high precision. Innovative approaches show efficacy against glioma stem cells, modulate the tumor microenvironment and address resistance mechanisms. Integration with radiotherapy and immunotherapy yields synergistic tumor suppression and immune activation, advancing personalized nanomedicine. Despite these advancements, translational hurdles remain nanogenotoxicity, long-term biosafety, immune responses and regulatory barriers. This review emphasizes such challenges while identifying opportunities for strategic innovation in GBM nanotherapy. By uniquely bridging preclinical advances with emerging clinical perspectives, we highlight its distinct contribution within the field. By bridging nanotechnology, molecular oncology and bioengineering, we highlight how rational nanoparticle design can shift GBM management toward targeted, multimodal precision therapy, offering renewed hope against one of oncology’s most intractable diseases.
Keywords: Glioblastoma, Nanoparticles, Blood-Brain Barrier, Nanotechnology, Nanomedicine, Nanotherapeutics.
Glioblastoma (GBM) is the most aggressive primary malignancy of the central nervous system. Chimeric antigen receptor T (CAR-T) cell therapy has shown promising therapeutic potential against GBM, yet its efficacy remains constrained by multiple barriers, including physical barriers imposed by the blood-brain barrier and extracellular matrix, the immunosuppressive tumor microenvironment, spatiotemporal antigen heterogeneity, and safety concerns. In this review, we summarize the major obstacles limiting CAR-T therapy in GBM and discuss emerging strategies to overcome these challenges. Next-generation engineered CAR-T cells-through armored modifications, logic-gated regulation, and dual-targeting approaches-enhance specificity, persistence, and controllability. Concurrently, combinatorial approaches leveraging biomaterials enable localized delivery and sustained release of CAR-T cells, while physical modalities, such as focused ultrasound and thermal modulation, can transiently disrupt the blood-brain barrier or induce immunogenic cell death. Integration with real-time imaging further enables dynamic monitoring of therapeutic responses. Together, these synergistic strategies may enhance antitumor efficacy while minimizing systemic toxicity, paving the way for future CAR-T-based therapies in glioblastoma.
Lin Chen, Z. Zou· Critical reviews in oncology...· 0 citations
Glioblastoma (GBM) is an intricate intracranial tumor that has cataclysmic outlook. It originates from glial cells having an average life expectancy of one and a half years. Despite intensive multimodal therapy, the tumor's innate invasiveness and cellular heterogeneity lead to nearly inevitable recurrence. Recent advancements have shifted the focus toward the interplay between genetic drivers and the dynamic epigenetic landscape. WHO classification defined GBM as an IDH-wildtype tumor, distinguishing it from IDH-mutant. Present review explores the complex epigenetic mechanisms such as DNA methylation, histone modification and RNA editing that drive GBM progression, shape the tumor microenvironment and facilitate immune evasion. The review further discusses severe translational barriers, including blood brain barrier penetrance, tumor heterogeneity, and the immunosuppressive effects of steroids. Finally, we highlight the therapeutic potential of targeting these epigenetic vulnerabilities through inhibitors of histone deacetylase and DNA methyltransferase, either alone or combined with modern immunotherapies to overcome treatment resistance and improve patient outcomes.
Glioblastoma (GBM) is a refractory and challenging malignant intracranial tumour due to its immunosuppressive microenvironment and vascular enrichment. Despite standard treatment and novel treatment modalities such as immunotherapy and the combination of medical and engineering technologies in therapy, the effectiveness of these methods remains limited, ultimately leading to unsatisfactory outcomes. Previous treatment strategies for glioma have focused mainly on tumour cells while neglecting the role of the tumour microenvironment (TME). Emerging immune, antiangiogenic, and targeted therapeutic strategies have shown promise in advancing the treatment of GBM. The immunosuppressive TME is involved in the accumulation of myeloid-derived suppressor cells, glioma-associated macrophages/microglia, regulatory T cells and immunosuppressive factors, fostering immune evasion. Moreover, the formation of abnormal blood vessels in GBM promotes the intratumoural infiltration of immunosuppressive cells. Therefore, the interaction between the immunosuppressive GBM microenvironment and neovascularisation facilitates tumour progression and recurrence. The aim of this review is to clarify the vascular-immune regulatory mechanisms embedded within the GBM microenvironment, investigate current antivascular and immunotherapy strategies, and identify potential therapeutic directions on the basis of vascular-immune crosstalk, ultimately improving the prognosis and quality of life for GBM patients.
Wan-wan Wen, Zhi Zhang, Yang Wang et al.· Critical reviews in oncology...· 0 citations
BACKGROUND
Glioma is one of the most aggressive and treatment-resistant malignancies of the central nervous system, characterized by rapid progression and poor prognosis. Conventional treatment approaches, including surgery, radiotherapy, and chemotherapy, often fail to achieve long-term remission due to the restrictive nature of the blood-brain barrier and the inherent heterogeneity of tumor cells.
METHODS
This review summarizes and critically analyzes current preclinical and clinical evidence on exosome biology, including their biogenesis, molecular cargo, and therapeutic engineering strategies. It further highlights recent advances in exosome-based delivery of chemotherapeutic agents, microRNAs, and gene-editing systems for glioma management.
RESULTS
Tumor- and stem cell-derived exosomes have demonstrated the ability to cross biological barriers while carrying functional biomolecules and modulating the tumor microenvironment. Their inherent stability, low immunogenicity, and capacity for surface modification make them promising nanocarriers for therapeutic applications. Engineered exosomes loaded with anti- tumor microRNAs, small interfering RNAs, or chemotherapeutic nanoparticles have shown promising results in enhancing drug sensitivity and reducing tumor proliferation in experimental glioma models.
DISCUSSION
The findings support the therapeutic potential of exosome-based platforms while also highlighting major challenges, including inconsistencies in isolation protocols, limited cargo- loading capacity, targeting specificity, and in vivo stability. Although exosomes have demonstrated the ability to overcome biological barriers and therapeutic resistance, standardized manufacturing protocols and robust clinical validation remain essential for successful clinical translation.
CONCLUSION
Exosome-based systems represent a promising approach for the diagnosis and treatment of glioma. Their dual role as biomarkers and therapeutic drug carriers offers significant potential for personalized medicine through non-invasive disease monitoring and targeted therapeutic strategies. However, further optimization of large-scale production, purification methods, and clinical translation is necessary before exosome-based therapeutics can be integrated into standard glioma treatment protocols.
Shatrudhan Prajapati, Shikha Yadav· Current Neurovascular Resear...· 0 citations