Copper/iron bimetal phenolic networks boosted apoptosis/ferroptosis/cuproptosis combined tumor therapy through dual glutathione depletion

•Copper/iron bimetal phenolic networks for multimodal combined tumor therapy were constructed.•The bimetal phenolic networks presented dual GSH consumption capacity for intracellular GSH depletion.•The bimetal phenolic networks could activate apoptosis, ferroptosis, and cuproptosis simultaneously to kill tumor cells. Cuproptosis, ferroptosis, and reactive oxygen species (ROS)-involved apoptosis are all bound by the overexpressed glutathione (GSH) in tumor microenvironment (TME). Herein, a dual GSH depletor is developed based on copper/iron bimetal gallic acid phenolic networks (CuFeGA MPNs) for combination tumor therapy by GSH depletion boosted apoptosis/ferroptosis/cuproptosis simultaneously. The CuFeGA MPNs are dissociated following exposure to the highly expressed GSH, causing the release of large quantities of GA, Fe2+, and Cu+. The released GA then further consumes the residual GSH. In conjunction with the GSH response-consumption behavior, the GSH depletion is achieved by those dual GSH consumption procedures. Subsequently, the expression of glutathione peroxides 4 (GPX4) is down-regulated by GSH depletion for further accumulation of lipid peroxides (LPO). Moreover, intracellular ROS levels are improved via Fenton reaction with released Cu+ and Fe2+, leading to buildup of LPO concurrently. Eventually, excess ROS can activate mitochondria-associated apoptosis, and the surge of LPO initiates ferroptosis without GSH homeostasis. Meanwhile, the oligomerization of lipoylated dihydrolipoamide S-acetyltransferase (DLAT) and decline of iron-sulfur cluster protein are induced by excessive Cu+ in the absence of GSH chelation, activating cuproptosis. This work provides a feasible approach for the realization of multiple mechanisms combined tumor therapy.