Spatially Compartmentalized DNA Nanodevices for Extra-/Intracellularly Synergistically Modulating Cancer Cell Behaviors.

Stimulus-responsive DNA nanodevices represent a frontier in therapeutic interventions. However, achieving an effective spatial division of labor following allosteric switching to enhance the regulation of cellular behaviors remains a challenge. To bridge this gap, we present the construction of a DNA nanodevice (GA-Tc/DOX), which is designed to respond to the elevated levels of K+ and ATP surrounding cancer cells. Upon co-recognition, the device executes a programmed structural reconfiguration. Its membrane-anchoring module docks selectively with the cell-surface c-Met receptor, simultaneously inhibiting downstream signaling and facilitating its degradation. In parallel, K+-induced G-quadruplex dimerization promotes the proximity of transferrin receptor (TfR) aptamers to activate TfR-mediated doxorubicin (DOX) delivery. The GA-Tc/DOX nanodevice significantly suppresses the proliferative and migratory capabilities of cancer cells through synergistic membrane-intracellular modulation, thus establishing a paradigm for spatially regulated cancer cell intervention and offering a sophisticated tool for advancing precision therapeutics.