Reprogramming Synthetic Cells for Targeted Cancer Therapy

[Image: see text] Advances in synthetic biology enable the reprogramming of bacteria as smart agents to specifically target tumors and locally release anticancer drugs in a highly controlled manner. However, the bench-to-bedside translation of engineered bacteria is often impeded by genetic instability and the potential risk of uncontrollable replication of engineered bacteria inside the patient. SimCells (simple cells) are chromosome-free bacteria controlled by designed gene circuits, which can bypass the interference of the native gene network in bacteria and eliminate the risk of bacterial uncontrolled growth. Here, we describe the reprogramming of SimCells and mini-SimCells to serve as “safe and live drugs” for targeted cancer therapy. We engineer SimCells to display nanobodies on the surface for the binding of carcinoembryonic antigen (CEA), which is an important biomarker found commonly in colorectal cancer cells. We show that SimCells and mini-SimCells with surface display of anti-CEA nanobody can specifically bind CEA-expressing Caco2 cancer cells in vitro while leaving the non-CEA-expressing SW80 cancer cells untouched. These cancer-targeting SimCells and mini-SimCells induced cancer cell death in vitro by compromising the plasma membrane of cancer cells. The cancer-killing effect can be further enhanced by an aspirin/salicylate inducible gene circuit that converts salicylate into catechol, a potent anticancer. This work highlights the potential of SimCells and mini-SimCells for targeted cancer therapy and lays the foundation for the application of synthetic biology to medicine.