Thiosulfate-Enhanced Fenton-Like Nanocatalyst for Synergistic Chemodynamic Therapy and Calcium Death in Tumor Treatment

To enhance chemodynamic therapy (CDT) and induce calcium overload in tumor cells, we developed a novel nanocatalyst, Cu/ZIF-8@CaS₂O₃@PEG (CZCaP) via a dual-pathway strategy. The system was constructed based on a biocompatible ZIF-8 scaffold, which incorporated Cu²⁺ ions as the catalytic center and was loaded with calcium thiosulfate (CaS₂O₃) as a therapeutic agent. The surface of the nanocatalyst was modified with PEG to enable a tumor microenvironment (TME)-responsive drug release. Under acidic TME conditions, CZCaP dissociated to release CaS₂O₃ and Cu²⁺. The thiosulfate ions (S₂O₃²⁻) acted as a cocatalyst by donating electrons to hydroperoxyl (•OOH) radicals generated from H₂O₂ decomposition. This reaction accelerated the Cu(II)/Cu(I) redox cycling, leading to an enhanced production of hydroxyl radicals (•OH). Consequently, glutathione (GSH) was depleted, compromising the antioxidant capacity of tumor cells. Simultaneously, •OH-mediated oxidative damage impaired PMCA4, a calcium efflux pump, resulting in intracellular accumulation of Ca²⁺ and ultimately calcium overload. Furthermore, •OH downregulated the antiapoptotic protein Bcl-2, collapsed the mitochondrial membrane potential, and promoted calcium influx into mitochondria, thereby inducing apoptosis. By integrating inorganic cocatalysis with the disruption of calcium signaling, this system overcomes the limitation of conventional CDT and presents an innovative multimodal strategy for tumor therapy.