Dual‐Depletion of Intratumoral Lactate and ATP with Radicals Generation for Cascade Metabolic‐Chemodynamic Therapy

Abstract Increasing evidence has demonstrated that lactate and adenosine triphosphate (ATP) both play important roles in regulating abnormal metabolism in the tumor microenvironment. Herein, an O 2 self‐supplying catalytic nanoagent, based on tannic acid (TA)–Fe(III) coordination complexes‐coated perfluorooctyl bromide (PFOB) nanodroplets with lactate oxidases (LOX) loading (PFOB@TA–Fe(III)–LOX, PTFL), is designed for cascade metabolic‐chemodynamic therapy (CDT) by dual‐depletion of lactate and ATP with hydroxyl • OH radicals generation. Benefiting from the catalytic property of loaded LOX and O 2 self‐supplying of PFOB nanodroplets, PTFL nanoparticles (NPs) efficiently deplete tumoral lactate for down‐regulation of vascular endothelial growth factor expression and supplement the insufficient endogenous H 2 O 2 . Simultaneously, TA–Fe(III) complexes release Fe(III) ions and TA in response to intracellular up‐regulated ATP in tumor cells followed by TA‐mediated Fe(III)/Fe(II) conversion, leading to the depletion of energy source ATP and the generation of cytotoxic • OH radicals from H 2 O 2 . Moreover, TA–Fe(III) complexes provide photoacoustic contrast as imaging guidance to enhance therapeutic accuracy. As a result, PTFL NPs efficiently accumulate in tumors for suppression of tumor growth and show evidence of anti‐angiogenesis and anti‐metastasis effects. This multifunctional nanoagent may provide new insight for targeting abnormal tumor metabolism with the combination of CDT to achieve a synergistic therapeutic effect.