Achieving Peroxidase-like Kinetics and ROS Production with Single-atom Iron Nanozymes

Antioxidant enzymes such as peroxidase, catalase, and superoxide dismutase perform the critical role of converting reactive oxygen species (ROS) like hydrogen peroxide and superoxide into benign molecules such as water and dioxygen. However, some modern cancer treatments seek to take advantage of the destructive effects of ROS to induce cell death in tumor cells¹. Native peroxidases are typically cytoprotective, but their ability to rapidly and selectively activate H₂O₂ into high-valent oxidants is attractive for controlled, targeted pro-oxidant therapy; however, enzyme-based drugs are limited by poor stability, unpredictable efficacy, and immunogenicity. Hence, alternative strategies to access ROS-regulating processes, such as nanozymes, are required. 

Nanozymes are nanomaterials with enzyme-like functions, particularly oxidoreductase activities. These nanometer-scale synthetic structures aim to replicate the selectivity and rapid kinetics of traditional enzymes while possessing the high stability and lower costs of metal catalysts. Since the discovery of the peroxidase-like activity of Fe₃O₄ particles in 2007², in which hydroxyl radicals are generated from Fe-bound hydrogen peroxide, this field has exploded to encompass a wide and ever-growing variety of nanozymes³. Emphasized in this literature seminar are single-atom iron nanozymes that mimic the structure and catalytic mechanism of heme in horseradish peroxidase. In one example, doping of the porphyrin-like FeN₄ framework with Pd nanoclusters converts the iron center from low spin to a medium spin electronic configuration, increasing its ability to bind and activate hydrogen peroxide to a Fe(IV)=O species⁴. In another, incorporation of a phosphorus ligand allows for peroxidase-like kinetics closely approaching those of traditional enzymes⁵. By rapidly generating ROS in the form of hydroxyl radicals and ferryl species, these nanozymes were demonstrated to have potent antitumor effects in vivo and in vitro. These characteristics position single-atom iron nanozymes to be a unique next-generation treatment for numerous forms of cancer. 

References

(1) Zhang, R.; Jiang, B.; Fan, K.; Gao, L.; Yan, X. Designing nanozymes for in vivo applications. Nature Reviews Bioengineering 2024, 2 (10), 849-868. DOI: 10.1038/s44222-024-00205-1.

(2) Gao, L.; Zhuang, J.; Nie, L.; Zhang, J.; Zhang, Y.; Gu, N.; Wang, T.; Feng, J.; Yang, D.; Perrett, S.; et al. Intrinsic peroxidase-like activity of ferromagnetic nanoparticles. Nature Nanotechnology 2007, 2 (9), 577-583. DOI: 10.1038/nnano.2007.260.

(3) Huang, Y.; Ren, J.; Qu, X. Nanozymes: Classification, Catalytic Mechanisms, Activity Regulation, and Applications. Chemical Reviews 2019, 119 (6), 4357-4412. DOI: 10.1021/acs.chemrev.8b00672.

(4) Wei, X.; Song, S.; Song, W.; Wen, Y.; Xu, W.; Chen, Y.; Wu, Z.; Qin, Y.; Jiao, L.; Wu, Y.; et al. Tuning iron spin states in single-atom nanozymes enables efficient peroxidase mimicking. Chemical Science 2022, 13 (45), 13574-13581, 10.1039/D2SC05679H. DOI: 10.1039/D2SC05679H.

(5) Ji, S.; Jiang, B.; Hao, H.; Chen, Y.; Dong, J.; Mao, Y.; Zhang, Z.; Gao, R.; Chen, W.; Zhang, R.; et al. Matching the kinetics of natural enzymes with a single-atom iron nanozyme. Nature Catalysis 2021, 4 (5), 407-417. DOI: 10.1038/s41929-021-00609-x.