Active-targeting biomimetic nanosystem for prostate cancer enhances radiotherapy efficacy by inducing ferroptosis.

Radioresistance and off-target toxicity remain major challenges in prostate cancer (PCa) radiotherapy. Here, we report a biomimetic nanoplatform (Au/MOF-FIN@M-gy1) that synergistically enhances radiation deposition and ferroptosis for precision radiosensitization. By engineering macrophage membranes with prostate-specific membrane antigen (PSMA)-targeting nanobodies (gy1), we achieve tumor-selective delivery of Au/MOF nanoparticles preloaded with ferroptosis inducers (FINs). Upon lysosomal release, FINs disrupt redox homeostasis via GPX4 suppression, while Au/MOF amplifies radiation-induced reactive oxygen species (ROS), collectively triggering lethal lipid peroxidation cascades. This dual mechanism is further demonstrated to elicit radiosensitizing effects in both bone-metastatic and radio-refractory PCa models without requiring radiation dose escalation, thereby improving the therapeutic index. Our study demonstrates a nanoparticle-enabled strategy to enhance tumor-specific radiotherapy by dual-targeting metabolic vulnerabilities.