A Biomimetic DNA‐Based Membrane Gate for Protein‐Controlled Transport of Cytotoxic Drugs

Chemistry is ideally placed to replicate biomolecular structures with tuneable building materials. Of particular interest are molecular nanopores, which transport cargo across membranes, as in DNA sequencing. Advanced nanopores control transport in response to triggers, but this cannot be easily replicated with biogenic proteins. Here we use DNA nanotechnology to build a synthetic molecular gate that opens in response to a specific protein. The gate self‐assembles from six DNA strands to form a bilayer‐spanning pore, and a lid strand comprising a protein‐binding DNA aptamer to block the channel entrance. Addition of the trigger protein, thrombin, selectively opens the gate and enables a 330‐fold increase inw the transport rate of small‐molecule cargo. The molecular gate incorporates in delivery vesicles to controllably release enclosed cytotoxic drugs and kill eukaryotic cells. The generically designed gate may be applied in biomedicine, biosensing or for building synthetic cells. DNA nanotechnology can be used to rationally design a molecular gate to control the transport of small‐molecule drugs across bilayer membranes. The DNA pore with a thrombin‐binding aptamer lid opens in the presence of thrombin to increase the transport of the cytotoxic drug topotecan by 330‐fold. The nanodevice could be adapted for a range of different protein triggers with applications in biosensing, research, and biomedicine.