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Theranostics 2024; 14(5):1939-1955. doi:10.7150/thno.92663 This issue Cite

Research Paper

Multifunctional Sr/Se co-doped ZIF-8 nanozyme for chemo/chemodynamic synergistic tumor therapy via apoptosis and ferroptosis

Aimin Wu^1,*, Ming Han^2,*, Zihan Ni⁶, Haoran Li³, Yinyin Chen³, Zhouping Yang¹, Yumei Feng⁴, Zufeng He⁵, Hua Zhen², Xianxiang Wang^2✉

1. Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu 611130, Sichuan, China.
2. College of Science, Sichuan Agricultural University, Chengdu 611130, Sichuan, China.
3. College of Agronomy, Sichuan Agricultural University, Chengdu 611130, Sichuan, China.
4. State Key Laboratory of Crop Gene Exploration and Utilization in Southwest China, Chengdu 611130, Sichuan, China.
5. Institute of New Rural Development, Sichuan Agricultural University, Chengdu 611130, Sichuan, China.
6. College Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, Sichuan, China.
*These authors contributed equally to this work.

✉ Corresponding author: Xianxiang Wang; E-mail address: wangxxedu.cn.

Abstract

Rationale: Cancer continues to be a significant public health issue. Traditional treatments such as surgery, radiotherapy, and chemotherapy often fall short because of intrinsic issues such as lack of specificity and poor drug delivery, leading to insufficient drug concentration at the tumor site and/or potential side effects. Consequently, improving the delivery of conventional chemotherapy drugs like doxorubicin (DOX) is crucial for their therapeutic efficacy. Successful cancer treatment is achieved when regulated cell death (RCD) of cancer cells, which includes apoptotic and non-apoptotic processes such as ferroptosis, is fundamental to successful cancer treatment. The developing field of nanozymes holds considerable promise for innovative cancer treatment approaches.

Methods: A dual-metallic nanozyme system encapsulated with DOX was created, derived from metal-organic frameworks (MOFs), designed to combat tumors by depleting glutathione (GSH) and concurrently liberating DOX. The initial phase of the study examined the GSH oxidase-mimicking function of the dimetallic nanozyme (ZIF-8/SrSe) through enzyme kinetic assays and Density Functional Theory (DFT) simulations. Following this, we probed the ability of ZIF-8/SrSe@DOX to release DOX in response to the tumor microenvironment in vitro, alongside examining its anticancer capabilities and mechanisms prompting apoptosis or ferroptosis in cancer cells. Moreover, we established tumor-bearing animal models to corroborate the anti-tumor effectiveness of our nanozyme complex and to identify the involved apoptotic and ferroptotic pathways implicated.

Results: Enzyme kinetic analyses demonstrated that the ZIF-8/SrSe nanozyme exhibits substantial GSH oxidase-like activity, effectively oxidizing reduced GSH to glutathione disulfide (GSSG), while also inhibiting glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11). This inhibition led to an imbalance in iron homeostasis, pronounced caspase activation, and subsequent induction of apoptosis and ferroptosis in tumor cells. Additionally, the ZIF-8/SrSe@DOX nanoparticles efficiently delivered DOX, causing DNA damage and further promoting apoptotic and ferroptotic pathways.

Conclusions: This research outlines the design of a novel platform that combines chemotherapeutic agents with a Fenton reaction catalyst, offering a promising strategy for cancer therapy that leverages the synergistic effects of apoptosis and ferroptosis.

Keywords: Apoptosis, Doxorubicin, Ferroptosis, Tumor therapy, ZIF-8/SrSe

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