ZIF‐Based Nanoparticles Combine X‐Ray‐Induced Nitrosative Stress with Autophagy Management for Hypoxic Prostate Cancer Therapy

Although reactive oxygen species (ROS)‐mediated tumor treatments are predominant in clinical applications, ROS‐induced protective autophagy promotes cell survival, especially in hypoxic tumors. Herein, X‐ray triggered nitrite (NO2−) is used for hypoxic prostate cancer therapy by inhibiting autophagy and inducing nitrosative stress based on an electrophilic zeolitic imidazole framework (ZIF‐82‐PVP). After internalization of pH‐responsive ZIF‐82‐PVP nanoparticles, electrophilic ligands and Zn2+ are delivered into cancer cells. Electrophilic ligands can not only consume GSH under hypoxia but also capture low‐energy electrons derived from X‐rays to generate NO2−, which inhibits autophagy and further elevates lethal nitrosative stress levels. In addition, dissociated Zn2+ specifically limits the migration and invasion of prostate cancer cells through ion interference. In vitro and in vivo results indicate that ZIF‐82‐PVP nanoparticles under X‐ray irradiation can effectively promote the apoptosis of hypoxic prostate cancer cells. Overall, this nitrosative stress‐mediated tumor therapy strategy provides a novel approach targeting hypoxic tumors. X‐ray‐triggered nitrite (NO2−) is used for hypoxic prostate cancer therapy by inhibiting protective autophagy and inducing lethal nitrosative stress based on ZIF‐82‐PVP. After entering tumor cells, the released 2‐nitroimidazole ligands capture low‐energy electrons derived from X‐rays to produce NO2−, and the Zn2+ inhibits the migration and invasion of tumor cells.