Frustrated Lewis Pair Engineered Metal–Organic Frameworks for Enhancing Peroxidase Mimicking

Abstract Natural enzymes achieve catalytic efficiency through the synergistic coupling of substrate activation and the efficient utilization of reactive intermediates. However, current nanozyme design paradigms focus predominantly on modulating substrate activation while overlooking the efficient utilization of highly reactive intermediates─a limitation that severely constrains substantial gains in catalytic activity. Inspired by the frustrated Lewis pair (FLP) composition of Fe2+ and tetrahydrobiopterin in tryptophan hydroxylase, we propose an FLP engineering approach to integrate 2,5-pyrazine-dicarboxylic acid (Pz) into the Materials of Institut Lavoisier-101 metal–organic framework (MIL-101(Fe)-H MOF) to construct MIL-101(Fe)-Pz MOF. This construct features pyrazine-nitrogen as a Lewis base and unsaturated Fe sites as Lewis acids. Compared with the Lewis acid-only MIL-101(Fe)-H MOF control, the as-fabricated FLP substantially accelerated the peroxidase-like activity of MIL-101(Fe)-Pz MOF, increasing the maximum reaction velocity by 4.83-fold when H2O2 was used as the substrate and by 17.88-fold when 3,3′,5,5′-tetramethylbenzidine (TMB) was used as the substrate. Combined experimental and theoretical analyses revealed that the distinct electronic interactions within FLP facilitate electron transfer, promote H2O2 activation, improve hydroxyl radical utilization, and lower the reaction energy barrier, thereby boosting the reaction kinetics. This work highlights the indispensable role of substrate activation and active intermediate utilization in enhancing nanozyme performance and also provides guidance for the design of next-generation bioinspired nanozymes.