Ultra-small radiosensitizers deliver epigenetic drugs to induce pyroptosis and boost triple-negative breast cancer radiotherapy

The pyroptosis of tumor cells can elicit a potent anti-tumor immune response, offering a promising approach to the therapy of triple-negative breast cancer (TNBC) and the prevention of tumor recurrence and metastasis. This study developed a nanocomposite system of ultra-small hafnium oxide nanoparticles (HfO2 NPs) loaded with Decitabine (DAC) to effectively transform radiation-induced tumor cell apoptosis into pyroptosis. Initially, DAC was delivered efficiently to the tumor tissues, owing to the well tumor osmosis and retention of HfO2 NPs. Furthermore, HfO2 NPs can generate more reactive oxygen species to activate Caspase-3 upon ionizing radiation. Ultimately, DAC can effectively suppress DNA methyltransferase, reverse the silencing state of GSDME in TNBC cells, and convert apoptosis into pyroptosis. Pyroptosis can activate more powerful anti-tumor immunity and effectively inhibit tumor metastasis. This study not only addresses the concerns of significant side effects and low induction rate of conventional pyroptosis-inducing drugs but also provides a novel strategy for the treatment of malignancies with low GSDME expression and extends the application of pyroptosis.