UCNPs@PVP‐Hemin‐GOx@CaCO3 Nanoplatform for Ferroptosis Self‐Amplification Combined with Calcium Overload

Abstract Due to the complexity of the tumor microenvironment (TME), current tumor treatments cannot achieve satisfactory results. A nanocomposite material, UCNPs@PVP‐Hemin‐GOx@CaCO3 (UPHGC NPs) is developed that responds to the TME and controls release to achieve multimodal synergistic therapy in tumor tissues. UPHGC NPs mediate photodynamic therapy (PDT), chemodynamic therapy (CDT), and starvation therapy (ST) synergistically, ultimately inducing self‐amplification of ferroptosis. The Hemin loaded in UPHGC NPs exhibits peroxidase (POD) activity, which can react with H2O2 to produce ·OH (CDT) and generate the maximum amount of ·O2− (PDT) under UV excitation from upconversion materials. Hemin can also consume glutathione (GSH), downregulate glutathione peroxidase 4 (GPX4), and combine with PDT/CDT to induce lipid peroxidation (LPO), leading to ferroptosis. In addition, Glucose oxidase (GOx) provides sufficient H2O2 for the ·OH production, amplifying ROS generation to further enhance ferroptosis. The gluconic acid produced by GOx during the ST process synergizes with the TME's acidic conditions to promote Ca2+ release, induce intracellular calcium overload, enhance oxidative stress, lead to mitochondrial dysfunction, and ultimately kill tumor cells through mitochondrial damage. Furthermore, the externally mineralized calcium carbonate can prevent premature drug release in normal tissues.