A pH/ATP-responsive nanomedicine via disrupting multipath homeostasis of ferroptosis for enhanced cancer therapy

Ferroptosis is a currently recognized non-apoptotic cell death mode based on reactive oxygen species (ROS)-induced lipid peroxidation, which provides a promising strategy for cancer treatment. However, ferroptosis therapy has great challenges due to the low intracellular iron levels and the overexpressed lipid hydroperoxidase glutathione peroxidase 4 (GPX4). Here, we engineered a sequential pH/adenosine triphosphate (ATP)-sensitive nanomedicine by initially synthesizing zeolitic imidazolate framework 90 (ZIF90) containing metformin (Met) and RSL3 (Met/RSL3@ZIF90) and then immobilizing it into iron ions and tannic acid (TA) integrated nanoscale coordination polymer (Fe-TA NCP) to obtain Met/RSL3@ZIF90@Fe-TA. After entering the weakly acidic tumor microenvironment (TME), the structure of Fe-TA NCP was ruptured and the Met/RSL3@ZIF90 was exposed. The overexpressed ATP in cells could destroy the structure of the Met/RSL3@ZIF90 to release the loaded Met and RSL3. The freed iron ions catalyzed H2O2 via the Fenton reaction to promote the accumulation of lethal lipid peroxide (LPO). The exposed RSL3 through down-regulating glutathione peroxidase 4 (GPX4) broke the balance of GSH/GPX4, and the released Met activated the AMPK pathway to upregulate p53 and down-regulate SLC7A11. The results showed that the combination of continuous ferroptosis and apoptosis could lead to conspicuous cell death and significant tumor inhibition. Overall, this study paves a promoting strategy to improve the effectiveness of ferroptosis therapy by multipath destruction of antioxidant system.