Biomimetic Engineering of Hybrid Radiosensitizers to Boost Radiotherapy against Cancer Metastasis

Abstract Over the past 120 years, significant efforts are dedicated to delivering maximum radiation doses to tumor sites while sparing adjacent normal tissues as much as possible. Despite encouraging progress in the development of heavy metal‐based nanoscale radiosensitizers, radiotherapy often fails to fully eradicate hypoxic tumors, leading to local recurrence or even progression to distant metastasis. In this study, a versatile biomimetic hybrid radiosensitizer is engineered by integrating the hypoxia‐activated prodrug banoxantrone and CeO 2 nanozymes into mesoporous silica‐coated Bi 2 O 3 nanoparticles (NPs), followed by camouflage coating with cancer‐cell‐derived membranes. Compared to naked Bi 2 O 3 NPs and free banoxantrone alone, the radiosensitization efficacy of the biomimetic NPs is substantially enhanced toward both normoxic and hypoxic cancer cells. Moreover, lung metastasis is markedly inhibited by reactive oxygen species‐mediated remodeling of the extracellular matrix through the activity of CeO 2 nanozymes. As confirmed by in vitro and in vivo results, the biomimetic hybrid radiosensitizer enhances radiotherapy against lung metastasis with fewer side effects. This study provides compelling evidence for the development of next‐generation radiosensitizers with optimized functionalities using biomimetic hybrid engineering to finely balance the benefits and risks of radiotherapy.