Researchers led by Profs. YAN Xiyun and FAN Kelong from the Institute of Biophysics of the Chinese Academy of Sciences have developed ultrasmall AuPd alloy nanozymes that mimic neutrophil enzymatic cascades for tumor catalytic therapy.

The study was published in Nature Communications.

Nanozymes are a new type of catalyst that can catalyze enzyme substrates under physiological or low-temperature/high-temperature conditions, serving as a substitute for natural enzymes for human health. In the field of tumor treatment, the strategy of nanozymes catalyzing hydrogen peroxide (H₂O₂) to generate reactive oxygen species to kill tumor cells has great potential. However, the low concentration of H₂O₂ (less than 0.1 mM) in the tumor microenvironment limits its therapeutic efficacy. The multi-enzyme cascade killing mechanism of neutrophils offers a novel approach to overcome this problem.

The researchers simulated the principle of neutrophil enzyme-mediated cascade killing of tumors and developed a nanozyme with both superoxide dismutase (SOD)-like and myeloperoxidase (MPO)-like activities. The study found that the Au₁Pd₃ alloy nanozyme could mimic the SOD-MPO cascade killing effect of neutrophils by generating hypochlorous acid (HClO) and singlet oxygen (¹O₂) to cause DNA damage and cell apoptosis. This nanozyme significantly inhibited tumor growth in mouse colon cancer CT26 and breast cancer 4T1 xenograft models, leading to a significant increase in survival time of tumor-bearing mice.

In addition, the Au₁Pd₃ alloy nanozyme exhibited good in vivo safety, mainly due to the high concentration of its catalytic substrate superoxide anion (O₂^·-) in tumor cells compared to normal cells, conferring tumor-specific cytotoxicity. The ultra-small size of this nanozyme (less than six nm) endowed it with a renal clearance function, avoiding long-term accumulation in the body.

The biomimetic strategy of this study to simulate neutrophil multi-enzyme cascade reactions for tumor treatment will drive the development of more biomimetic treatment methods for use in antibacterial, antitumor, or other disease treatments.

Furthermore, the approach of using nanozymes with multi-enzyme activity to mimic various natural enzymes in phagosomes will also promote research on nanozyme-mimicking organelles (such as lysosomes, peroxisomes, etc.).

The MPO-like activity possessed by the nanozyme in this study is a novel type of nanozyme catalysis, with limited current research. Given its potential applications in tumor treatment, antibacterial, and other fields, as well as the elucidation of its catalytic mechanism in this study, more discoveries and designs of MPO-like activity nanozymes are likely to be promoted.

Development of neutrophil enzyme-induced nanozymes and their application in tumor catalytic therapy. (Image by FAN Kelong's group)