Engineering Whole Mammalian Cells for Target‐Cell‐Specific Invasion/Fusion

Abstract

Live mammalian cells are equipped with a synthetic cell invasion system that enables their target‐specific insertion into other live mammalian cells. By conjugating RhoA activator to a transmembrane protein that is segregated from cell–cell interface when specific cell contact occurs, polarization of RhoA activity is synthetically induced inside the cells in response to specific cell contact. This polarization is a sufficient condition for invader cells to selectively penetrate cells expressing a target antigen. Further, when an acid‐responsive fusogenic protein is expressed on invader cells, invader/receiver cell fusion occurs after invasion, and the invader's intracellular contents are released into the recipient's cytosol. It is shown that this system can be used for specific cell ablation. This synthetic‐biology‐inspired cell invasion/fusion system might open the door to using whole mammalian cells for cargo delivery purposes or for ablation of a specific cell type.

Molecular mechanisms underlying cell-in-cell formation: core machineries and beyond

“…Moreover, despite many mechanistic insights that had been obtained, genetic engineering of CICs for technical and therapeutic purposes was relatively rare. Two Japanese groups had made interesting exploration in utilizing CICs as vectors to transfer therapeutic reagents such as oncolytic viruses ( Onishi et al, 2016 ; Kojima and Fussenegger, 2018 ), which provided a proof-of-principle example, though preliminary and to be optimized, for the potential applications of engineered CICs. It is conceivable that more promising strategies aiming for technical and therapeutic purposes would be available with efforts endeavored in the future.…”

Building sophisticated sensors of extracellular cues that enable mammalian cells to work as “doctors” in the body

“…We also showed that this kind of physical movement of signaling proteins upon specific cell contact can be used to programme a totally different function; target-specific synthetic cell invasion [ 43 ] (Fig. 4 b).…”

Synthetic Biology: Engineering Mammalian Cells To Control Cell‐to‐Cell Communication at Will

“…Conversely, inspired by the cell invasion phenomena observed in nature (e.g., entosis, emperipolesis), we succeeded in endowing nonimmune cells with the ability to “invade” specific cell types (Figure B). In the process of entosis, it has been reported that polarisation of RhoA activity occurs (low RhoA activity at the invader‐target cell interface, high RhoA activity at the other side) .…”