Hypoxia-tropic delivery of nanozymes targeting transferrin receptor 1 for nasopharyngeal carcinoma radiotherapy sensitization

Ruofei Zhang, Yanfang Shen, Xiaoying Zhou, Jianru Li, Hanqing Zhao, Zixia Zhang, Jun Zhao, Hongjun Jin, Shuanshuan Guo, Hui Ding, Guohui Nie, Zhe Zhang (), Ying Wang (), Xiyun Yan () and Kelong Fan ()
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Ruofei Zhang: Chinese Academy of Sciences
Yanfang Shen: Sun Yat-sen University
Xiaoying Zhou: Guangxi Medical University, Ministry of Education
Jianru Li: Chinese Academy of Sciences
Hanqing Zhao: Chinese Academy of Sciences
Zixia Zhang: Chinese Academy of Sciences
Jun Zhao: Guangxi Medical University, Ministry of Education
Hongjun Jin: Sun Yat-sen University
Shuanshuan Guo: The Fifth Affiliated Hospital of Sun Yat-Sen University
Hui Ding: Shenzhen Second People’s Hospital/the First Affiliated Hospital of Shenzhen University Health Science Center
Guohui Nie: Shenzhen Second People’s Hospital/the First Affiliated Hospital of Shenzhen University Health Science Center
Zhe Zhang: First Affiliated Hospital of Guangxi Medical University
Ying Wang: Sun Yat-sen University
Xiyun Yan: Chinese Academy of Sciences
Kelong Fan: Chinese Academy of Sciences

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: Abstract Nasopharyngeal carcinoma (NPC), a malignancy highly prevalent in East and Southeast Asia, is primarily treated with radiotherapy (RT). However, hypoxia-induced radioresistance presents a significant challenge. Nanozymes, nanomaterials with catalase-like activity, have emerged as a promising strategy for radiosensitization by converting elevated hydrogen peroxide in the tumor microenvironment into oxygen. Despite their potential, effectively targeting hypoxic lesions has been difficult. Here, we identify transferrin receptor 1 (TfR1) as an upregulated target in NPC, with its expression levels positively correlated with hypoxia. Human heavy-chain ferritin, a specific ligand of TfR1, selectively recognizes hypoxic NPC lesions in preclinical models. Based on these findings, we design a hypoxia-targeted nanozyme by loading platinum nanoparticles into ferritin. This nanozyme exhibits enhanced catalase-like activity and effectively alleviates tumor hypoxia in NPC xenografts. When combined with RT, a single injection of the nanozyme significantly inhibits tumor growth and prolongs mouse survival, outperforming sodium glycididazole, a clinically used radiosensitizer. In summary, our findings highlight TfR1 as an accessible cell surface target in hypoxic NPC lesions. The nanozyme targeting TfR1 holds promise for enhancing the therapeutic effectiveness of RT in NPC through an in situ oxygen-generation mechanism.

Date: 2025
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DOI: 10.1038/s41467-025-56134-z

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