In Situ Coupling of Catalytic Centers into Artificial Substrate Mesochannels as Super‐Active Metalloenzyme Mimics

Abstract Highly evolved substrate channels in natural enzymes facilitate the rapid capture of substrates and direct transfer of intermediates between cascaded catalytic units, thus rationalizing their efficient catalysis. In this study, a nanoscale ordered mesoporous Ce‐based metal–organic framework (OMUiO‐66(Ce)) is designed as an artificial substrate channel, where MnO 2 is coupled to Ce–O clusters as a super‐active catalase (CAT). An in situ soft template reduction strategy is developed to deposit well‐dispersed and exposed MnO 2 in the mesochannels of OMUiO‐66(Ce). Several synthesis parameters are optimized to minimize the particle size to ≈150 nm for efficient intracellular endocytosis. The mesochannels provide interaction guidance that not only rapidly drove H 2 O 2 substrates to CAT‐like catalytic centers, but also seamlessly transfer H 2 O 2 intermediates between superoxide dismutase‐like and CAT‐like biocatalytic cascades. As a result, the biomimetic system exhibits high efficiency, low dosage, and long‐lasting intracellular antioxidant function. Under disease‐related oxidative stress, the artificial substrate channels promote the rate of the reactions catalyzed by MnO 2 , which exceeds that of the reactions catalyzed by natural CAT. Based on this observation, a set of design rules for substrate channels are proposed to guide the rational design of super‐active biomimetic systems.