Nanozymes are inorganic, organic and metal-organic framework nanoparticles that reveal catalytic functions by emulating native enzyme activities. Recently, these nanozymes have attracted growing scientific interest, finding diverse analytical and medical applications. However, the catalytic activities and functions of nanozymes are limited, due to the lack of substrate binding sites that concentrate on the substrate at the catalytic site (molarity effect), introduce substrate specificity and allow functional complexity of the catalysts (cascaded, switchable and cooperative catalysis). The modification of nanozymes with functional nucleic acids provides means to overcome these limitations and engineer nucleic acid/nanozyme hybrids for diverse applications. This is exemplified with the synthesis of aptananozymes, which are supramolecular aptamer-modified nanozymes. Aptananozymes exhibit combined specific binding and catalytic properties that drive diverse chemical transformations, revealing enhanced catalytic activities, as compared to the separated nanozyme/aptamer constituents. Relationships of structure-catalytic functions in the aptananozyme constructs are demonstrated. In addition, modification of nanozymes exhibiting multimodal catalytic functions with aptamers allows the engineering of nanozyme-based bioreactors for cascaded catalysis. Also, the functionalization of reactive oxygen species (ROS)-generating nanozymes with cancer cell-recognizing aptamers yields aptananozymes for targeted chemodynamic treatment of cancer cells and cancer tumors elicited in mice. Finally, nucleic acid-modified enzyme (glucose oxidase)-loaded metal-organic framework nanoparticles yield switchable biocatalytic nanozymes that drive the ON/OFF biocatalyzed oxidation of Amplex Red, dopamine or the generation of chemiluminescence. Herein, future challenges of the topic are addressed.