Programming Cell-Cell Interactions through Non-genetic Membrane Engineering

The ability to direct targeted intercellular interactions has the potential to enable and expand the use of cell-based therapies for regenerative medicine, tissue engineering, and immunotherapy. While genetic engineering approaches have proven effective, these techniques are not amenable to all cell types and often yield permanent modifications with potentially long-lasting adverse effects, restricting their application. To circumvent these limitations, there is intense interest in developing non-genetic methods to modify cell membranes with functional groups that will enable the recognition of target cells. While many such techniques have been developed, relatively few have been applied to directing specific cell-cell interactions. This review details these non-genetic membrane engineering approaches—namely, hydrophobic membrane insertion, chemical modification, liposome fusion, metabolic engineering, and enzymatic remodeling—and summarizes their major applications. Based on this analysis, perspective is provided on the ideal features of these systems with an emphasis on the potential for clinical translation. Non-genetic techniques for modifying cell membranes with artificial targeting ligands have emerged as powerful and flexible tools for controlling cellular interactions. Csizmar et al. review the current techniques and applications for this expanding field, and provide perspective on key features that may enhance the clinical translatability of these systems.