Optimizing liposomal drug release <i>via</i> γ-irradiation and iron-based radiosensitization

Chemotherapy remains a cornerstone of cancer treatment, yet its lack of tumor specificity often leads to systemic toxicity and limits the maximum tolerable dose. To address these limitations, drug-loaded nanocarriers responsive to ionizing radiation have emerged as a promising strategy to achieve localized drug release within irradiated tumor regions, thereby enhancing therapeutic efficacy while minimizing off-target effects. However, current radiation-responsive nanosystems often exhibit limited drug release at clinically relevant radiation doses. In our previous work, we evaluated liposomal formulations varying lipid composition, sensitizers, and particle size. While these systems demonstrated moderate immediate release upon irradiation followed by sustained passive leakage, they were incompatible with remote drug loading and failed to achieve rapid release. In the present study, we optimized the liposomal membrane composition through modulation of polyunsaturated and saturated phospholipids to enhance radiation sensitivity and colloidal stability. Furthermore, we introduced a radiosensitization mechanism based on the encapsulation of Fe³⁺ ions, which are reduced to Fe²⁺ upon γ-irradiation. This redox transition triggers a Fenton-like reaction that catalyzes the degradation of lipid hydroperoxides, leading to localized lipid peroxidation and membrane disruption. This dual strategy, membrane composition tuning and iron-mediated oxidative activation, resulted in significantly enhanced drug release upon exposure to low-dose radiation.