Recent developments in drug delivery strategies for targeting DNA damage response in glioblastoma

Glioblastoma is the most frequent and malignant brain tumor. The median survival for this disease is approximately 15 months, and despite all the available treatment strategies employed, it remains an incurable disease. Preclinical and clinical research have shown that the resistance process related to DNA damage repair pathways, glioma stem cells, blood-brain barrier selectivity, and dose-limiting toxicity of systemic treatment leads to poor clinical outcomes. In this context, the advent of drug delivery systems associated with localized treatment seems to be a promising and versatile alternative to overcome the failure of the current treatment approaches. In order to bypass therapeutic tumor resistance mechanisms, more effective combinatorial therapies should be identified, such as the use of cytotoxic drugs combined with the inhibition of DNA damage response (DDR)-related targets. Additionally, critical reasoning about the delivery approach and administration route in brain tumors treatment innovation is essential. The outcomes of future experimental studies regarding the association of delivery systems, alternative treatment routes, and DDR targets are expected to lead to the development of refined therapeutic interventions. Novel therapeutic approaches could improve the life's quality of glioblastoma patients and increase their survival rate. •DNA repair activation is related to the failure of current treatments against GBM.•Clinical results with drugs that modulate the response to DNA damage in GBM are not highly promising.•Drug delivery systems demonstrate the potential of gene-based therapies to target brain cancer cells.