Assembly Pathway Selection with DNA Reaction Circuits for Programming Multiple Cell–Cell Interactions

The manipulation of cell–cell interactions promotes the study of multicellular behavior, but it remains a great challenge for programming multicellular assembly in complex reaction pathways with multiple cell types. Here we report a DNA reaction circuit-based approach to cell–surface engineering for the programmable regulation of multiple cell–cell interactions. The DNA circuits are designed on the basis of a stem-loop-integrated DNA hairpin motif, which has the capability of programming diverse molecular self-assembly and disassembly pathways by sequential allosteric activation. Modifying the cell surface with such DNA reaction circuits allows for performing programmable chemical functions on cell membranes and the control of multicellular self-assembly with selectivity. We demonstrate the selective control of targeting the capability of natural killer (NK) cells to two types of tumor cells, which show selectively enhanced cell-specific adaptive immunotherapy efficacy. We hope that our method provides new ideas for the programmable control of multiple cell–cell interactions in complex reaction pathways and potentially promotes the development of cell immunotherapy.