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

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, genetic circuit programming strategy is utilized 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 an expressing α-hemolysin (SAH) circuit based on quorum-sensing system is introduced to augment anti-tumor effect. Furthermore, coagulase (Coa) induced by high-level lactate creates the closure to deprive tumor of nutrients and oxygen and may help prevent the 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, this work takes a step toward safer and more effective application of living bacteria for tumor treatment in practice.