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

Abstract 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 G asdermin E and T annic acid‐based nanoassembly (GT) loaded with manganese tetroxide (Mn 3 O 4 ) (termed as Mn 3 O 4 @GT) is developed to suppress tumor repopulation and improve the treatment outcome of radiotherapy. Mn 3 O 4 @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 Mn 3 O 4 @GT significantly reduced the IR induced tumor repopulation by 2.7 fold, resulting in 92% complete regression of tumors. In addition, Mn 3 O 4 @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.