A Nanoradiosensitizer Potentiates Tumor Radiotherapy through JFK Inhibition and Hypoxia Alleviation.

Radiotherapy (RT) is a primary treatment for breast cancer, but its effectiveness is often compromised by hypoxia and intrinsic resistance mechanisms. The F-box protein JFK is overexpressed in breast cancer and is associated with reduced radiosensitivity, but specific JFK inhibitors are currently unavailable. Herein, we developed spherical nanoparticles (SNP-JC) designed to co-deliver small interfering RNA targeting JFK and catalase to the tumor, aiming to silence JFK and alleviate hypoxia to overcome RT resistance. Positron emission tomography imaging demonstrated that SNP-JC efficiently accumulated in the tumors. SNP-JC significantly increased DNA damage in tumor cells after RT and promoted the immunogenic cell death. The combination of SNP-JC and RT activated CD8+ T cells and elicited a robust antitumor immunity, resulting in suppressed primary tumor growth and reduced lung metastasis. Our findings demonstrate that a nanoplatform capable of simultaneously silencing JFK and mitigating hypoxia can enhance tumor radiosensitivity, improve antitumor efficacy, and prevent metastasis.