Programming higher-order receptor clustering driven by DNA logic circuits for precise and efficient cell behavior modulation

Higher-order assembly of cell surface receptors plays a crucial role in fine-tuning signal transduction and regulating cell behavior. However, precise and efficient receptor manipulation is challenged by off-target effects when relying on single-parameter input. Herein, we developed a programmable DNA logic circuit-mediated receptor clustering (LCRC) strategy capable of multi-input recognition and cellular modulation. By integrating i-motif and ATP-binding aptamers as stimulus-responsive modules, the dynamic DNA circuitry enables logic-gated recognition of elevated protons and ATP in the tumor microenvironment, triggering nanoassembly between protein-anchored modulator modules. LCRC drives higher-order receptor clustering, effectively inhibiting tumor cell movement in the tumor-like microenvironment. Moreover, the DNA circuit enables fine-tuned inhibition of cell activity by customizing the number of engaged receptors per assembly. Our data demonstrate that higher-order receptor clustering leads to more efficient and robust modulation of cellular behavior compared to lower-order clustering. This strategy provides a versatile platform for controllable receptor clustering and programmable cell regulation, paving the way for precision therapeutic applications.