Metal–Organic Framework Dimensionality and Interfacial Interactions Govern DNA Hydrolysis

Abstract

Cleavage of phosphodiester bonds in DNA is a challenging yet essential reaction in many medical and biotechnological applications. This has motivated the development of synthetic catalysts that mimic nuclease reactivity while offering greater robustness, tunability, and cost-efficiency than natural enzymes. Three-dimensional metal–organic frameworks (MOFs) containing well-defined Lewis acidic sites are capable of activating phosphoester bonds, however, their small pore apertures limit accessibility of large biomolecular substrates such as DNA. Here, we report two-dimensional MOF nanosheets as superior catalysts for DNA hydrolysis, demonstrating that reduced dimensionality enhances catalytic performance compared to their three-dimensional counterparts. Comparison of 3D hcp/hxl UiO-67 and 2D hns UiO-67, constructed from identical Zr-oxo clusters and linkers, reveals that increased active site exposure enhances cleavage of both DNA and the model substrate para-nitrophenyl phosphate (pNPP). In contrast, the discrete [Zr6O4(OH)4(CH3CO2)12]2 cluster, analogous to the framework nodes, showed exceptionally high activity toward pNPP hydrolysis but was inactive in DNA cleavage because it induced extensive DNA aggregation. This indicates that, beyond intrinsic reactivity of the metal-oxo node, framework architecture plays a crucial role in regulating DNA adsorption/desorption. Taken together, we establish two-dimensional MOF nanosheets as superior, tunable platforms for DNA hydrolysis, owing to their enhanced active site exposure.