CCR2-overexpressing biomimetic carrier-free nanoplatform for enhanced cascade ferroptosis tumor therapy

Xinyu Zhang; Xueli Xu; Huimin Liu; Nengyi Ni; Shuangqing Liu; Yufang Gong; Guiqi Ma; Linlin Song; Qingwei Meng; Qing Fan; Xiao Sun

doi:10.1016/j.actbio.2023.05.006

CCR2-overexpressing biomimetic carrier-free nanoplatform for enhanced cascade ferroptosis tumor therapy

Acta Biomater. 2023 Aug:166:604-614. doi: 10.1016/j.actbio.2023.05.006. Epub 2023 May 6.

Authors

Xinyu Zhang¹, Xueli Xu², Huimin Liu³, Nengyi Ni⁴, Shuangqing Liu¹, Yufang Gong¹, Guiqi Ma³, Linlin Song³, Qingwei Meng⁵, Qing Fan⁶, Xiao Sun⁷

Affiliations

¹ Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin 150081, China.
² School of Science, Shandong Jianzhu University, Jinan 250101, China.
³ Department of Pharmacy, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan 250117, China.
⁴ Department of Chemical and Biomolecular Engineering, National University of Singapore, Singapore 117585, Singapore.
⁵ Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin 150081, China. Electronic address: mengqw@hrbmu.edu.cn.
⁶ Department of Pharmacy, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan 250117, China. Electronic address: fanqing@sdfmu.edu.cn.
⁷ Department of Pharmacy, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan 250117, China. Electronic address: sunxiao@sdfmu.edu.cn.

PMID: 37156432
DOI: 10.1016/j.actbio.2023.05.006

Abstract

Ferroptosis-based nanoplatforms have shown great potential in cancer therapy. However, they also face issues such as degradation and metabolism. Carrier-free nanoplatforms consisting of active drugs can effectively avoid the security issues associated with additional carrier ingredients. Herein, a biomimetic carrier-free nanoplatform (HESN@CM) was designed to treat cancer by modulating cascade metabolic pathways of ferroptosis. CCR2-overexpressing macrophage membrane-modified HESN can target cancer cells via the CCR2-CCL2 axis. The acidic tumor microenvironment (TME) can disrupt the supramolecular interaction of HESN, releasing hemin and erastin. Then, erastin could induce cancer cells ferroptosis by inhibiting system X_C^- pathways, while hemin, a vital component of blood to transport oxygen, could be broken down by heme oxygenase-1 (HO-1), increasing the intracellular Fe²⁺ concentration to induce cancer cells' ferroptosis further. Meanwhile, erastin could enhance the activity of HO-1, further promoting the release of Fe²⁺ from hemin. As a result, HESN@CM demonstrated superior therapeutic efficacy in both primary and metastatic tumors in vitro and in vivo. The carrier-free HESN@CM provided cascade ferroptosis tumor therapy strategies for potential clinical application. STATEMENT OF SIGNIFICANCE: CCR2-overexpressing biomimetic carrier-free nanoplatform (HESN@CM) was designed for cancer treatment by modulating metabolic pathways of ferroptosis. HESN modified with CCR2-overexpressing macrophage membrane can target tumor cells via the CCR2-CCL2 axis. HESN was composed of hemin and erastin without additional vectors. Erastin could directly induce ferroptosis, while hemin could be broken down by heme oxygenase-1 (HO-1), increasing the intracellular Fe²⁺ concentration to enhance ferroptosis further. Meanwhile, erastin could improve the activity of HO-1, promoting the release of Fe²⁺ from hemin. Therefore, HESN@CM with good bioavailability, stability, and simple preparation can realize cascade ferroptosis tumor therapy and have the potential prospect of clinical translation.

Keywords: Biomimetic; Carrier-free; Cascade therapy; Drug release; Ferroptosis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Biomimetics
Cell Line, Tumor
Ferroptosis*
Heme Oxygenase-1 / metabolism
Heme Oxygenase-1 / pharmacology
Hemin / pharmacology

Substances

Heme Oxygenase-1
Hemin