A T‐Cell Inspired Sonoporation System Enhances Low‐Dose X‐Ray‐Mediated Pyroptosis and Radioimmunotherapy Efficacy by Restoring Gasdermin‐E Expression

Abstract Genome editing has the potential to improve the unsatisfactory therapeutic effect of antitumor immunotherapy. However, the cell plasma membrane prevents the entry of almost all free genome‐manipulation agents. Therefore, a system can be spatiotemporally controlled and can instantly open the cellular membrane to allow the entry of genome‐editing agents into target cells is needed. Here, inspired by the ability of T cells to deliver cytotoxins to cancer cells by perforation, an ultrasound (US)‐controlled perforation system (UPS) is established to enhance the delivery of free genome‐manipulating agents. The UPS can perforate the tumor cell membrane while maintaining cell viability via a controllable lipid peroxidation reaction. In vitro, transmembrane‐incapable plasmids can enter cells and perform genome editing with the assistance of UPS, achieving an efficiency of up to 90%. In vivo, the UPS is biodegradable, nonimmunogenic, and tumor‐targeting, enabling the puncturing of tumor cells under US. With the application of UPS‐assisted genome editing, gasdermin‐E expression in 4T1 tumor‐bearing mice is successfully restored, which leads to pyroptosis‐mediated antitumor immunotherapy via low‐dose X‐ray irradiation. This study provides new insights for designing a sonoporation system for genome editing. Moreover, the results demonstrate that restoring gasdermin expression by genome editing significantly improves the efficacy of radioimmunotherapy.