Dual-responsive engineered bacteria with spatiotemporal controlled release of Cytolysin-A for oral management of...

Bacterial therapy is an emerging, promising option for tumor management. Enhancing the controllability of engineered bacteria to improve therapeutic efficacy and minimize undesirable side effects is essential to facilitate the clinical translation of bacterial therapies. In this work, a dual-responsive engineered bacteria based on the E. coli Nissle 1917 probiotic was constructed for tumor therapy. The therapeutic activity of this engineered bacteria is cis-controlled by lactic acid molecules and photothermal signaling. The engineered bacteria produce and accumulate cytolysin-A in the tumor lactate-rich microenvironment, followed by the self-lysis release of cytolysin-A by near-infrared light-initiated bacterial expression of melittin. This process makes the engineered bacteria highly tumor-suppressive and promotes necrotic apoptosis of tumor cells. This strategy allows the production and release of proteins from engineered bacteria to be precisely confined in tumor tissues, improving the precision and safety of engineered bacteria-based therapies. This double-instruction confirmation platform could provide a flexible and safe personalized approach for applying multiple protein drugs to tumor therapy.