Intelligent DNA Nanodevice for Accurate Modulation of Cellular Behaviors and Intercellular Interactions In Vitro

The precise modulation of cellular behaviors and intercellular interactions in a complex microenvironment remains a significant challenge, especially in biomedical research and cell-based therapies. In this study, we designed an intelligent DNA nanodevice with a responsiveness to multiple environmental stimuli to accurately regulate cellular behaviors and modulate cell–cell interactions in vitro. In this system, a DNA logic gate employes an i-motif and an ATP-aptamer to respond to extracellular acidity. Upon both ATP and protons existing simultaneously, the DNA logic gate could be activated to reprogram cancer cell membrane receptors, resulting in regulating cellular behaviors. Following the introduction of a triggering hairpin, a DNA cycle was performed on the cancer cell surface, releasing a single-stranded trigger. Subsequently, the released triggering strand could induce a branch migration reaction process on the T cells’ surface, leading to the opening of a DNA hairpin. Furthermore, the activated “AND” logic gate could hybridize with DNA fragments on T cells, effectively bridging the gap between T cells and cancer cells. Due to DNA cycle-driven signal amplification, this DNA logic gate could not only identify cancer cells and regulate their behavior but also promote the aggregation of cancer cells and T cells. This work underscores the great potential of DNA logic gates and DNA aptamers in precision therapeutics, providing a paradigm for the development of cell therapy.