Self-adjusting Engineered Probiotic for Targeted Tumor Colonization and Local Therapeutics Delivery

SUMMARY Engineered bacteria have demonstrated great potential for treating a broad array of tumors. However, the precision and safety of controlling the performance of engineered bacteria in vivo remains a central challenge. Here, we utilized genetic circuit programming strategy to construct an engineered Escherichia coli Nissle 1917 with accurate targeted colonizing and on-demand payloads releasing ability. The engineered probiotic survives only in the presence of more than 5 mM L-lactate by employing an improved lactate-sensing system, which leads to preventing the growth outside the permissive environments in mice. Meanwhile we introduce an expressing α-hemolysin (SAH) circuit based on quorum-sensing system to augment anti-tumor effect. Furthermore, coagulase induced by high-level lactate creates the closure to deprive tumor of nutrients and oxygen and prevents leakage of bacteria and SAH, which enhances the therapeutic effectiveness and biosafety. This self-adjusting living biotherapeutics significantly inhibits tumor proliferation and prolongs the survival time of colorectal tumor-bearing mice. Together, our work takes a step towards safer and more effective application of living bacteria for tumor treatment in practice.