Meng Xiangqin, Li Dandan, Chen Lei, He Helen, Wang Qian, Hong Chaoyi, He Jiuyang, Gao Xingfa, Yang Yili, Jiang Bing, Nie Guohui, Yan Xiyun, Gao Lizeng, Fan Kelong
CAS Engineering Laboratory for Nanozyme, Key Laboratory of Protein and Peptide Pharmaceutical, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
School of Future Technology, University of Chinese Academy of Sciences, Beijing 101408, China.
ACS Nano. 2021 Mar 23;15(3):5735-5751. doi: 10.1021/acsnano.1c01248. Epub 2021 Mar 11.
As next-generation artificial enzymes, nanozymes have shown great promise for tumor catalytic therapy. In particular, their peroxidase-like activity has been employed to catalyze hydrogen peroxide (HO) to produce highly toxic hydroxyl radicals (OH) to kill tumor cells. However, limited by the low affinity between nanozymes with HO and the low level of HO in the tumor microenvironment, peroxidase nanozymes usually produced insufficient OH to kill tumor cells for therapeutic purposes. Herein, we present a pyrite peroxidase nanozyme with ultrahigh HO affinity, resulting in a 4144- and 3086-fold increase of catalytic activity compared with that of classical FeO nanozyme and natural horseradish peroxidase, respectively. We found that the pyrite nanozyme also possesses intrinsic glutathione oxidase-like activity, which catalyzes the oxidation of reduced glutathione accompanied by HO generation. Thus, the dual-activity pyrite nanozyme constitutes a self-cascade platform to generate abundant OH and deplete reduced glutathione, which induces apoptosis as well as ferroptosis of tumor cells. Consequently, it killed apoptosis-resistant tumor cells harboring KRAS mutation by inducing ferroptosis. The pyrite nanozyme also exhibited favorable tumor-specific cytotoxicity and biodegradability to ensure its biosafety. These results indicate that the high-performance pyrite nanozyme is an effective therapeutic reagent and may aid the development of nanozyme-based tumor catalytic therapy.
作为下一代人工酶，纳米酶在肿瘤催化治疗方面展现出了巨大的潜力。特别是，它们的类过氧化物酶活性已被用于催化过氧化氢（H₂O₂）生成剧毒的羟基自由基（·OH）来杀死肿瘤细胞。然而，受纳米酶与H₂O₂之间低亲和力以及肿瘤微环境中H₂O₂水平较低的限制，过氧化物酶纳米酶通常产生的·OH不足以用于治疗目的来杀死肿瘤细胞。在此，我们展示了一种具有超高H₂O₂亲和力的黄铁矿过氧化物酶纳米酶，与经典的Fe₃O₄纳米酶和天然辣根过氧化物酶相比，其催化活性分别提高了4144倍和3086倍。我们发现黄铁矿纳米酶还具有内在的谷胱甘肽氧化酶样活性，可催化还原型谷胱甘肽的氧化并伴随H₂O₂的生成。因此，具有双活性的黄铁矿纳米酶构成了一个自级联平台，可产生大量的·OH并消耗还原型谷胱甘肽，从而诱导肿瘤细胞的凋亡以及铁死亡。结果，它通过诱导铁死亡杀死了携带KRAS突变的抗凋亡肿瘤细胞。黄铁矿纳米酶还表现出良好的肿瘤特异性细胞毒性和生物降解性，以确保其生物安全性。这些结果表明，高性能的黄铁矿纳米酶是一种有效的治疗试剂，可能有助于基于纳米酶的肿瘤催化治疗的发展。
