Logic Nanodevice-Mediated Receptor Assembly for Nongenetic Regulation of Cell Behavior in Tumor-like Microenvironment

The reprogramming of cell signaling and behavior through the artificial control of cell surface receptor oligomeriza-tion shows great promise in biomedical research and cell-based therapy. However, it remains challenging to achieve combinatorial recognition in a complicated environment and logical regulation of receptors for desirable cellular behavior. Herein, we develop a logic-gated DNA nanodevice with responsiveness to multiple environmental inputs for logically controlled assembly of heterogeneous receptors to modulate signaling. The "AND" gate nanodevice uses an i-motif and an ATP-binding aptamer as environmental cue-responsive units, which can successfully imple-ment a logic operation to manipulate receptors on the cell surface. In the presence of both protons and ATP, the DNA nanodevice is activated to selectively assemble MET and CD71, which modulate the HGF/MET signaling, resulting in cytoskeletal reorganization to inhibit cancer cell motility in a tumor-like microenvironment. Our strategy would be highly promising for precision therapeutics, including controlled drug release and cancer treatment.