Endogenous Enzyme‐Operated Spherical Nucleic Acids for Cell‐Selective Protein Capture and Localization Regulation

Abstract Precise regulation of protein activity and localization in cancer cells is crucial to dissect the function of the protein‐involved cellular network in tumorigenesis, but there is a lack of suitable methodology. Here we report the design of enzyme‐operated spherical nucleic acids (E‐SNAs) for manipulation of the nucleocytoplasmic translocation of proteins with cancer‐cell selectivity. The E‐SNAs are constructed by programmable engineering of aptamer‐based modules bearing enzyme‐responsive units in predesigned sites and further combination with SNA nanotechnology. We demonstrate that E‐SNAs are able to regulate cytoplasmic‐to‐nuclear shuttling of RelA protein efficiently and specifically in tumor cells, while they remain inactive in normal cells due to insufficient enzyme expression. We further confirmed the generality of this strategy by investigating the enzyme‐modulated inhibition/activation of thrombin activity by varying the aptamer‐based design.