Ferroptosis-Based Nanotherapeutic Strategies to Overcome Temozolomide Resistance in Glioblastoma: A Systematic Review and Meta-Analysis

Glioblastoma multiforme (GBM) is one of the most aggressive and treatment-resistant forms of brain cancer, posing challenges to modern oncology. Current treatments, including surgery, radiation, and chemotherapy (e.g., Temozolomide or TMZ), often fail due to the inevitable development of drug resistance. TMZ resistance remains a major therapeutic challenge for the reasons that it is the first-line treatment. Recent studies indicate a rising GBM tumour burden and a trend towards earlier age of onset. It highlights the urgent need for evidence-based policymaking and intensified research to address this most difficult-to-treat malignancy in clinical settings. Ferroptosis, a newly recognized type of controlled cell death induced by iron-dependent lipid peroxidation, has emerged as a potential approach to overcome apoptosis resistance and restore drug sensitivity in GBM. This mechanism is modulated by key molecules that can be specifically targeted to either enhance oxidative stress or inhibit antioxidant defences, ultimately leading to tumour cell death. This review conducts a meta-analysis of preclinical evidence to better understand the potential of activating ferroptosis as a key target for developing nanoparticles to resensitize TMZ-resistant GBM cells. Current evidence indicates that combining ferroptosis induction with strategically engineered nanocarrier systems can serve as a novel and effective therapeutic approach to overcome TMZ resistance and advance precision-based GBM treatment.