Smart Nanozymes for Cancer Therapy: The Next Frontier in Oncology

Abstract

Nanomaterials that mimic the catalytic activity of natural enzymes in the complex biological environment of the human body are called nanozymes. Recently, nanozyme systems have been reported with diagnostic, imaging, and/or therapeutic capabilities. Smart nanozymes strategically exploit the tumor microenvironment (TME) by the in situ generation of reactive species or by the modulation of the TME itself to result in effective cancer therapy. This topical review focuses on such smart nanozymes for cancer diagnosis, and therapy modalities with enhanced therapeutic effects. The dominant factors that guide the rational design and synthesis of nanozymes for cancer therapy include an understanding of the dynamic TME, structure-activity relationships, surface chemistry for imparting selectivity, and site-specific therapy, and stimulus-responsive modulation of nanozyme activity. This article presents a comprehensive analysis of the subject including the diverse catalytic mechanisms of different types of nanozyme systems, an overview of the TME, cancer diagnosis, and synergistic cancer therapies. The strategic application of nanozymes in cancer treatment can well be a game changer in future oncology. Moreover, recent developments may pave the way for the deployment of nanozyme therapy into other complex healthcare challenges, such as genetic diseases, immune disorders, and ageing.

Keywords: cancer; catalytic activities; nanotechnology; nanozymes; oncology; therapies; tumor microenvironments.

Figure 1

Schematic representation of the desirable characteristics of novel nanozymes for cancer theranostics, and enzymatic reactions exhibited by four common types of nanozymes, that is, catalase (CAT)‐, superoxide dismutase (SOD)‐, peroxidase (POD)‐ and oxidase (OXD)‐mimicking nanozymes.

Figure 2

Determination of nanozyme activity using standard chromogenic assays; A) TEM images of three typical peroxidase nanozymes based on Fe₃O₄, carbon, and gold; scale bars 200, 200, and 100 nm, respectively. B) All the three nanozymes exhibited peroxidase activity and induced oxidation of TMB, DAB, and OPD substrates clearly visible from the color change. C) Left, reaction time curves for the TMB oxidation reaction, center, the reaction time curves selectively shown from 0–60 s, right, comparison of the specific activities for the three nanozymes, determined using the nanozyme activity standardization method and D) comparison of the determined kinetic constants for Fe₃O₄, carbon, and gold nanozymes against horseradish peroxidase (HRP). Reproduced with permission.^{[ 177 ]} Copyright 2018, Springer Nature.

Figure 3

Schematic representation of characteristics of nanozymes and its applicability for treating cancer. Reproduced under the terms of the CC‐BY license.^{[ 188 ]} Copyright 2019, the Authors. Published by Springer Nature; Reproduced with permission.^{[ 189 ]} Copyright 2019, Elsevier; Reproduced with permission.^{[ 190 ]} Copyright 2020, Springer Nature; Reproduced with permission.^{[ 191 ]} Copyright 2014, Wiley‐VCH GmbH; Reproduced with permission.^{[ 192 ]} Copyright 2021, Wiley‐VCH GmbH; Reproduced with permission.^{[ 84 ]} Copyright 2021, the Royal Society of Chemistry; Reproduced under the terms of the CC‐BY license.^{[ 193 ]} Copyright 2014, the Authors. Published by MDPI; Reproduced under the terms of the CC‐BY license.^{[ 194 ]} Copyright 2021, the Authors. Published by Springer Nature; Reproduced under the terms of the CC‐BY license.^{[ 195 ]} Copyright 2022, the Authors. Published by Wiley‐VCH GmbH; Reproduced with permission.^{[ 196 ]} Copyright 2012, Wiley‐VCH GmbH; Reproduced under the terms of the CC‐BY license.^{[ 197 ]} Copyright 2018, the Authors. Published by American Chemical Society; Reproduced under the terms of the CC‐BY license.^{[ 198 ]} Copyright 2017, the Authors. Published by the Royal Society of Chemistry; Reproduced with permission.^{[ 199 ]} Copyright 2012, The Royal Society of Chemistry; Reproduced with permission.^{[ 200 ]} Copyright 2010, Wiley‐VCH GmbH.

Figure 4

Distinct morphological and biological characteristics of a novel form of cell death termed nanoptosis induced by peroxidase‐mimicking nanozymes: A) Condition of HepG2 cells after exposure to Fe₃O₄ nanozyme for different duration and B) comparison of nanoptosis with PBS buffer treated HepG2 cells; the region in the white box is depicted in lower panels, the yellow arrow points toward chromatin condensation, margination, and nucleolus disintegration, black arrows point toward the formation of monomembrane vesicles, white arrows point toward swelling of mitochondria and vacuolation, and red arrows point toward internalization of Fe₃O₄ nanozymes in lysosomes. Reproduced with permission.^{[ 141 ]} Copyright 2020, Wiley‐VCH GmbH.

Figure 5

Schematic illustration of the multiple enzyme mimic activity of PtCu₃ nanocages and its use in sonodynamic chemotherapy. PtCu₃ nanozyme exhibited fivefold benefits such as enhanced peroxidase activity under ultrasound irradiation, generation of reactive oxygen species due to peroxidase activity, glutathione peroxidase activity for glutathione depletion, high near‐infrared absorption for photoacoustic imaging, and X‐ray attenuation for computer tomography imaging. Reproduced with permission.^{[ 155 ]} Copyright 2019, Wiley‐VCH GmbH.

Figure 6

A) Schematic representation of a nitrogen‐doped carbon‐based nanozyme, termed N‐PCNSs‐3, which exhibited multiple enzyme‐like catalytic activities, that is, oxidase‐, peroxidase‐, superoxide dismutase‐ and catalase‐like properties. B) Schematic representation of ferritin‐mediated specific delivery of N‐PCNSs through the lysosomal pathway for ROS generation and tumor cell apoptosis and C) morphology of tumors and the deterioration after treatment with different types of HFn‐N‐PCNSs‐3 nanozymes and treatment durations. Reproduced under the terms of the CC‐BY license.^{[ 157 ]} Copyright 2018, the Authors. Published by Springer Nature.

Figure 7

A) Schematic representation of H₂O₂ self‐producing single‐atom nanozyme hydrogels as light‐controlled oxidative stress amplifiers for enhanced synergistic therapy, and B) representation of 808 nm‐laser induced release of CPT and SAEs and hydroxyl radical generation. Reproduced with permission.^{[ 161 ]} Copyright 2022, Wiley‐VCH GmbH.

Figure 8

A) Schematic illustration of the synthesis of MPDA‐WS₂@MnO₂ nanozymes and their application in oxygen‐sensitized radiotherapy by ameliorating tumor hypoxia. B) In vivo multispectral optoacoustic tomography (MSOT) imaging capturing the internalization of nanozymes in tumor cells with time. C) Computed tomography imaging of tumor in mice before and after intravenous injection of MPDA‐WS₂@MnO₂ nanozymes, white circles depict the location of the tumor, the concentration of nanozymes in tumor cells is evident from CT imaging. D) T1‐weighted in vivo magnetic resonance images of the tumor before and after injection of MPDA‐WS₂@MnO₂ nanozymes, a higher concentration of Mn in the tumor after injection is evident from the increase in intensity. E) Thermal images of the control sample (PBS‐treated) and MPDA‐WS₂@MnO₂ nanozymes aqueous dispersions after irradiation with a NIR laser for 5 min. Reproduced with permission.^{[ 167 ]} Copyright 2019, Elsevier.

Figure 9

A) Schematic illustration of the synthesis of SFS/GOx/HGN@Pt nanozyme consisting of an enzyme‐based silk fibroin hydrogel (SFS) matrix, natural enzyme glucose oxidase (GOx), and hollow Ag–Au metallic cages decorated by Pt nanoparticles (HGN@Pt). B) Schematic illustration of the mechanism of cancer therapy involving intravenous injection of the nanozyme, in situ condensation of hydrogel solution into a gel under light irradiation and heating of cancerous tissues generated by the photothermal effect. Reproduced with permission.^{[ 174 ]} Copyright 2021, American Chemical Society.

Figure 10

A) Schematic illustration of the synthesis and antitumor mode of action of PEG‐Ce6‐PEI@PB nanozymes consisting of polyethylene glycol, photosensitizer Ce6, polyethylenimine, and Prussian blue nanoparticles for dual‐enhanced photodynamic therapy induced by modulation of the polyethyleneimine cytotoxicity and hypoxia relief. B) Fluorescence imaging to capture the time‐dependent biodistribution of free Ce6, Ce6‐PEI@PB, by dynamic Schiff base crosslinking in response to pH changes. The cellular uptake of PEG‐Ce6‐PEI@PB nanoparticles was enhanced through extracellular pH‐triggered PEG detachment and PEG‐Ce6‐PEI@PB in mouse models bearing tumors. C) Ex vivo fluorescence images of major organs and tumors 24 h after treatment. Repoduced with permission.^{[ 176 ]} Copyright 2022, Royal Society of Chemistry.