The reactivity of DNA modifying enzymes on their natural nucleic acid substrates has been fully understood. However, their reactivity on self-assembled nanostructures of nucleic acid is complicated and unpredictable. Here, we employed the molecular dynamic simulation to forecast the reactivity of tumor biomarker enzymes on DNA nanotubes by coarse grained model. It is found that the enzyme accessibility and the potential energy of the reaction products co-determine the structural change of DNA nanotubes. The reactivity can be regulated by the position of enzyme recognition site. According to the simulation results, stimuli-responsive drug nanocarrier with superior sensitivity and selectivity was developed. Drug payloads released in cancer cells is 3.7~5.5-fold higher than that in normal cells. The DNA nanocarrier equipped with cancer-specific aptamer AS1411 is used to deliver doxorubicin (DOX) to tumor-bearing mice not only effectively inhibiting tumor growth but also protecting major organs from drug-caused damage. This work provides new insights into the enzymatic reactivity of DNA nanostructures enriching the library of DNA-based reactions and heralding broad applications in nanomedicine.
