DNA-Enzyme Hybrid Nanostructures: Functional Materials to Modulate Enzymatic Activity.

DNA nanotechnology enables the precise assembly of complex and versatile 2-dimensional (2D) and 3-dimensional (3D) nanostructures. Coupling enzymes to such DNA nanostructures offers great control over the enzymes' positioning and stoichiometry to modify their activity and unleash their maximum catalytic capacity. While enzymes hosted on DNA nanostructures have shown predominantly enhanced enzymatic activity, existing hypotheses such as proximity effects, electrostatic interactions, and pH modulation fail to fully account for the observed enhancement. Protection against enzymatic deactivation plays a role, but additional mechanisms, including potential hydration layer stabilization, require further investigation. Furthermore, spatial proximity alone does not guarantee efficiency in multi-enzyme cascades, particularly in systems with unbalanced kinetics. Another big challenge remains when it comes to addressing disproportionally large enzymes. In this review, we summarize recent literature on DNA-enzyme hybrid nanostructures and critically discuss the proposed hypotheses, aiming to shed light on the change in enzymatic activity upon conjugation to DNA nanostructures. We highlight gaps and remaining open questions in the field as well as giving a brief overview of potential applications of such DNA-enzyme hybrid nanostructures.