Enhanced Chemodynamic Therapy Mediated by a Tumor‐Specific Catalyst in Synergy with Mitophagy Inhibition Improves the Efficacy for Endometrial Cancer

Abstract

Chemodynamic therapy (CDT) relies on the tumor microenvironment (e.g., high H ₂O ₂ level) responsive Fenton‐like reactions to produce hydroxyl radicals (·OH) against tumors. However, endogenous H ₂O ₂ is insufficient for effective chemodynamic responses. An NAD(P)H: quinone oxidoreductase 1 (NQO1) ^high catalase (CAT) ^low therapeutic window for the use of NQO1 bioactive drug β‐lapachone (β‐Lap) is first identified in endometrial cancer (EC). Accompanied by NADH depletion, NQO1 catalyzes β‐Lap to produce excess H ₂O ₂ and initiate oxidative stress, which selectively suppress NQO1 ^high EC cell proliferation, induce DNA double‐strand breaks, and promote apoptosis. Moreover, shRNA‐mediated NQO1 knockdown or dicoumarol rescues NQO1 ^high EC cells from β‐Lap‐induced cytotoxicity. Arginine‐glycine‐aspartic acid (RGD)‐functionalized iron‐based metal‐organic frameworks (MOF(Fe)) further promote the conversion of the accumulated H ₂O ₂ into highly oxidative ·OH, which in turn, exacerbates the oxidative damage to RGD‐positive target cells. Furthermore, mitophagy inhibition by Mdivi‐1 blocks a powerful antioxidant defense approach, ultimately ensuring the anti‐tumor efficacy of stepwise‐amplified reactive oxygen species signals. The tumor growth inhibition rate (TGI) is about 85.92%. However, the TGI of MOF(Fe)‐based synergistic antitumor therapy decreases to only 50.46% in NQO1‐deficient KLE tumors. Tumor‐specific chemotherapy and CDT‐triggered therapeutic modality present unprecedented therapeutic benefits in treating NQO1 ^high EC.