A light-activated Fe²⁺ release nanosystem for enhanced chemodynamic/chemo therapy <i>via</i> cascade amplification of ROS generation

Ferrous iron (Fe²⁺)-based chemodynamic therapy (CDT) shows great potential for improving chemotherapeutic efficacy and reducing side effects. However, spontaneous oxidation and biological matrixes can influence the catalytic reactive oxygen species (ROS) generation of Fe²⁺, thereby limiting the efficacy of CDT. Herein, we reported a simple and convenient method to construct hyaluronic acid (HA)-stabilized iron/zinc oxide nanoparticles (IZ@H NPs), which showed intrinsic peroxidase (POD)-like activity and excellent light-activated Fe²⁺ release performance. Moreover, we demonstrate that catalytic ROS generation follows a cascade amplification manner due to the light-activated release of Fe²⁺ from IZ@H NPs, leading to formation of iron-DNA complexes (IDCs). After loading doxorubicin (DOX), the nanosystem (termed IZD@H NPs) exhibits tumor cell targeting, robust ROS generation and high cytotoxicity, significantly suppressing tumor growth in xenograft mouse models while maintaining good biosafety. This work gives novel insight into amplifying Fe²⁺-mediated catalytic ROS generation and presents a new strategy for <i>in vivo</i> Fe²⁺ delivery to enhance chemodynamic/chemotherapy.