Nanomedicine Strategies for Overcoming Temozolomide Resistance in Glioblastoma

Glioblastoma multiforme (GBM) is among the deadliest of brain tumors. While temozolomide (TMZ) is the standard treatment, tumors quickly develop resistance, leading to patient relapse. The blood-brain barrier (BBB) and complex tumor microenvironments further limit drug efficacy.

We reviewed literature from 2015 to 2024 via PubMed and Web of Science, focusing on nanoparticle-based strategies designed to overcome TMZ resistance. We specifically analyzed how these carriers tackle mechanisms like MGMT overexpression and drug efflux.

Emerging nanomedicines-including liposomes, polymeric nanoparticles, and inorganic carriers-show promise in preclinical models. Key advances include co-delivering TMZ with MGMT inhibitors or siRNAs to re-sensitize tumor cells. Stimuli-responsive systems that release drugs only within the tumor acidity or hypoxia also reduce systemic toxicity.

While nanotechnology offers tools to bypass biological barriers and reverse resistance, clinical translation remains slow. Future success depends on solving manufacturing scalability, ensuring long-term safety, and navigating regulatory pathways. Integrating these tools with personalized molecular profiling represents the next step in GBM therapy.