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

Nasopharyngeal carcinoma (NPC) is a malignant tumor arising from the nasopharyngeal mucosal lining and is prevalent in East and Southeast Asia. Radiotherapy (RT) is the main treatment for NPC, but the highly hypoxic tumor microenvironment promotes RT resistance, recurrence, and metastasis of solid tumors. Nanomaterials with catalase-like activity have emerged as promising radiosensitizer candidates by converting hydrogen peroxide into oxygen. However, effective targeting of hypoxic lesions remains difficult. The development of highly active nanozymes with powerful targeting approaches is the main goal of this work.

Here, we identified transferrin receptor 1 (TFR1) as an upregulated target in NPC, and its expression level is positively correlated with hypoxia. We then created a hypoxia-targeted nanozyme (Pt-HFn) by loading platinum nanoparticles (PtNPs) into caged human heavy chain ferritin (HFn), a specific ligand for TfR1. The nanozyme exhibited enhanced catalase-like activity and effectively alleviated tumor hypoxia in NPC xenografts. When combined with RT, its efficacy was superior to that of RT alone or RT combined with free PtNPs or clinical radiosensitizers. In conclusion, nanozymes targeting TFR1 are expected to enhance the therapeutic effectiveness of RT in NPC via an in situ oxygen mechanism.