Activatable Biomineralized Nanoplatform Remodels the Intracellular Environment of Multidrug‐Resistant Tumors for Enhanced Ferroptosis/Apoptosis Therapy

Abstract Ferroptosis is a new form of regulated cell death with significant therapeutic prospect, but its application against drug‐resistant tumor cells is challenging due to their ability to effuse antitumor agents via p‐glycoprotein (P‐gp) and anti‐lipid peroxidation alkaline intracellular environment. Herein, an amorphous calcium phosphate (ACP)‐based nanoplatform is reported for the targeted combinational ferroptosis/apoptosis therapy of drug resistant tumor cells by blocking the MCT4‐mediated efflux of lactic acid (LA). The nanoplatform is fabricated through the biomineralization of doxorubicin‐Fe 2+ (DOX‐Fe 2+ ) complex and MCT4‐inhibiting siRNAs (siMCT4) and can release them to the tumor cytoplasm after the hydrolysis of ACP and dissociation of DOX‐Fe 2+ in the acidic lysosomes. siMCT4 can inhibit MCT4 expression and force the glycolysis‐generated lactic acid (LA) to remain in cytoplasm for rapid acidification. The nanoplatform‐induced remodeling of the tumor intracellular environment can not only interrupt the ATP supply required for P‐gp‐dependent DOX effusion to enhance H 2 O 2 production, but also increase the overall catalytic efficiency of Fe 2+ for the initiation and propagation of lipid peroxidation. These features could act in concert to enhance the efficacy of the combinational ferroptosis/chemotherapy and prolong the survival of tumor‐bearing mice. This study may provide new avenues for the treatment of multidrug‐resistant tumors.