Programming Receptor Clustering with DNA Probabilistic Circuits for Enhanced Natural Killer Cell Recognition

Abstract Developing strategies to enhance the recognition ability of immune cells is important to the success of cell‐based cancer immunotherapy. Herein, we report programming receptor clustering on membrane with DNA probabilistic circuits for enhanced immune cell recognition. By designing the circuit output to activate receptors for binding to adjacent receptors, we can engineer DNA probabilistic circuits for programmable regulation of receptor clustering. The generated receptor clusters show higher binding affinity to target cancer cells and improved membrane‐anchoring stability compared with monomers. We demonstrate that programming receptor clustering could allow to modulate the recognition capability of natural killer cells and control natural killer cell–cancer cell interactions to promote efficient cancer cell killing. This work provides insights for precise control over cellular recognition and opens new opportunities for the development of cell‐based immunotherapy.