Yuan Zhongwen, Liu Xinxin, Ling Jiabao, Huang Guanning, Huang Jiarun, Zhu Xueqiong, He Lizhen, Chen Tianfeng
Department of Neurology and Stroke Center, The First Affiliated Hospital, College of Chemistry and Materials Science, Jinan University, Guangzhou, 510632, China.
Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
Biomaterials. 2022 Aug;287:121620. doi: 10.1016/j.biomaterials.2022.121620. Epub 2022 Jun 7.
Disrupting redox homeostasis in the tumor microenvironment (TME), like excessive HO, glutathione (GSH) and weak acidity, has been proved as an effective tumor therapeutic strategy. Herein, we constructed a TME-responsive nanozyme, DOX@HMSN/MnO(R), with reversible Mn/Mn transition in situ triggered by TME to perturb the intrinsic redox homeostasis and catalyze reactive oxygen species (ROS) overproduction. In addition, this nanozyme could react with excess GSH in TME to produce GSSG, resulting in the consumption of reducing agents to suppress ROS clearance. Density functional theory calculations further confirmed that the nanozyme mainly exhibited the oxidase-like activity to catalyze the formation of hydroxyl radicals from O, thus strengthening the oxidation environment in the TME. Combined with radiotherapy, the high-energy X-ray could excite the outer-layer electrons in the nanozyme, forming photoelectrons that participate in the oxidase-like enzymatic reaction, thus intensifying ROS accumulation and amplifying the radio-/chemotherapeutic efficacy.
破坏肿瘤微环境（TME）中的氧化还原稳态，如过量的过氧化氢（HO）、谷胱甘肽（GSH）和弱酸性，已被证明是一种有效的肿瘤治疗策略。在此，我们构建了一种TME响应性纳米酶DOX@HMSN/MnO(R)，其原位Mn/Mn可逆转变由TME触发，以扰乱内在氧化还原稳态并催化活性氧（ROS）过量产生。此外，这种纳米酶可与TME中过量的GSH反应生成谷胱甘肽二硫化物（GSSG），导致还原剂消耗以抑制ROS清除。密度泛函理论计算进一步证实，该纳米酶主要表现出类氧化酶活性，催化O形成羟基自由基，从而强化TME中的氧化环境。与放疗相结合，高能X射线可激发纳米酶中的外层电子，形成参与类氧化酶酶促反应的光电子，从而增强ROS积累并放大放射/化学治疗效果。
