An iron-containing ferritin-based nanosensitizer for synergistic ferroptosis/sono-photodynamic cancer therapy

Ferroptosis is a newly detected iron-dependent form of regulated cell death. Sono-photodynamic therapy (SPDT) can generate reactive oxygen species (ROS) and induce cell death under light and ultrasound. Due to the complexity of tumor physiology and pathology, single-modality often fails to achieve a satisfactory therapeutic effect. The development of a formulation platform with integration of multiple therapeutic modalities using a simple and convenient method is still a challenge. Here, we report the facile construction of a ferritin-based nanosensitizer FCD by co-encapsulating chlorin e6 (Ce6) and dihydroartemisinin (DHA) in horse spleen ferritin, and was employed for synergistic ferroptosis and SPDT. Ferritin in FCD can release Fe³⁺ under acidic conditions and Fe³⁺ can be reduced to Fe²⁺ in the presence of glutathione (GSH). The Fe²⁺ can react with hydrogen peroxide (H₂O₂) to produce harmful hydroxyl radicals. Furthermore, a large amount of ROS can be generated via the reaction of Fe²⁺ with DHA and by simultaneously irradiation of FCD with both light and ultrasound. More importantly, the depletion of GSH by FCD could decrease glutathione peroxidase 4 (GPX4) and increase lipid peroxidation (LPO) levels, thereby inducing ferroptosis. Therefore, by integrating the advantageous GSH-depletion capacity, ROS generation ability, and ferroptosis induction capability into one single nanosystem, FCD can serve as a promising platform for combined chemo-sono-photodynamic therapy of cancer.