An artificial enzyme developed by researchers in China catalyzes a redox reaction 12 times more efficiently than a natural enzyme found in horseradish. It is the highest efficiency that an artificial enzyme has achieved to outperform its natural counterpart.

Enzymes evolve over billions of years and are the ultimate catalysts necessary for life. While man-made versions have been studied for several decades, adapting their catalytic performance to nature’s enzymes has remained a challenge. Nanomaterials with enzyme-like properties – so-called nanozymes – that are more stable, cheaper and easier to store than natural enzymes, have shown potential for biomedical and biosensor applications. However, their catalytic activity has remained limited.

An illustration showing the artificial nanoenzyme and the natural enzyme.  The former consists mainly of gray carbon atoms, which are arranged in a lattice and over which some colorful active sites (iron, nitrogen, phosphorus) are distributed.

Now, a team led by Yadong Li from Tsinghua University in Beijing has developed a nanozyme whose electronic and geometric structure mimics the natural enzyme horseradish peroxidase, but whose catalytic efficiency is better. “More importantly, we show that the catalytic performance can be modulated via the local structural control of the active centers and their coordination environment,” explains team member Dingsheng Wang.

Most natural enzymes are proteins that have a unique three-dimensional amino acid structure. However, some evolved to contain a metal ion that acts as a catalytically active site a at which substrate binding occurs. In peroxidases, the metal is usually iron. Found in a wide variety of organisms including plants, humans, and bacteria, peroxidases are one of the most well-studied enzymes with various uses such as diagnostic tests and the removal of toxic phenols from industrial wastewater. Their main function is to catalyze redox reactions by oxidizing electron donor substrates that convert hydrogen peroxide to water and oxygen.

To replicate this in a nanozyme, the researchers developed a zeolite framework made of carbon and nitrogen at the atomic level that mimics the natural amino acid structure. Phosphorus was then added to the mixture, as the element often plays a key role in enzyme activity, acts as an anchor for the metal-active center and transports electrons from the substrate to it. Iron was then introduced prior to a pyrolysis step that formed the final nanozyme powder. Analyzes showed that iron, nitrogen, and phosphorus atoms formed individual clusters that were evenly distributed across the carbon lattice.

Tests of peroxidase activity using a tetramethylbenzidine substrate showed that the nanoenzyme was 12 times more efficient than horseradish peroxidase under the same reaction conditions, more than any other artificial enzyme has so far achieved compared to its natural counterpart.

After experiments showing that the nanoenzyme’s superior peroxidase activity can induce rapid oxidative death of tumor cells, the team tested them on live mice. When the nanoenzyme was injected into tumors, 14 days later they were less than half the size of tumors in untreated controls and no toxic effects were found.

‘Nature uses exquisite control over metal ligature to provide highly efficient catalysts. This structural control is elegantly modeled here in single-metal catalysts, ”comments Vince Rotello, who studies artificial enzymes at the University of Massachusetts, USA. “The single atom strategy presented is a promising direction for the development of nanocatalysts for biological, environmental and chemical applications.”

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