Bioorthogonal regulation of DNA circuit for smart intracellular microRNA imaging

Catalytic DNA circuit represents a versatile toolbox for tracking intracellular biomarkers yet is constrained with low anti-interference capacity originating from their severe off-site activation. Herein, by introducing an unprecedented endogenous DNA repairing enzyme-powered pre-selection strategy, we develop a sequential and specific on-site activated catalytic DNA circuit for achieving the cancer cell-selective imaging of microRNA with high anti-interference capacity. Initially, the circuitry reactant is firmly caged by an elongated stabilizing duplex segment with the recognition/cleavage site of cell-specific DNA repairing enzyme, which can prevent the undesired signal leakage prior to its exposure in target cells. Then the intrinsic DNA repairing enzyme of target cells can liberate the DNA probe for efficient intracellular microRNA imaging via the multiply guaranteed molecular recognition/activation procedures. This bioorthogonal regulated DNA circuit presents a modular and programmable amplification strategy for highly reliable assay of intracellular biomarkers, and provides a pivotal molecular toolbox for living systems.