化学动力疗法（CDT）依赖于肿瘤微环境（例如，高H2O2水平）响应性的类Fenton反应，产生对抗肿瘤的羟基自由基（·OH）。然而，内源性H2O2不足以实现有效的化学动力反应。在子宫内膜癌（EC）中首次确定了使用NQO1生物活性药物β-萝芙木酚（β-Lap）的NAD（P）H：醌氧还酶1（NQO1）高催化剂过氧化氢酶（CAT）低治疗窗口。随着NADH的消耗，NQO1催化β-Lap产生过量的H2O2并引发氧化应激，选择性地抑制NQO1高EC细胞增殖，诱导DNA双链断裂并促进凋亡。而且，shRNA介导的NQO1沉默或二羟基香豆素救助NQO1高EC细胞免受β-Lap诱导的细胞毒性。精氨酸-甘氨酸-天冬氨酸（RGD）功能化的铁基金属有机框架（MOF（Fe））进一步促进了累积的H2O2转化为高度氧化的·OH，进而加剧了对RGD阳性靶细胞的氧化损伤。此外，通过Mdivi-1抑制线粒体自噬可阻止强大的抗氧化防御策略，最终确保分步放大的反应性氧化物质信号的抗肿瘤效力。肿瘤生长抑制率（TGI）约为85.92％。然而，在缺乏NQO1的KLE肿瘤中，MOF（Fe）基于协同抗肿瘤疗法的TGI仅下降到50.46％。肿瘤特异性化疗和CDT触发的治疗方式在治疗NQO1高EC方面展现出前所未有的治疗益处。© 2023 The Authors. Small published by Wiley-VCH GmbH.

Chemodynamic therapy (CDT) relies on the tumor microenvironment (e.g., high H2 O2 level) responsive Fenton-like reactions to produce hydroxyl radicals (·OH) against tumors. However, endogenous H2 O2 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 H2 O2 and initiate oxidative stress, which selectively suppress NQO1high EC cell proliferation, induce DNA double-strand breaks, and promote apoptosis. Moreover, shRNA-mediated NQO1 knockdown or dicoumarol rescues NQO1high 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 H2 O2 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 NQO1high EC.© 2023 The Authors. Small published by Wiley-VCH GmbH.