化学动力学疗法（CDT）是一种新颖的抗肿瘤策略，利用芬顿或类芬顿反应从过氧化氢（H2O2）中产生剧毒的羟基自由基（OH·）以诱导肿瘤细胞死亡。然而，CDT策略的抗肿瘤功效受到肿瘤细胞氧化还原稳态的严重限制。尤其是OH·容易被谷胱甘肽(GSH)清除，肿瘤细胞内H2O2水平不足。在此，我们提出Mn2-甲萘醌（也称为维生素K3、MK3）级联生物催化策略，以破坏肿瘤细胞的氧化还原稳态并诱导OH·风暴，从而增强CDT效应。本研究制备了包裹Mn-MK3的纳米脂质体（Mn-MK3@LP）用于治疗肝肿瘤。 Mn-MK3@LPs被肿瘤细胞摄取后，甲萘醌可以通过氧化还原循环促进细胞内H2O2的产生，并进一步通过Mn2介导的类芬顿反应诱导细胞毒性OH·爆发。此外，高价锰离子被GSH还原，GSH的消耗进一步破坏肿瘤细胞的氧化还原稳态，从而实现协同增强CDT。总体而言，细胞和动物实验均证实Mn-MK3@LP级联生物催化纳米脂质体表现出优异的生物安全性和肿瘤抑制功效。这项研究可能为开发基于 CDT 的新型肿瘤治疗策略提供深刻见解。

Chemodynamic therapy (CDT) is a novel antitumor strategy that employs Fenton or Fenton-like reactions to generate highly toxic hydroxyl radical (OH•) from hydrogen peroxide (H2O2) for inducing tumor cell death. However, the antitumor efficacy of the CDT strategy is harshly limited by the redox homeostasis of tumor cells; especially the OH • is easily scavenged by glutathione (GSH) and the intracellular H2O2 level is insufficient in the tumor cells. Herein, we propose the Mn2+-menadione (also known as vitamin K3, MK3) cascade biocatalysis strategy to disrupt the redox homeostasis of tumor cells and induce a OH• storm, resulting in enhanced CDT effect. A nanoliposome encapsulating Mn-MK3 (Mn-MK3@LP) was prepared for the treatment of hepatic tumors in this study. After Mn-MK3@LPs were taken up by tumor cells, menadione could facilitate the production of intracellular H2O2 via redox cycling, and further the cytotoxic OH • burst was induced by Mn2+-mediated Fenton-like reaction. Moreover, high-valent manganese ions were reduced by GSH and the depletion of GSH further disrupted the redox homeostasis of tumor cells, thus achieving synergistically enhanced CDT. Overall, both cellular and animal experiments confirmed that the Mn-MK3@LP cascade biocatalysis nanoliposome exhibited excellent biosafety and tumor suppression efficacy. This study may provide deep insights for developing novel CDT-based strategies for tumor therapy.