Engineering H₂S-Activatable Aptameric Binders for Tailored Cell Manipulation

Cell surface receptors play a crucial role in mediating cellular communication and precisely regulating cellular functions. Dysregulation of these receptors is closely associated with various diseases. To enable precise and dynamic receptor control, we developed a gas-responsive aptameric binder based on a chemically masked configuration, enabling stimulus-triggered reactivation. Specifically, the receptor-targeting activity of the aptamer is sterically blocked via azide modifications at critical residues, with selective restoration of function upon exposure to hydrogen sulfide (H₂S), enabling precise receptor modulation. Using this strategy, we successfully achieved H₂S-triggered receptor dimerization, leading to controlled activation of downstream signaling pathways and regulation of cellular behaviors such as migration and proliferation. Furthermore, we extended this approach to facilitate highly selective receptor degradation. By harnessing gasotransmitter cues for molecular switching, this system expands the toolkit for receptor engineering and holds great potential for targeted therapeutic interventions in regenerative medicine and oncology.