A Caspase 3‐Hijacking Nanosystem Enhances Cancer Radiotherapy by Suppressing Tumor Repopulation.

Radiotherapy is used in the treatment of ≈50% of patients with cancer. However, tumor repopulation is a major cause of treatment failure after radiotherapy. It is observed that apoptotic tumor following ionizing radiation (IR) accelerated the growth of surviving tumor cells. Here a <bold>G</bold>asdermin E and <bold>T</bold>annic acid‐based nanoassembly (GT) loaded with manganese tetroxide (Mn3O4) (termed as Mn3O4@GT) is developed to suppress tumor repopulation and improve the treatment outcome of radiotherapy. Mn3O4@GT enables an increase in the reactive oxygen species accumulation in tumor cells, enhancing radiotherapy‐mediated tumor killing. What's more, it can hijack activated caspase 3 to induce tumor pyroptosis, reversing apoptosis‐mediated tumor repopulation. In vivo results shows that Mn3O4@GT significantly reduced the IR induced tumor repopulation by 2.7 fold, resulting in 92% complete regression of tumors. In addition, Mn3O4@GT can sensitize tumors to anti‐PD‐L1 therapy by inducing immunogenic pyroptosis with 85% regression of distant tumors. The caspase 3‐hijacking nanosystem holds a great potential for improving the clinical benefits of radiotherapy. [ABSTRACT FROM AUTHOR]