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.