Nucleic Acid-Based Membrane Surface Engineering For Programming Cell-Cell Interactions

Intercellular communication plays an important role in living systems.Regulation of cell-cell interaction and cell behavior through cell surface engineering is of great significance for life science research such as cell fate control and cell-based immunotherapy.Nucleic acid has the advantages of easy synthesis,easy modification,high programmability and good biocompatibility,making it an ideal material for accurately controlling the cell-cell interaction.Despite that many studies have realized the cell-cell assembly by engineering cell surface with DNA nanotechnology,the established cell assemblies often lack specificity and controllability,and it remains challenging to realize rapid remote disassembly.Here,we designed a dual aptamer-regulatory and photo-active DNA circuit.By engineering DNA circuit elements on the surface of cell membranes,we can effectively manipulate the interactions between cells and realize the specific assembly and controllable disassembly between cells.We first used DNA circuits with aptamer specific responses to regulate the cell assembly.The construction module of DNA circuit is composed of DNA circuit element with functional aptamer and another DNA circuit element with complementary sequence.In the presence of a target substance with high binding ability to the aptamer,the DNA circuit element with the aptamer will undergo a conformational change and turn into an activated state containing a stem-loop structure.It will hybridize with another circuit element through the principle of base pair complementary to realize the assembly.Next,we introduced photocleavage groups to design a DNA circuit with light-controlled dissociation ability.After its regulation of the cells-selective assembly,the effective remote disassembly of assembled cells was achieved by UV irradiation.Finally,we applied DNA circuit to natural killer(NK)cell-based immunotherapies.The assembly and disassembly between NK cells and cancer cells can be regulated by the DNA circuit with dual responses,which promotes the ability of NK cell to target and recombine cancer cells,and enhances the killing ability of NK cells,thereby enhancing its great potential in cellular immunotherapy.With a wide variety of cell-specific aptamers and easy replacement in modular construction,our approach provides an intelligent and flexible tool for regulating the dynamic behavior of cells.