In situ-transition nanozyme triggered by tumor microenvironment boosts synergistic cancer radio-/chemotherapy through disrupting redox homeostasis

Zhongwen Yuan; Xinxin Liu; Jiabao Ling; Guanning Huang; Jiarun Huang; Xueqiong Zhu; Lizhen He; Tianfeng Chen

doi:10.1016/j.biomaterials.2022.121620

In situ-transition nanozyme triggered by tumor microenvironment boosts synergistic cancer radio-/chemotherapy through disrupting redox homeostasis

Biomaterials. 2022 Aug:287:121620. doi: 10.1016/j.biomaterials.2022.121620. Epub 2022 Jun 7.

Authors

Zhongwen Yuan¹, Xinxin Liu¹, Jiabao Ling¹, Guanning Huang¹, Jiarun Huang¹, Xueqiong Zhu², Lizhen He³, Tianfeng Chen⁴

Affiliations

¹ Department of Neurology and Stroke Center, The First Affiliated Hospital, College of Chemistry and Materials Science, Jinan University, Guangzhou, 510632, China.
² Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
³ Department of Neurology and Stroke Center, The First Affiliated Hospital, College of Chemistry and Materials Science, Jinan University, Guangzhou, 510632, China. Electronic address: hlz6371@jnu.edu.cn.
⁴ Department of Neurology and Stroke Center, The First Affiliated Hospital, College of Chemistry and Materials Science, Jinan University, Guangzhou, 510632, China. Electronic address: tchentf@jnu.edu.cn.

PMID: 35709558
DOI: 10.1016/j.biomaterials.2022.121620

Abstract

Disrupting redox homeostasis in the tumor microenvironment (TME), like excessive H₂O₂, glutathione (GSH) and weak acidity, has been proved as an effective tumor therapeutic strategy. Herein, we constructed a TME-responsive nanozyme, DOX@HMSN/Mn₃O₄(R), with reversible Mn³⁺/Mn²⁺ 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 O₂, 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.

Keywords: Mn; Nanozyme; Radiosensitization; Radiotherapy; Redox balance; Tumor microenvironment.