Potential of the Coordinated Actions of Multiple Protein-Based Micromachines for Medical Applications

Untethered mobile micromachines hold great promise in the development of effective and minimally invasive therapies. Although diverse medical micromachines for specific applications have been developed over the past few decades, the coordinated action of multiple machines with different functions remains largely unexplored. In this study, we created three types of biocompatible micromachines using proteins and demonstrated the potential of their coordinated action for medical applications. As a proof of concept, we demonstrated neural replacement therapy, in which neuroblastomas were killed by using an anticancer prodrug and the first machine that contains enzymes, enabling the conversion of the prodrug into a cytotoxic drug. Subsequently, a second machine composed of extracellular matrix was placed on the dead cancer cells to provide a suitable environment for cell adhesion, on which embryonic stem (ES) cells and stromal cells that promote neural differentiation of stem cells were attached by using third machines capable of delivering cells to target positions with desired patterns. As a result, neuroblastomas were replaced with novel healthy neurons derived from ES cells by teaming multiple protein-based machines. We believe that this work highlights the potential of heterogeneous machine groups for medical treatment and the utility of highly biocompatible and functional micromachines made from proteins, representing an important step forward in building more sophisticated micromachine-based therapies.