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Metal nanoclusters, made up of several to one hundred metal atoms (e.g., Au, Ag, Cu, Pt), are a novel class of intermediate between metal atoms and nanoparticles. As their size (<2 nm) borders on the Fermi wavelength of electrons, metal nanoclusters possess strong photoluminescence in comparison with large metal nanoparticles (>2 nm). This, combined with tunable fluorescence emissions, high photostability, good quantum yields and facile synthesis, make them excellent fluorescent labels for biomedical applications.

However, the reduction of metal ions in liquid solution during synthesis usually causes large nanoparticles rather than small metal nanocluster formation because of their tendency to aggregate. In light of this, proteins whose thiol, amino, and carboxyl groups have a strong affinity for metal atoms are typically used to stabilize metal nanoclusters to protect them from aggregationthese proctected clusters are commonly called protein-protected metal nanoclusters.

Protein-protected metal nanoclusters have excellent biocompatibility and have received considerable attention as a luminescent probe in a number of fields such as biosensing, bioimaging, and imaging-guided therapy. However, apart from unique optical properties, protein-protected metal nanoclusters also possess interesting biological properties such as enzyme-like activity similar to that of natural enzymes; until recently, this has been an overlooked quality that is starting to shine in basic research and practical applications.

Nanozymes is a new termed used to refer to nanomaterials with intrinsic enzyme-like activity. Since professor Yan and coworkers first discovered that nanoparticleswhich are traditionally assumed to be inertpossessed intrinsic enzyme-like activity, a substantial amount of work has focused on further developing and harnessing the advantageous properties of nanozymes, which include high catalytic ability, high stability, and low cost. Nowadays, more than 540 kinds of nanomaterials, which possess intrinsic enzymatic activity, have been reported from 350 laboratories in 30 countries and have been used in biological analysis, environmental treatment, as antibacterial agents, cancer therapy, and antioxidation therapy.

In a recent study published in WIREs Nanomedicine and Nanobiotechnology, Professor Xiyun Yan and Kelong Fan explore the newly developing field of biologically active protein-protected metal nanoclusters, namely those that possess peroxidase, oxidase, and catalase activities, and are consequently used for biological analysis and environmental treatment.

An intriguing example of this is bovine serum albumin-protected gold (Au) nanoclusters, which exhibit peroxidase enzymatic activity to catalyze the oxidation of colored organic substrates, which is currently carried out using natural peroxidases. This method showed an advantage over the natural peroxidase-based methods because bovine serum albumin-protected Au nanoclusters exhibited higher robustness and retained enzymatic activity over a wide range of pH and temperatures. In another example, lysozyme-protected platinum (Pt) nanoclusters exhibit oxidase enzymatic activity which has been applied to the oxidative degradation of pollutants, such as methylene blue in lake water.

The proteins themselves not only provide protection and stabilization during synthesis, but can also provide a myriad of other functions to the nanoclusters. Proteins have been shown to enable in vivo applications because of their enhanced biocompatibility. In fact, a protease-responsive sensor for in vivo disease monitoring was designed by utilizing the peroxidase activity of peptide-protected Au nanoclusters and their ultra-small size dependent tumor accumulation and renal clearance properties.

The sensor was developed using peptides which are the substrates/targets of disease related proteases as protective ligands to synthesis the Au nanoclusters nanozymes, which were then conjugated to a carrier. After reaching the site of disease, the sensor was disassembled in response to the dysregulated protease and the liberated Au nanoclusters were filtered through the kidneys and into urine to produce a rapid and sensitive colorimetric readout of diseases state. By employing different enzymatic substrate as protective ligands for Au nanoclusters, this modular approach could enable the rapid detection of a diverse range of diseases with dysregulated protease activities such as cancer, inflammation, and thrombosis.

These findings have extended the horizon of protein-protected metal nanoclusters properties as well as their application in various fields, says Kelong Fan. Furthermore, in the field of nanozymes, protein-protected metal nanoclusters have emerged as an outstanding new addition. Due to their ultra-small size (<2 nm), they usually have higher catalytic activity, more suitable size for in vivo application, better biocompatibility and photoluminescence in comparison with large size nanozymes. We think that ultra-small nanozymes based on protein-protected MNCs are on the verge of attracting great interest across various disciplines and will stimulate research in the fields of nanotechnology and biology.

Despite the advantages and advancedprogress in the development of protein-protected metal nanoclusters asultra-small nanozymes, there are still some challenges that need to be addressedin future work.

First, most researchers still only rely on bovine serum albumin as both the reducing agent and stabilizer. Since we know that protein-protected metal nanoclusters may retain the bioactivity of the protein ligand, it is necessary to explore methods for synthesizing other new protein-protected metal nanoclusters, which will widen the diagnostic and therapeutic applications of protein-protected metal nanoclusters nanozymes.

Second, there are six types of catalytic reactions in nature: oxidoreductases, transferases, hydrolases, isomerases, ligases, and lyases. Thus far, although many protein-protected metal nanoclusters have demonstrated enzyme activities they all are oxidoreductase-like activities such as peroxidase, oxidase, and catalase. Therefore, there is a ample room to develop other types of nanozymes based on protein-protected metal nanoclusters. In this regard, more understanding of the structures and catalytic mechanisms of protein-protected metal nanoclusters is required in addition to the deeper understanding on natural enzymes themselves.

Third, a considerable number of reports have suggested that ultra-small nanozymes based on protein-protected metal nanoclusters are promising tools for biological analysis. However, little is known about the therapeutic function of these ultra-small clusters in vivo despite their advantages of suitable size and good biocompatibility. It is well known that peroxidase, oxidase, and catalase are main enzymes in biological systems involved in the maintenance of redox homeostasis. Thus, more attention should be paid to the usage of these ultra-small nanozymes based on protein-protected metal nanoclusters as bio-catalysts in various human diseases involved in redox dysregulation such as cancer, inflammation, cardiovascular diseases. It is also possible to employ the products of redox nanozymes to treat other diseases, for example, use the toxic hydroxyl radicals produced by peroxidase nanozymes to treat bacterial infection.

Overall, there is still much room for future research and application of ultra-small nanozymes based on protein-protected metal nanoclusters. It is expected that the enzyme-like activity of protein-protected metal nanoclusters will certainly attract broader interests across various disciplines and stimulate research in the fields of nanotechnology and biology, making these emerging ultra-small nanozymes become novel multifunctional nanomaterials for a number of biomedical applications.

Kindly contributed by the authors.

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Protein-Protected Metal Nanoclusters That Behave Like Natural Enzymes - Advanced Science News