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Review

Peroxidase Mimetic Nanozymes in Cancer Phototherapy: Progress and Perspectives

by
Suresh Thangudu
1 and
Chia-Hao Su
1,2,*
1
Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan
2
Department of Biomedical Imaging and Radiological Sciences, National Yang Ming Chiao Tung University, Taipei 112, Taiwan
*
Author to whom correspondence should be addressed.
Biomolecules 2021, 11(7), 1015; https://doi.org/10.3390/biom11071015
Submission received: 4 June 2021 / Revised: 8 July 2021 / Accepted: 9 July 2021 / Published: 11 July 2021
(This article belongs to the Special Issue Applications of Nanomaterials: Theranostic Imaging in Health and Disease)
Browse Figures
Versions Notes

Abstract

:
Nanomaterial-mediated cancer therapeutics is a fast developing field and has been utilized in potential clinical applications. However, most effective therapies, such as photodynamic therapy (PDT) and radio therapy (RT), are strongly oxygen-dependent, which hinders their practical applications. Later on, several strategies were developed to overcome tumor hypoxia, such as oxygen carrier nanomaterials and oxygen generated nanomaterials. Among these, oxygen species generation on nanozymes, especially catalase (CAT) mimetic nanozymes, convert endogenous hydrogen peroxide (H2O2) to oxygen (O2) and peroxidase (POD) mimetic nanozymes converts endogenous H2O2 to water (H2O) and reactive oxygen species (ROS) in a hypoxic tumor microenvironment is a fascinating approach. The present review provides a detailed examination of past, present and future perspectives of POD mimetic nanozymes for effective oxygen-dependent cancer phototherapeutics.

1. Introduction

Cancer is one of the leading causes of human mortality [1]. Major problems associated with cancer treatment include the reoccurrence of tumors, tumor metastasis and resistance to chemo drugs [2,3]. Chemotherapy, radiotherapy (RT), and surgery are currently the most efficient treatment modalities, but have significant drawbacks including damage to normal cells, tumor reoccurrence, poor visualization and tumor hypoxia [4,5,6]. Therapeutic and diagnostic strategies for treating the cancer efficiently are needed. Recently, significant attention has been focused on nanomaterial-mediated phototherapies such as photothermal therapy (NmPTT) and photodynamic therapy (NmPDT) for the treatment of many diseases including cancers, bacterial infections, etc. [7,8,9,10,11,12]. NmPTT relies on photothermal heat and NmPDT mainly relies on reactive oxygen species (ROS). Compared to traditional therapeutic modalities, NmPDT is highly selectivity, can be remote controlled, has low systemic toxicity and is noninvasive [13,14]. In terms of its mechanism, PDT is strongly dependent on oxygen, and insufficient oxygen in the tumor microenvironment (tumor hypoxia) makes PDT less effective in in vivo systems [6]. Several factors contribute to tumor hypoxia, such as excess extracellular matrix, low pH values, and immunosuppressive factors resulting from altered metabolic pathways and abnormal tumor vasculature [15]. Several studies have found that tumor hypoxia promotes tumor growth [16,17]. Promising results have been achieved in addressing tumor hypoxia by supplying tumors with oxygen using oxygen carriers such as Hb oxygen carriers, non- Hb oxygen carriers and hybrid proteins, etc. [18,19]. However, limited loading efficiency and release of O2 on oxygen nanocarriers is still a limiting factor [20]. To this end, increased attention has been focused on generating O2 on nanomaterials, specifically on enzyme mimetic nanomaterials, known as “nanozymes”, to overcome tumor hypoxia and mediate cancer therapeutics [21]. Two different therapeutic approaches, direct killing (increasing ROS) and indirect killing (depletion of ROS) have been used to investigate cancer therapeutics using various nanozymes, mainly peroxidase (POD), oxidase (OXD), superoxide dismutase (SOD) and catalase (CAT) mimetic nanomaterials [22]. The approach of increasing ROS promotes therapeutic efficiency particularly with the use of POD mimetics by overcoming tumor hypoxia in oxygen-dependent PDT. POD mimetic nanozymes catalyze the endogenous H2O2 and produce H2O and ROS in the tumor microenvironment. However, a detailed review of POD mimetic nanozymes reports for cancer therapeutics is still lacking.
This review presents current advancements and future perspectives of the use of POD mimetic nanozymes in oxygen-dependent cancer PDT. A graphical summary of the present review is shown in Scheme 1.

2. Nanozymes

Enzymes can serve as biological catalysts (e.g., POD, OXD SOD and CAT, etc.) for various in vivo biological reactions [23]. Like all catalysts, enzymes have two fundamental properties: firstly, they increase the catalytic reaction without being consumed themselves, and secondly, they increase the reaction rates without altering the chemical equilibrium. In general, natural enzymes consist mainly of two parts: a protein and a metallic cofactor. The protein part contains various functional groups and facilitates absorption of the substrate and provides an active site for substrate binding, whereas the metallic part (generally metal ion or metallic complex) facilitates electron transmission. The simultaneous action of the two parts enhances the enzyme’s catalytic activity [24]. Due to superior catalytic activity and excellent substrate specificity, several enzymes have been used in various applications such as agrochemical production, pharmaceutical processes, food industry applications and biomedical applications [25,26,27]. However, the practical applications of enzymes are restricted due to some serious limitations. As shown in Figure 1, enzymes have disadvantages such as low operational stability, low sensitivity and high cost, etc. Thus, an alternative strategy to mimic natural enzymes and enhance catalytic reactions is urgently required.
Thus, considerable effort has been devoted to developing nanozymes which are similar to natural enzymes and can effectively catalyze the conversion of enzyme substrates under mild conditions, and exhibit similar catalytic efficiency and enzymatic reaction kinetics [28]. As shown in Figure 1, nanozymes exhibit several advantages over natural enzymes, including multifunctionality, tunability of catalytic activities, low cost, production scalability, recyclability and high stability. Moreover, these nanozymes can function in ambient conditions. Nanozyme activity can be tuned by simply varying their shape, structure, and composition, and considerable effort has focused on investigating the theoretical mechanisms and kinetics of nanozymes [29].
The advantages of nanozymes have led to their use in energy, environmental and biomedical applications. For instance, nanozymes can be used to qualitatively and quantitatively detect environmental toxins such as ions, molecules and organic compounds [30]. Nanozymes have also been used to treat bacterial infections, offering exciting broad-spectrum antimicrobial properties with negligible cytotoxicities [31]. They have also been used in biosensors for the rapid, reliable, and highly sensitive detection of various diseases [32,33]. Recently, nanomaterial-based nanozymes have been extensively investigated for use in the treatment of cancer through overcoming tumor hypoxia, since oxygen plays a pivotal role in cancer development and treatment [34]. Various enzyme mimetic nanomaterials, such POD OXD, SOD and CAT mimetic nanozymes, have been extensively studied for use in cancer therapeutics [34]. The present review mainly focuses on POD mimetic nanomaterials in cancer theranostic applications, and offers a detailed discussion of current advances and future perspectives.

2.1. Peroxidase Mimetic Nanozymes: Mechanisms and Role

Peroxidase is a natural enzyme found in wide variety of organisms, from plants to humans to bacteria [35]. The main function of the peroxidase enzyme is the decomposition of H2O2 to nontoxic components. H2O2 is a toxic byproduct formed by respiration of O2 [36]. Peroxide enzymes act as detoxifying agents for free radicals (e.g., glutathione peroxidase) and also aid defense against invading pathogens (e.g., myeloperoxidase). Peroxidases are also widely used in bioanalytical and clinical chemistry applications for the detection of analytes via colorimetric assays. As mentioned earlier, to overcome the drawbacks of natural enzymes, significant effort has gone into developing effective alternative POD mimetic enzymatic strategies.
The first evidence of Fe3O4 nanoparticles as peroxidase mimetic was reported in 2007 [37]. Several Fe-based nanocomposites have been found to exhibit activity very similar to that of natural horseradish peroxidase (HRP) for converting H2O2 to O2 and hydroxyl radicals [38]. To date, ≥40 NMs have been found that exhibit POD-like activity [39]. As shown in Figure 2, 3,3′,5,5′-Tetramethylbenzidine (TMB assay) is a promising protocol for examining materials whether they exhibit POD-like activity or not [39,40]. In the mechanism, NMs can decompose the H2O2 results oxidation of colorless TMB to colored product (ox-TMB). The overall H2O2-TMB system process on NMs follows Michaelis–Menten behavior, which strongly confirms the real enzymatic behavior of NMs. Nanozymes have distinct advantages over enzymes, such as high stability, low cost, cyclical use and easy multifunctionalization, making them potential candidates for various environmental and biological applications [41,42]. This review mainly focuses on the biomedical applications of POD mimetic NMs in cancer therapeutics.

2.2. Peroxidase Mimetic Nanozymes in Oxygen-dependent Cancer Photodynamic Therapy

PDT is a modern and non-invasive cancer treatment modality [14,43]. As shown Figure 3, in PDT, the first photosensitizer absorbs the incident light of the appropriate wavelength and initiates the activation process [44]. The excited electrons react with the tissue oxygen and generate cytotoxic ROS responsible for cell death. This process shows that, for any efficient PDT effects, three main factors should be considered: (i) the photosensitizer, (ii) appropriate light wavelengths and (iii) dissolved oxygen in cells/tissue. From the type I or type II PDT mechanisms, it is clear that PDT is oxygen-dependent. Unfortunately, oxygen levels in solid tumors are very low, within micromolars (partial pressure of O2 < 5 mmHg corresponding to 7 µM) [45]. This is mainly due to the aggressive proliferation of cancer cells and limited blood supply available to solid tumors. Low oxygen in tumors significantly impacts the efficacy of PDT despite its in vitro potential. Efforts to overcome tumor hypoxia have focused on the production of O2 via catalytic reactions [20,46,47], O2 carriers and delivery [48,49,50], and O2 independent photosensitizers [51,52,53]. However, improved efficacy requires the development of photosensitizers to effectively mediate PDT by addressing tumor hypoxia. To this end, in recent years more efforts have been devoted to developing enzyme mimetic materials, especially POD mimetics, to efficiently overcome tumor hypoxia and mediate the PDT effects converting intracellur/intratumoral H2O2 to H2O and ROS.
With the discovery of the enzymatic properties of iron oxide nanoparticles (Fe3O4 NPs) and iron-based NPs (Au@Fe3O4 [54], Fe3O4 coated Ag [55], Pt48Pd52-Fe3O4 [56], Fe3O4@Pt [57], metal organic framework-based MnFe2O4/C nanozymes, [58], etc.), new attention has focused on bioapplications of peroxidaselike Fe3O4 nanostructures [38,59]. For instance, cobalt-doped Magnetoferritin (M-HFn) NPs (M-HFn-Cox Fe3-xO4) with different amounts of cobalt were successfully synthesized. By varying the amounts of cobalt loading into M-HFn cores significantly enhances the peroxidaselike activity and efficacy of visualizing the tumor-specific tissue [60]. Wang et al. reported cobalt-doped Fe3O4 (Co@Fe3O4) nanozymes that exhibited stronger peroxidase activity than Fe3O4 nanozymes alone (100-fold higher affinity) [61]. As a result, Co@Fe3O4 nanozymes can efficiently catalyze intracellular H2O2 under low doses, and show promising in vitro and in vivo antitumor efficiency. In another report, An et al. developed a folate conjugated Fe3O4@C NPs which exhibiting peroxidaselike activity. These POD-like activity of NPs significantly promotes ascorbic acid-induced oxidative stress in cancer cells and maximizes the antitumor efficiency [62]. Subsequently, Fe-based nanocomposites were applied to cancer combined phototherapies by overcoming tumor hypoxia via POD-like activities. Zhang et al. fabricated multifunctional chitosan-encapsulated Fe3O4 nanoparticles modified with CuS and porphyrin (FCCP NPs) for multimodal image guided phototheranostics [63]. As shown in Figure 4, FCCP NPs possess enhanced intrinsic peroxidase mimetic activity to generate ROS from endogenous H2O2. The in situ generation of ˙OH as a therapeutic agent and provide O2 for overcoming resistance to photodynamic therapy results in enhanced in vivo therapeutic efficacy for the treatment of cancer tumors. Notably, Fe3O4 nanozyme also believed to be CAT activity but authors did not distinguish the difference between the POD-like activity and the CAT-like activity of Fe3O4 nanozyme. Liu et al. designed and demonstrated a dual enzymelike activities of PtFe@Fe3O4 nanostructures [64]. Interestingly, PtFe@Fe3O4 exhibited both the CAT and POD-like activities under acidic conditions which could effectively overcome hypoxia. As a result, successful inhibition of pancreatic cell growth was achieved via photo-enhanced enzyme catalytic therapy. Yang et al. designed a hollow nitrogen-doped carbon nanospheres (HNCSs) and iron phthalocyanine (FePc) for synergistic catalytic and dual phototherapy [65]. FePc/HNCSs simultaneously exhibit POD- and CAT-like activities and facilitates to convert endogenous H2O2 into ROS and O2 for tumor catalytic therapy as well as enhance O2-dependent PDT.
Aside from Fe-based POD-like nanozymes, other nanomaterials such as platinum (Pt), palladium(Pd), Gold (Au) based nanocomposites, etc. have been examined for use in cancer theranostics. For instance, Cai et al. designed a three-dimensional dendritic mesoporous silica nanosphere (3D-dendritic MSN) material which contains a photosensitizer (Ce6) and Pt NPs for hpoxia overcoming PDT [66]. The incorporated peroxidaselike Pt NPs significantly alleviate the tumor hypoxia by decompostion of intracellular H2O2 to oxygen species and provide sufficient O2 levels to the environment in the tumor for PDT. As a result, this design shows an enhanced PDT effect of killing A549 cells, by overcoming tumor hypoxia. Au NP-doped metal-organic frameworks (GIM) were shown to be potenial candidates to treat hypoxic tumors, where GIM exhibited NIR light-induced glucose oxidase (GOx) activity to generate endogenous H2O2, which was converted to O2 and highly toxic ROS on GIM [67]. Zhang et al. repoted a NIR780 loated serum albumin folate stabilized gold-doped mesoporous carbon (OMCAPs@ rBSA-FA@IR780) nanoprobes as a multifunctional theranostic platform [68]. Besides the therapeutic platform, incorporating Au NPs into mesoporous carbon can facilitate the action of POD mimitic activity and generate ROS for intracellular oxidative damage of cancer cells. As shown in Figure 5, Sheng et al. designed a hyaluronic acid shielded chlorin e6 (Ce6) loaded into a POD mimic metal-organic framework (MOF) MIL-100 nanoparticles (CMH NPs) for synrgetic chemo-PDT [69]. Besides, the generation of cytotoxic singlet oxygen (1O2) under NIR light irradiation also generates H2O2. Further, H2O2 converts to ·OH and O2 in a catalytic cascade reactions and alleviates tumor hypoxia. Jana et al. reported a ultrasmall trimetallic (Pd, Cu, and Fe) alloy nanozyme (PCF-a NEs) for ultrasound- and light-enhanced tumor therapy [70]. PCF-a NEs exhibit a cascade POD and GSH peroidase mimitic activities under circumneutral pH. Moreover, photothermal enhanced POD properties on PCF-a NEs facilitate effective tumor cell apoptosis. Most recently, Zeng et al. designed biodegradable POD mimetic boron oxynitride (BON) nanospheres (NSs) for efficient breast cancer therapy [71]. Further, these POD mimetic BON NSs catalytically generate cytotoxic OH radicals for successful inhibition of cancer cells both in in vitro and in vivo.
In addition to the previously mentioned advantages of nanozymes in cancer therapeutics, several further POD mimetic nanozyme platforms such as Au@Co-Fe NPs [72], CuO Nanorods [73], Fe3O4@MoS2-Ag nanozyme [74], Pd nanocrystals [75], and Pt hollow nanodendrites [76], N-doped spongelike carbon spheres (N-SCSs) [77], PEGylated palladium nanozyme (Pd-PEG) [78], tungsten sulfide quantum dots (WS2 QDs) [79], nickel disulfide (ND) nanozyme [80], iridium (Ir) nanoplates [81] and MoS2 [82] have been successfully utilized in antibacterial applications with significant outcomes. Table 1 summarizes POD-based nanozyme applications in cancer phototherapeutics.

3. Current Trends and Future Perspectives

As discussed earlier, several POD mimetic nanozymes have been successfully used to overcome tumor hypoxia. However, the mechanism by which current POD mimetic NMs generate cytotoxic ROS mainly relies on the amount of intracellular H2O2 and pH. Intracellular H2O2 concentrations are very low, estimated at around (50 − 100 × 10−6 M) [64,99]. As a result, most nanozymes have limited therapeutic efficiency in the tumor microenvironment, and catalytic nanozyme therapy alone is not comparable to combination therapy. To this end, some studies have shown that ROS generation on nanozymes can be improved by photothermal therapy [64,88,100]. Zhang et al. fabricated a viruslike Fe3O4@Bi2S3 nanocatalyst (F-BS NCs) by simple ultrasound. Synergistic coupling of POD mimetic Fe3O4 NPs with a narrow band gap semiconductor Bi2S3 (BS) significantly increased POD mimetic activity [101]. As shown in Figure 6, MNP particles exhibit better enzyme POD-like catalytic activity under mild temperatures compared to at room temperature/no temperature applied. As a result, POD-like activity promotes the conversion frequency of Fe3+/Fe2+ under mild hyperthermia effect on BS under 808 nm laser irradiation [102,103]. Furthermore, POD enzymatic reaction in the tumor microenvironment improves the yield of ROS and resists the cancer under this mild photothermal effect.
The synergistic effects of dual enzyme mimetic nanostructures in tumor therapy were later investigated. Gao et al. reported a dual inorganic nanozyme-based nanoplatform of Gold (Au) NPs and Fe3O4 NPs co-loaded mesoporous silica materials for nanocatalytic tumor therapy [104]. Since Au NPs as a GOx mimic, so it will also catalyze β-D-glucose oxidation into gluconic acid and H2O2, which is subsequently catalyzed by the peroxidase-mimic Fe3O4 NPs to liberate high-toxic hydroxyl radicals to induce tumor-cell death by the typical Fenton-based catalytic reaction. To further enhance the efficacy of dual nanozyme catalytic therapy, Yi et al. fabricated Wonton-like Bismuth@poly vinyl pyrrolidine@gold platinum (Bi@PVP@AuPt) NPs which exhibited both POD and oxidaselike activity. The stable dual enzymatic behavior of NPs will produce oxygen in hypoxic tumors. Applying the hyperthermia effect to the dual nanozyme significantly promotes ROS generation, resulting in good therapeutic outcomes under combined photothermal and nanocatalytic treatment. Xu et al. designed glucose–oxidase (GOx)-loaded biomimetic Au–Ag hollow nanotriangles (Au–Ag–GOx HTNs) for NIR light-triggered tumor therapy by regulating the tumor environment, where GOx in HTNs triggers the generation of gluconic acid and H2O2 [105]. Subsequently, H2O2 will be converted to O2 on the POD mimetic HTNs, eventually boosting the formation of •OH radicals under NIR II light for efficient tumor therapy. Dong et al. reported ceria nanozymes decorating uniform Bismuth sulfide nanorods (Bi2S3 NRs) with dendritic mesoporous silica (Bi2S3@DMSN) material for tumor catalytic therapy [106]. Synthesized nanozymes exhibited a dual enzyme mimic such as POD and CAT properties under acidic conditions, significantly overcoming tumor hypoxia and elevating oxidative stress under hyperthermia. Recently, Alizadeh et al. reported pH-switchable POD and CAT mimic activities of hierarchical Co(OH)2/FeOOH/WO3 ternary nanoflowers [107]. The POD activities of the as-synthesized nanoflowers were dominant at acidic pH whereas the CAT activities were dominant at basic pH. Indeed, these catalytic materials produced ROS by decomposition of H2O2 in both acidic and basic condition, resulting in good anticancer behavior as well as cancer cell detection. Building on these advancements in dual nanozymes and their efficacy in tumor treatment, Ai et al. fabricated a manganese dioxide encapsulated selenium-melanin (Se@Me@MnO2) multishell nanozyme for intracellular antioxidation [108]. Se@Me@MnO2 nanozyme exhibits multiple enzyme activities such as CAT, SOD and glutathione peroxidase (GPx). This multishell platform can effectively scavenge the ROS species via synergistic and fast electron transfer between Se, Me and MnO2. These multienzyme mimetic nanoplatforms are good candidates for future tumor therapy applications.
Single-atom-based nanozymes are being developed for various applications. Cost effective and atomically dispersed single atom metal centers can significantly enhance enzyme mimetic properties by maximizing the atomic utilization efficiency and density of active sites. As a result, single atom-based platforms have been developed for various kinds of enzymelike properties such as POD, SOD, CAT, OXD, etc. [109]. By using the enzyme mimetic properties of single atoms, Xu et al. fabricated a zinc-based single atom supported by a metal organic framework and observed excellent POD-like properties [110]. These POD-like activities further help to efficiently deactivate in vivo bacterial infections. Huo et al. fabricated PEGylated single-atom Fe-containing nanocatalysts (PSAF NCs) atoms and observed that the present Fe-based single atom could effectively trigger intracellular H2O2 and selectively generate hydroxyl radicals (•OH) in acidic tumor environments [111]. More recently, Wang et al. fabricated single-atom ruthenium as the active catalytic site anchored in a metal-organic framework Mn3[Co(CN)6]2 with encapsulated chlorin e6 (Ce6), which serves as a catalaselike nanozyme for oxygen generation [112]. Figure 7 presents a schematic representation of the detailed fabrication and in vivo applications. Single-atom Ru loading content can degrade intracellular H2O2 to O2 to relieve hypoxia in solid tumors, leading to enhanced ROS generation, and finally causing apoptotic cell death both in vitro and in vivo.
Despite nanozymes offering significant advantages such as high stability, low cost, long-term stability and large scale production, several considerations/improvements are needed for future practical applications. Some key considerations for future nanozymes in cancer applications are as follows.
(i)
Activity: Most nanozymes exhibit lower activity than natural enzymes, possibly due to the additional surface conjugation on NMs, thus, the development of new surface conjugation strategies to improve nanozyme activity is highly desired.
(ii)
Sensitivity: Most nanozymes show good performance in in vitro studies but their application in biomedical applications is still questionable. For example, POD mimetic nanozymes in cancer therapy were designed to alleviate tumor hypoxia, but the presence of in vivo endogenous H2O2 is at concentrations of a few micromolars, thus, nanozymes must be ultra-sensitive to detect and decompose the H2O2 to O2.
(iii)
Toxicity/biosafety: Unlike natural enzymes, the cytotoxicity effects and biocompatibility of nanozymes are still unconfirmed. Therefore, more research is needed prior to the development of practical applications.
(iv)
Selectivity: Most nanozymes can catalyze a broad range of substrates for multiple enzyme activity. For example, some enzymes exhibit both POD and CAT or POD and OXD mimetic activities. Although several studies have examined various types of surface conjugation techniques to attain selectivity, a complete investigation of catalytic mechanisms is still needed.
(v)
Theoretical studies: Additional theoretical studies of nanozymes are needed to combine both experimental and computational results to better understand their complete mechanisms of nanozymes.
(vi)
Limited to cancer therapy: Currently, most nanozymes are limited to cancer therapy. Nanozyme-mediated disease diagnostics and therapeutics should be applied to other diseases as well as the environmental and agricultural domains.
(vii)
Single atoms: Single atom nanozymes represent potential candidates for cancer therapeutic applications. However, more studies are needed on long term cytotoxicity, biosafety, stability and mechanisms.
(viii)
Most nanozymes are limited to only POD, CAT, OXD and SOD. Future work should explore nanozymes in terms of other enzyme mimetic activities for use in a wide variety of applications.
Besides a good design of POD nanozymes, one should also consider the current objective evaluation indicators in tumor treatment for significant future therapeutic improvements. By addressing all the concerns, the design/fabrication of novel and efficient nanozymes will show considerable potential for a broad range of research for future environmental, agricultural and biomedical applications.

4. Conclusions

In summary, this review presents past and current advancements in the development of nanozymes, especially POD mimetic nanomaterials for oxygen-dependent phototherapy, with a detailed explanation of the mechanisms and roles of POD mimetic nanozymes in cancer therapeutics. The main obstacle of effective tumor phototherapy is tumor hypoxia. Most phototherapy modalities are oxygen-dependent, and tumor microenvironments contain insufficient oxygen for effective therapeutic application. To overcome this limitation, we review the advantages of POD mimetic nanomaterials which can catalyze endogenous H2O2 to H2O and ROS, thus overcoming tumor hypoxia. Further therapeutic improvement can be achieved through combining therapeutic platforms such as mild PTT-induced enhancement of nanozyme activities and dual, multienzyme strategies. Future perspectives and challenges facing the continued development of nanozyme applications are discussed to elucidate directions for future nanozyme-based therapeutics and to transform clinical settings. We believe the present review helps to provide a more systematic understanding of the advantages, mechanisms and challenges of nanozymes and will facilitate the development of novel POD mimetic nanozymes for efficient cancer phototherapy applications.

Author Contributions

Conceptualization, S.T. and C.-H.S.; funding acquisition, C.-H.S.; formal analysis, S.T. and C.-H.S.; investigation, both authors; methodology, both authors; project administration, C.-H.S.; resources, C.-H.S.; supervision, C.-H.S.; validation, both authors; writing—original draft preparation, S.T.; writing—review and editing, both authors. Both authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the Ministry of Science and Technology, Taiwan (MOST 106-2314-B-182A-008-MY3, 109-2811-B-182A-527-, and 109-2314-B-182A-011 -MY3) and Chang Gung Medical Foundation, Taiwan (CMRPG8I0141-3 and CMRPG8J0451-3).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Sung, H.; Ferlay, J.; Siegel, R.L.; Laversanne, M.; Soerjomataram, I.; Jemal, A.; Bray, F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J. Clin. 2021, 71, 209–249. [Google Scholar] [CrossRef]
  2. Riggio, A.I.; Varley, K.E.; Welm, A.L. The lingering mysteries of metastatic recurrence in breast cancer. Br. J. Cancer 2021, 124, 13–26. [Google Scholar] [CrossRef]
  3. Bukowski, K.; Kciuk, M.; Kontek, R. Mechanisms of Multidrug Resistance in Cancer Chemotherapy. Int. J. Mol. Sci. 2020, 21, 3233. [Google Scholar] [CrossRef]
  4. Azim, H.A., Jr.; de Azambuja, E.; Colozza, M.; Bines, J.; Piccart, M.J. Long-term toxic effects of adjuvant chemotherapy in breast cancer. Ann. Oncol. Off. J. Eur. Soc. Med. Oncol. 2011, 22, 1939–1947. [Google Scholar] [CrossRef]
  5. Majeed, H.; Gupta, V. Adverse Effects Of Radiation Therapy. In StatPearls; StatPearls Publishing Copyright © 2021; StatPearls Publishing LLC.: Treasure Island, FL, USA, 2021. [Google Scholar]
  6. Brown, J.M. Tumor hypoxia in cancer therapy. Methods Enzymol. 2007, 435, 297–321. [Google Scholar] [CrossRef]
  7. Vankayala, R.; Hwang, K.C. Near-Infrared-Light-Activatable Nanomaterial-Mediated Phototheranostic Nanomedicines: An Emerging Paradigm for Cancer Treatment. Adv. Mater. 2018, 30, 1706320. [Google Scholar] [CrossRef] [PubMed]
  8. Thangudu, S.; Cheng, F.-Y.; Su, C.-H. Advancements in the Blood–Brain Barrier Penetrating Nanoplatforms for Brain Related Disease Diagnostics and Therapeutic Applications. Polymers 2020, 12, 3055. [Google Scholar] [CrossRef] [PubMed]
  9. Thangudu, S. Next Generation Nanomaterials: Smart Nanomaterials, Significance, and Biomedical Applications. In Applications of Nanomaterials in Human Health; Khan, F.A., Ed.; Springer: Singapore, 2020; pp. 287–312. [Google Scholar] [CrossRef]
  10. Thangudu, S.; Kulkarni, S.S.; Vankayala, R.; Chiang, C.-S.; Hwang, K.C. Photosensitized reactive chlorine species-mediated therapeutic destruction of drug-resistant bacteria using plasmonic core–shell Ag@AgCl nanocubes as an external nanomedicine. Nanoscale 2020, 12, 12970–12984. [Google Scholar] [CrossRef] [PubMed]
  11. Korupalli, C.; Kalluru, P.; Nuthalapati, K.; Kuthala, N.; Thangudu, S.; Vankayala, R. Recent Advances of Polyaniline-Based Biomaterials for Phototherapeutic Treatments of Tumors and Bacterial Infections. Bioengineering 2020, 7, 94. [Google Scholar] [CrossRef] [PubMed]
  12. Thangudu, S.; Kaur, N.; Korupalli, C.; Sharma, V.; Kalluru, P.; Vankayala, R. Recent Advances on Near Infrared Light Responsive Multifunctional Nanostructures for Phototheranostic Applications. Biomater. Sci. 2021. [Google Scholar] [CrossRef]
  13. Dolmans, D.E.J.G.J.; Fukumura, D.; Jain, R.K. Photodynamic therapy for cancer. Nat. Rev. Cancer 2003, 3, 380–387. [Google Scholar] [CrossRef]
  14. Maloth, K.N.; Velpula, N.; Kodangal, S.; Sangmesh, M.; Vallamchetla, K.; Ugrappa, S.; Meka, N. Photodynamic Therapy—A Non-invasive Treatment Modality for Precancerous Lesions. J. Lasers Med. Sci. 2016, 7, 30–36. [Google Scholar] [CrossRef] [PubMed]
  15. Muz, B.; de la Puente, P.; Azab, F.; Azab, A.K. The role of hypoxia in cancer progression, angiogenesis, metastasis, and resistance to therapy. Hypoxia 2015, 3, 83–92. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  16. Brahimi-Horn, M.C.; Chiche, J.; Pouysségur, J. Hypoxia and cancer. J. Mol. Med. 2007, 85, 1301–1307. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  17. Thomas, S.; Harding, M.A.; Smith, S.C.; Overdevest, J.B.; Nitz, M.D.; Frierson, H.F.; Tomlins, S.A.; Kristiansen, G.; Theodorescu, D. CD24 Is an Effector of HIF-1–Driven Primary Tumor Growth and Metastasis. Cancer Res. 2012, 72, 5600–5612. [Google Scholar] [CrossRef] [Green Version]
  18. Wang, H.; Li, J.; Wang, Y.; Gong, X.; Xu, X.; Wang, J.; Li, Y.; Sha, X.; Zhang, Z. Nanoparticles-mediated reoxygenation strategy relieves tumor hypoxia for enhanced cancer therapy. J. Control. Release 2020, 319, 25–45. [Google Scholar] [CrossRef] [PubMed]
  19. Luo, Z.; Tian, H.; Liu, L.; Chen, Z.; Liang, R.; Chen, Z.; Wu, Z.; Ma, A.; Zheng, M.; Cai, L. Tumor-targeted hybrid protein oxygen carrier to simultaneously enhance hypoxia-dampened chemotherapy and photodynamic therapy at a single dose. Theranostics 2018, 8, 3584–3596. [Google Scholar] [CrossRef]
  20. Sun, Y.; Zhao, D.; Wang, G.; Wang, Y.; Cao, L.; Sun, J.; Jiang, Q.; He, Z. Recent progress of hypoxia-modulated multifunctional nanomedicines to enhance photodynamic therapy: Opportunities, challenges, and future development. Acta Pharm. Sin. B 2020, 10, 1382–1396. [Google Scholar] [CrossRef]
  21. Sutrisno, L.; Hu, Y.; Hou, Y.; Cai, K.; Li, M.; Luo, Z. Progress of Iron-Based Nanozymes for Antitumor Therapy. Front. Chem. 2020, 8. [Google Scholar] [CrossRef]
  22. Zhang, Y.; Jin, Y.; Cui, H.; Yan, X.; Fan, K. Nanozyme-based catalytic theranostics. RSC Adv. 2020, 10, 10–20. [Google Scholar] [CrossRef] [Green Version]
  23. Robinson, P.K. Enzymes: Principles and biotechnological applications. Essays Biochem. 2015, 59, 1–41. [Google Scholar] [CrossRef] [PubMed]
  24. Hong, S.; Zhang, Q.-L.; Zheng, D.-W.; Zhang, C.; Zhang, Y.; Ye, J.-J.; Cheng, H.; Zhang, X.-Z. Enzyme Mimicking Based on the Natural Melanin Particles from Human Hair. iScience 2020, 23. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  25. Chapman, J.; Ismail, A.E.; Dinu, C.Z. Industrial Applications of Enzymes: Recent Advances, Techniques, and Outlooks. Catalysts 2018, 8, 238. [Google Scholar] [CrossRef] [Green Version]
  26. Cormode, D.P.; Gao, L.; Koo, H. Emerging Biomedical Applications of Enzyme-Like Catalytic Nanomaterials. Trends Biotechnol. 2018, 36, 15–29. [Google Scholar] [CrossRef]
  27. Alcalde, M.; Ferrer, M.; Plou, F.J.; Ballesteros, A. Environmental biocatalysis: From remediation with enzymes to novel green processes. Trends Biotechnol. 2006, 24, 281–287. [Google Scholar] [CrossRef] [Green Version]
  28. Liang, M.; Yan, X. Nanozymes: From New Concepts, Mechanisms, and Standards to Applications. Acc. Chem. Res. 2019, 52, 2190–2200. [Google Scholar] [CrossRef] [PubMed]
  29. Lou-Franco, J.; Das, B.; Elliott, C.; Cao, C. Gold Nanozymes: From Concept to Biomedical Applications. Nano-Micro Lett. 2020, 13, 10. [Google Scholar] [CrossRef] [PubMed]
  30. Meng, Y.; Li, W.; Pan, X.; Gadd, G.M. Applications of nanozymes in the environment. Environ. Sci. Nano 2020, 7, 1305–1318. [Google Scholar] [CrossRef]
  31. Yang, D.; Chen, Z.; Gao, Z.; Tammina, S.K.; Yang, Y. Nanozymes used for antimicrobials and their applications. Colloids Surf. B Biointerfaces 2020, 195, 111252. [Google Scholar] [CrossRef] [PubMed]
  32. Tao, X.; Wang, X.; Liu, B.; Liu, J. Conjugation of antibodies and aptamers on nanozymes for developing biosensors. Biosens. Bioelectron. 2020, 168, 112537. [Google Scholar] [CrossRef]
  33. Mahmudunnabi, R.G.; Farhana, F.Z.; Kashaninejad, N.; Firoz, S.H.; Shim, Y.-B.; Shiddiky, M.J.A. Nanozyme-based electrochemical biosensors for disease biomarker detection. Analyst 2020, 145, 4398–4420. [Google Scholar] [CrossRef]
  34. Jiang, D.; Ni, D.; Rosenkrans, Z.T.; Huang, P.; Yan, X.; Cai, W. Nanozyme: New horizons for responsive biomedical applications. Chem. Soc. Rev. 2019, 48, 3683–3704. [Google Scholar] [CrossRef] [PubMed]
  35. Khan, A.A.; Rahmani, A.H.; Aldebasi, Y.H.; Aly, S.M. Biochemical and pathological studies on peroxidases—An updated review. Glob. J. Health Sci. 2014, 6, 87–98. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  36. Mahaseth, T.; Kuzminov, A. Potentiation of hydrogen peroxide toxicity: From catalase inhibition to stable DNA-iron complexes. Mutat. Res./Rev. Mutat. Res. 2017, 773, 274–281. [Google Scholar] [CrossRef] [PubMed]
  37. 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. Nat. Nanotechnol. 2007, 2, 577–583. [Google Scholar] [CrossRef] [PubMed]
  38. Gao, L.; Fan, K.; Yan, X. Iron Oxide Nanozyme: A Multifunctional Enzyme Mimetic for Biomedical Applications. Theranostics 2017, 7, 3207–3227. [Google Scholar] [CrossRef]
  39. Jiang, B.; Duan, D.; Gao, L.; Zhou, M.; Fan, K.; Tang, Y.; Xi, J.; Bi, Y.; Tong, Z.; Gao, G.F.; et al. Standardized assays for determining the catalytic activity and kinetics of peroxidase-like nanozymes. Nat. Protoc. 2018, 13, 1506–1520. [Google Scholar] [CrossRef]
  40. Thangudu, S.; Lee, M.T.; Rtimi, S. Tandem Synthesis of High Yield MoS2 Nanosheets and Enzyme Peroxidase Mimicking Properties. Catalysts 2020, 10, 1009. [Google Scholar] [CrossRef]
  41. Li, X.; Wang, L.; Du, D.; Ni, L.; Pan, J.; Niu, X. Emerging applications of nanozymes in environmental analysis: Opportunities and trends. TrAC Trends Anal. Chem. 2019, 120, 115653. [Google Scholar] [CrossRef]
  42. Wu, J.; Li, S.; Wei, H. Integrated nanozymes: Facile preparation and biomedical applications. Chem. Commun. 2018, 54, 6520–6530. [Google Scholar] [CrossRef]
  43. Li, X.; Lovell, J.F.; Yoon, J.; Chen, X. Clinical development and potential of photothermal and photodynamic therapies for cancer. Nat. Rev. Clin. Oncol. 2020, 17, 657–674. [Google Scholar] [CrossRef]
  44. Kwiatkowski, S.; Knap, B.; Przystupski, D.; Saczko, J.; Kędzierska, E.; Knap-Czop, K.; Kotlińska, J.; Michel, O.; Kotowski, K.; Kulbacka, J. Photodynamic therapy—Mechanisms, photosensitizers and combinations. Biomed. Pharmacother. 2018, 106, 1098–1107. [Google Scholar] [CrossRef] [PubMed]
  45. Li, X.; Kwon, N.; Guo, T.; Liu, Z.; Yoon, J. Innovative Strategies for Hypoxic-Tumor Photodynamic Therapy. Angew. Chem. Int. Ed. 2018, 57, 11522–11531. [Google Scholar] [CrossRef] [PubMed]
  46. Yao, C.; Wang, W.; Wang, P.; Zhao, M.; Li, X.; Zhang, F. Near-Infrared Upconversion Mesoporous Cerium Oxide Hollow Biophotocatalyst for Concurrent pH-/H2O2-Responsive O2-Evolving Synergetic Cancer Therapy. Adv. Mater. 2018, 30, 1704833. [Google Scholar] [CrossRef] [PubMed]
  47. Cui, X.; Zhao, Q.; Huang, Z.; Xiao, Y.; Wan, Y.; Li, S.; Lee, C.-S. Water-Splitting Based and Related Therapeutic Effects: Evolving Concepts, Progress, and Perspectives. Small 2020, 16, 2004551. [Google Scholar] [CrossRef]
  48. Feng, L.; Betzer, O.; Tao, D.; Sadan, T.; Popovtzer, R.; Liu, Z. Oxygen Nanoshuttles for Tumor Oxygenation and Enhanced Cancer Treatment. CCS Chem. 2019, 1, 239–250. [Google Scholar] [CrossRef]
  49. Song, G.; Liang, C.; Yi, X.; Zhao, Q.; Cheng, L.; Yang, K.; Liu, Z. Perfluorocarbon-Loaded Hollow Bi2Se3 Nanoparticles for Timely Supply of Oxygen under Near-Infrared Light to Enhance the Radiotherapy of Cancer. Adv. Mater. 2016, 28, 2716–2723. [Google Scholar] [CrossRef]
  50. Zou, M.-Z.; Liu, W.-L.; Chen, H.-S.; Bai, X.-F.; Gao, F.; Ye, J.-J.; Cheng, H.; Zhang, X.-Z. Advances in nanomaterials for treatment of hypoxic tumor. Natl. Sci. Rev. 2020, 8. [Google Scholar] [CrossRef]
  51. Li, X.; Liu, Y.; Fu, F.; Cheng, M.; Liu, Y.; Yu, L.; Wang, W.; Wan, Y.; Yuan, Z. Single NIR Laser-Activated Multifunctional Nanoparticles for Cascaded Photothermal and Oxygen-Independent Photodynamic Therapy. Nano-Micro Lett. 2019, 11, 68. [Google Scholar] [CrossRef] [Green Version]
  52. Li, T.; Yan, L. Functional Polymer Nanocarriers for Photodynamic Therapy. Pharmaceuticals 2018, 11, 133. [Google Scholar] [CrossRef] [Green Version]
  53. Sai, D.L.; Lee, J.; Nguyen, D.L.; Kim, Y.-P. Tailoring photosensitive ROS for advanced photodynamic therapy. Exp. Mol. Med. 2021, 53, 495–504. [Google Scholar] [CrossRef] [PubMed]
  54. Lee, Y.; Garcia, M.A.; Frey Huls, N.A.; Sun, S. Synthetic Tuning of the Catalytic Properties of Au-Fe3O4 Nanoparticles. Angew. Chem. Int. Ed. 2010, 49, 1271–1274. [Google Scholar] [CrossRef] [PubMed]
  55. Chen, J.; Liu, Y.; Zhu, G.; Yuan, A. Ag@Fe3O4 nanowire: Fabrication, characterization and peroxidase-like activity. Cryst. Res. Technol. 2014, 49, 309–314. [Google Scholar] [CrossRef]
  56. Sun, X.; Guo, S.; Chung, C.S.; Zhu, W.; Sun, S. A sensitive H2O2 assay based on dumbbell-like PtPd-Fe3O4 nanoparticles. Adv. Mater. 2013, 25, 132–136. [Google Scholar] [CrossRef]
  57. Ma, M.; Xie, J.; Zhang, Y.; Chen, Z.; Gu, N. Fe3O4@Pt nanoparticles with enhanced peroxidase-like catalytic activity. Mater. Lett. 2013, 105, 36–39. [Google Scholar] [CrossRef]
  58. Han, X.; Li, Y.; Zhou, Y.; Song, Z.; Deng, Y.; Qin, J.; Jiang, Z. Metal-organic frameworks-derived bimetallic nanozyme platform enhances cytotoxic effect of photodynamic therapy in hypoxic cancer cells. Mater. Des. 2021, 204, 109646. [Google Scholar] [CrossRef]
  59. Shi, C.; Li, Y.; Gu, N. Iron-Based Nanozymes in Disease Diagnosis and Treatment. ChemBioChem Eur. J. Chem. Biol. 2020, 21, 2722–2732. [Google Scholar] [CrossRef]
  60. Zhang, T.; Cao, C.; Tang, X.; Cai, Y.; Yang, C.; Pan, Y. Enhanced peroxidase activity and tumour tissue visualization by cobalt-doped magnetoferritin nanoparticles. Nanotechnology 2017, 28, 045704. [Google Scholar] [CrossRef]
  61. Wang, Y.; Li, H.; Guo, L.; Jiang, Q.; Liu, F. A cobalt-doped iron oxide nanozyme as a highly active peroxidase for renal tumor catalytic therapy. RSC Adv. 2019, 9, 18815–18822. [Google Scholar] [CrossRef] [Green Version]
  62. An, Q.; Sun, C.; Li, D.; Xu, K.; Guo, J.; Wang, C. Peroxidase-Like Activity of Fe3O4@Carbon Nanoparticles Enhances Ascorbic Acid-Induced Oxidative Stress and Selective Damage to PC-3 Prostate Cancer Cells. ACS Appl. Mater. Interfaces 2013, 5, 13248–13257. [Google Scholar] [CrossRef]
  63. Zhang, K.; Yang, Z.; Meng, X.; Cao, Y.; Zhang, Y.; Dai, W.; Lu, H.; Yu, Z.; Dong, H.; Zhang, X. Peroxidase-like Fe3O4 nanocomposite for activatable reactive oxygen species generation and cancer theranostics. Mater. Chem. Front. 2018, 2, 1184–1194. [Google Scholar] [CrossRef]
  64. Li, S.; Shang, L.; Xu, B.; Wang, S.; Gu, K.; Wu, Q.; Sun, Y.; Zhang, Q.; Yang, H.; Zhang, F.; et al. A Nanozyme with Photo-Enhanced Dual Enzyme-Like Activities for Deep Pancreatic Cancer Therapy. Angew. Chem. Int. Ed. 2019, 58, 12624–12631. [Google Scholar] [CrossRef] [PubMed]
  65. Yang, H.; Xu, B.; Li, S.; Wu, Q.; Lu, M.; Han, A.; Liu, H. A Photoresponsive Nanozyme for Synergistic Catalytic Therapy and Dual Phototherapy. Small 2021, 17, 2007090. [Google Scholar] [CrossRef]
  66. Cai, X.; Luo, Y.; Song, Y.; Liu, D.; Yan, H.; Li, H.; Du, D.; Zhu, C.; Lin, Y. Integrating in situ formation of nanozymes with three-dimensional dendritic mesoporous silica nanospheres for hypoxia-overcoming photodynamic therapy. Nanoscale 2018, 10, 22937–22945. [Google Scholar] [CrossRef] [PubMed]
  67. Liu, X.; Pan, Y.; Yang, J.; Gao, Y.; Huang, T.; Luan, X.; Wang, Y.; Song, Y. Gold nanoparticles doped metal-organic frameworks as near-infrared light-enhanced cascade nanozyme against hypoxic tumors. Nano Res. 2020, 13, 653–660. [Google Scholar] [CrossRef]
  68. Zhang, A.; Pan, S.; Zhang, Y.; Chang, J.; Cheng, J.; Huang, Z.; Li, T.; Zhang, C.; Fuentea, J.M.D.L.; Zhang, Q.; et al. Carbon-gold hybrid nanoprobes for real-time imaging, photothermal/photodynamic and nanozyme oxidative therapy. Theranostics 2019, 9, 3443–3458. [Google Scholar] [CrossRef] [PubMed]
  69. Sheng, S.; Liu, F.; Lin, L.; Yan, N.; Wang, Y.; Xu, C.; Tian, H.; Chen, X. Nanozyme-mediated cascade reaction based on metal-organic framework for synergetic chemo-photodynamic tumor therapy. J. Control. Release 2020, 328, 631–639. [Google Scholar] [CrossRef]
  70. Jana, D.; Wang, D.; Bindra, A.K.; Guo, Y.; Liu, J.; Zhao, Y. Ultrasmall Alloy Nanozyme for Ultrasound- and Near-Infrared Light-Promoted Tumor Ablation. ACS Nano 2021, 15, 7774–7782. [Google Scholar] [CrossRef]
  71. Zeng, L.; Han, Y.; Chen, Z.; Jiang, K.; Golberg, D.; Weng, Q. Biodegradable and Peroxidase-Mimetic Boron Oxynitride Nanozyme for Breast Cancer Therapy. Adv. Sci. 2021, 2101184. [Google Scholar] [CrossRef]
  72. Mirhosseini, M.; Shekari-Far, A.; Hakimian, F.; Haghiralsadat, B.F.; Fatemi, S.K.; Dashtestani, F. Core-shell Au@Co-Fe hybrid nanoparticles as peroxidase mimetic nanozyme for antibacterial application. Process Biochem. 2020, 95, 131–138. [Google Scholar] [CrossRef]
  73. Karim, M.N.; Singh, M.; Weerathunge, P.; Bian, P.; Zheng, R.; Dekiwadia, C.; Ahmed, T.; Walia, S.; Della Gaspera, E.; Singh, S.; et al. Visible-Light-Triggered Reactive-Oxygen-Species-Mediated Antibacterial Activity of Peroxidase-Mimic CuO Nanorods. ACS Appl. Nano Mater. 2018, 1, 1694–1704. [Google Scholar] [CrossRef]
  74. Wei, F.; Cui, X.; Wang, Z.; Dong, C.; Li, J.; Han, X. Recoverable peroxidase-like Fe3O4@MoS2-Ag nanozyme with enhanced antibacterial ability. Chem. Eng. J. 2021, 408, 127240. [Google Scholar] [CrossRef]
  75. Fang, G.; Li, W.; Shen, X.; Perez-Aguilar, J.M.; Chong, Y.; Gao, X.; Chai, Z.; Chen, C.; Ge, C.; Zhou, R. Differential Pd-nanocrystal facets demonstrate distinct antibacterial activity against Gram-positive and Gram-negative bacteria. Nat. Commun. 2018, 9, 129. [Google Scholar] [CrossRef] [Green Version]
  76. Ge, C.; Wu, R.; Chong, Y.; Fang, G.; Jiang, X.; Pan, Y.; Chen, C.; Yin, J.-J. Synthesis of Pt Hollow Nanodendrites with Enhanced Peroxidase-Like Activity against Bacterial Infections: Implication for Wound Healing. Adv. Funct. Mater. 2018, 28, 1801484. [Google Scholar] [CrossRef]
  77. Xi, J.; Wei, G.; Wu, Q.; Xu, Z.; Liu, Y.; Han, J.; Fan, L.; Gao, L. Light-enhanced sponge-like carbon nanozyme used for synergetic antibacterial therapy. Biomater. Sci. 2019, 7, 4131–4141. [Google Scholar] [CrossRef]
  78. Xiang, S.; Fan, Z.; Sun, D.; Zhu, T.; Ming, J.; Chen, X. Near-Infrared Light Enhanced Peroxidase-Like Activity of PEGylated Palladium Nanozyme for Highly Efficient Biofilm Eradication. J. Biomed. Nanotechnol. 2021, 17, 1131–1147. [Google Scholar] [CrossRef]
  79. Xu, M.; Hu, Y.; Xiao, Y.; Zhang, Y.; Sun, K.; Wu, T.; Lv, N.; Wang, W.; Ding, W.; Li, F.; et al. Near-Infrared-Controlled Nanoplatform Exploiting Photothermal Promotion of Peroxidase-like and OXD-like Activities for Potent Antibacterial and Anti-biofilm Therapies. ACS Appl. Mater. Interfaces 2020, 12, 50260–50274. [Google Scholar] [CrossRef] [PubMed]
  80. Wang, X.; Fan, L.; Cheng, L.; Sun, Y.; Wang, X.; Zhong, X.; Shi, Q.; Gong, F.; Yang, Y.; Ma, Y.; et al. Biodegradable Nickel Disulfide Nanozymes with GSH-Depleting Function for High-Efficiency Photothermal-Catalytic Antibacterial Therapy. iScience 2020, 23, 101281. [Google Scholar] [CrossRef] [PubMed]
  81. Yim, G.; Kim, C.Y.; Kang, S.; Min, D.-H.; Kang, K.; Jang, H. Intrinsic Peroxidase-Mimicking Ir Nanoplates for Nanozymatic Anticancer and Antibacterial Treatment. ACS Appl. Mater. Interfaces 2020, 12, 41062–41070. [Google Scholar] [CrossRef] [PubMed]
  82. Niu, J.; Sun, Y.; Wang, F.; Zhao, C.; Ren, J.; Qu, X. Photomodulated Nanozyme Used for a Gram-Selective Antimicrobial. Chem. Mater. 2018, 30, 7027–7033. [Google Scholar] [CrossRef]
  83. Wang, M.; Chang, M.; Chen, Q.; Wang, D.; Li, C.; Hou, Z.; Lin, J.; Jin, D.; Xing, B. Au2Pt-PEG-Ce6 nanoformulation with dual nanozyme activities for synergistic chemodynamic therapy/phototherapy. Biomaterials 2020, 252, 120093. [Google Scholar] [CrossRef] [PubMed]
  84. Feng, L.; Liu, B.; Xie, R.; Wang, D.; Qian, C.; Zhou, W.; Liu, J.; Jana, D.; Yang, P.; Zhao, Y. An Ultrasmall SnFe2O4 Nanozyme with Endogenous Oxygen Generation and Glutathione Depletion for Synergistic Cancer Therapy. Adv. Funct. Mater. 2021, 31, 2006216. [Google Scholar] [CrossRef]
  85. Bai, J.; Peng, C.; Guo, L.; Zhou, M. Metal–Organic Framework-Integrated Enzymes as Bioreactor for Enhanced Therapy against Solid Tumor via a Cascade Catalytic Reaction. ACS Biomater. Sci. Eng. 2019, 5, 6207–6215. [Google Scholar] [CrossRef]
  86. Mahalunkar, S.; Yadav, A.S.; Gorain, M.; Pawar, V.; Braathen, R.; Weiss, S.; Bogen, B.; Gosavi, S.W.; Kundu, G.C. Functional design of pH-responsive folate-targeted polymer-coated gold nanoparticles for drug delivery and in vivo therapy in breast cancer. Int. J. Nanomed. 2019, 14, 8285–8302. [Google Scholar] [CrossRef] [Green Version]
  87. Chong, Y.; Huang, J.; Xu, X.; Yu, C.; Ning, X.; Fan, S.; Zhang, Z. Hyaluronic Acid-Modified Au–Ag Alloy Nanoparticles for Radiation/Nanozyme/Ag+ Multimodal Synergistically Enhanced Cancer Therapy. Bioconjugate Chem. 2020, 31, 1756–1765. [Google Scholar] [CrossRef]
  88. Fan, L.; Xu, X.; Zhu, C.; Han, J.; Gao, L.; Xi, J.; Guo, R. Tumor Catalytic-Photothermal Therapy with Yolk-Shell Gold@Carbon Nanozymes. ACS Appl. Mater. Interfaces 2018, 10, 4502–4511. [Google Scholar] [CrossRef]
  89. Chen, Y.; Yin, C.; Zhang, Y.; Liu, Y.; Zan, J.; Xie, C.; Fan, Q.; Huang, W. “Dual lock-and-key”-controlled ceria nanotubes-based nanozymes for tumor-specific photothermal therapy. Dye. Pigment. 2021, 191, 109350. [Google Scholar] [CrossRef]
  90. Li, H.; Zhang, W.; Ding, L.; Li, X.-W.; Wu, Y.; Tang, J.-H. Prussian blue-modified ferritin nanoparticles for effective tumor chemo-photothermal combination therapy via enhancing reactive oxygen species production. J. Biomater. Appl. 2019, 33, 1202–1213. [Google Scholar] [CrossRef]
  91. Zhang, Y.; Wang, F.; Liu, C.; Wang, Z.; Kang, L.; Huang, Y.; Dong, K.; Ren, J.; Qu, X. Nanozyme Decorated Metal–Organic Frameworks for Enhanced Photodynamic Therapy. ACS Nano 2018, 12, 651–661. [Google Scholar] [CrossRef]
  92. Li, L.; Liu, H.; Bian, J.; Zhang, X.; Fu, Y.; Li, Z.; Wei, S.; Xu, Z.; Liu, X.; Liu, Z.; et al. Ag/Pd bimetal nanozyme with enhanced catalytic and photothermal effects for ROS/hyperthermia/chemotherapy triple-modality antitumor therapy. Chem. Eng. J. 2020, 397, 125438. [Google Scholar] [CrossRef]
  93. Ma, Z.; Zhang, M.; Jia, X.; Bai, J.; Ruan, Y.; Wang, C.; Sun, X.; Jiang, X. FeIII-Doped Two-Dimensional C3N4 Nanofusiform: A New O2-Evolving and Mitochondria-Targeting Photodynamic Agent for MRI and Enhanced Antitumor Therapy. Small 2016, 12, 5477–5487. [Google Scholar] [CrossRef] [PubMed]
  94. Mansur, A.A.P.; Mansur, H.S.; Carvalho, S.M. Engineered hybrid nanozyme catalyst cascade based on polysaccharide-enzyme-magnetic iron oxide nanostructures for potential application in cancer therapy. Catal. Today 2020. [Google Scholar] [CrossRef]
  95. Xu, K.; Cheng, Y.; Yan, J.; Feng, Y.; Zheng, R.; Wu, X.; Wang, Y.; Song, P.; Zhang, H. Polydopamine and ammonium bicarbonate coated and doxorubicin loaded hollow cerium oxide nanoparticles for synergistic tumor therapy. Nano Res. 2019, 12, 2947–2953. [Google Scholar] [CrossRef]
  96. Hu, L.; Sun, W.; Tang, Y.; Li, S.; Zhang, B.; Sun, X.; Ji, W.; Ma, L.; Deng, H.; Han, S.; et al. Photothermal effect enhancing graphene quantum dots/semiconducting polymer/nanozyme-mediated cancer catalytic therapy. Carbon 2021, 176, 148–156. [Google Scholar] [CrossRef]
  97. Xiang, X.; Pang, H.; Ma, T.; Du, F.; Li, L.; Huang, J.; Ma, L.; Qiu, L. Ultrasound targeted microbubble destruction combined with Fe-MOF based bio-/enzyme-mimics nanoparticles for treating of cancer. J. Nanobiotechnol. 2021, 19, 92. [Google Scholar] [CrossRef] [PubMed]
  98. Lin, S.; Wang, Y.; Chen, Z.; Li, L.; Zeng, J.; Dong, Q.; Wang, Y.; Chai, Z. Biomineralized Enzyme-Like Cobalt Sulfide Nanodots for Synergetic Phototherapy with Tumor Multimodal Imaging Navigation. ACS Sustain. Chem. Eng. 2018, 6, 12061–12069. [Google Scholar] [CrossRef]
  99. Ma, Z.; Jia, X.; Bai, J.; Ruan, Y.; Wang, C.; Li, J.; Zhang, M.; Jiang, X. MnO2 Gatekeeper: An Intelligent and O2-Evolving Shell for Preventing Premature Release of High Cargo Payload Core, Overcoming Tumor Hypoxia, and Acidic H2O2-Sensitive MRI. Adv. Funct. Mater. 2017, 27, 1604258. [Google Scholar] [CrossRef]
  100. Feng, W.; Han, X.; Wang, R.; Gao, X.; Hu, P.; Yue, W.; Chen, Y.; Shi, J. Nanocatalysts-Augmented and Photothermal-Enhanced Tumor-Specific Sequential Nanocatalytic Therapy in Both NIR-I and NIR-II Biowindows. Adv. Mater. 2019, 31, 1805919. [Google Scholar] [CrossRef]
  101. Zhao, Y.; Ding, B.; Xiao, X.; Jiang, F.; Wang, M.; Hou, Z.; Xing, B.; Teng, B.; Cheng, Z.; Ma, P.a.; et al. Virus-Like Fe3O4@Bi2S3 Nanozymes with Resistance-Free Apoptotic Hyperthermia-Augmented Nanozymitic Activity for Enhanced Synergetic Cancer Therapy. ACS Appl. Mater. Interfaces 2020, 12, 11320–11328. [Google Scholar] [CrossRef]
  102. Liu, Y.; Zhen, W.; Wang, Y.; Liu, J.; Jin, L.; Zhang, T.; Zhang, S.; Zhao, Y.; Song, S.; Li, C.; et al. One-Dimensional Fe2P Acts as a Fenton Agent in Response to NIR II Light and Ultrasound for Deep Tumor Synergetic Theranostics. Angew. Chem. Int. Ed. 2019, 58, 2407–2412. [Google Scholar] [CrossRef]
  103. Tang, Z.; Zhang, H.; Liu, Y.; Ni, D.; Zhang, H.; Zhang, J.; Yao, Z.; He, M.; Shi, J.; Bu, W. Antiferromagnetic Pyrite as the Tumor Microenvironment-Mediated Nanoplatform for Self-Enhanced Tumor Imaging and Therapy. Adv. Mater. 2017, 29, 1701683. [Google Scholar] [CrossRef] [PubMed]
  104. Gao, S.; Lin, H.; Zhang, H.; Yao, H.; Chen, Y.; Shi, J. Nanocatalytic Tumor Therapy by Biomimetic Dual Inorganic Nanozyme-Catalyzed Cascade Reaction. Adv. Sci. 2019, 6, 1801733. [Google Scholar] [CrossRef] [PubMed]
  105. Xu, M.; Lu, Q.; Song, Y.; Yang, L.; Ren, C.; Li, W.; Liu, P.; Wang, Y.; Zhu, Y.; Li, N. NIR-II driven plasmon-enhanced cascade reaction for tumor microenvironment-regulated catalytic therapy based on bio-breakable Au–Ag nanozyme. Nano Res. 2020, 13, 2118–2129. [Google Scholar] [CrossRef]
  106. Dong, S.; Dong, Y.; Jia, T.; Liu, S.; Liu, J.; Yang, D.; He, F.; Gai, S.; Yang, P.; Lin, J. GSH-Depleted Nanozymes with Hyperthermia-Enhanced Dual Enzyme-Mimic Activities for Tumor Nanocatalytic Therapy. Adv. Mater. 2020, 32, 2002439. [Google Scholar] [CrossRef] [PubMed]
  107. Alizadeh, N.; Salimi, A.; Sham, T.-K.; Bazylewski, P.; Fanchini, G.; Fathi, F.; Soleimani, F. Hierarchical Co(OH)2/FeOOH/WO3 ternary nanoflowers as a dual-function enzyme with pH-switchable peroxidase and catalase mimic activities for cancer cell detection and enhanced photodynamic therapy. Chem. Eng. J. 2021, 417, 129134. [Google Scholar] [CrossRef]
  108. Ai, Y.; You, J.; Gao, J.; Wang, J.; Sun, H.-B.; Ding, M.; Liang, Q. Multi-shell nanocomposites based multienzyme mimetics for efficient intracellular antioxidation. Nano Res. 2021. [Google Scholar] [CrossRef]
  109. Pei, J.; Zhao, R.; Mu, X.; Wang, J.; Liu, C.; Zhang, X.-D. Single-atom nanozymes for biological applications. Biomater. Sci. 2020, 8, 6428–6441. [Google Scholar] [CrossRef]
  110. Xu, B.; Wang, H.; Wang, W.; Gao, L.; Li, S.; Pan, X.; Wang, H.; Yang, H.; Meng, X.; Wu, Q.; et al. A Single-Atom Nanozyme for Wound Disinfection Applications. Angew. Chem. (Int. Ed. Engl.) 2019, 58, 4911–4916. [Google Scholar] [CrossRef]
  111. Huo, M.; Wang, L.; Wang, Y.; Chen, Y.; Shi, J. Nanocatalytic Tumor Therapy by Single-Atom Catalysts. ACS Nano 2019, 13, 2643–2653. [Google Scholar] [CrossRef] [PubMed]
  112. Wang, D.; Wu, H.; Phua, S.Z.F.; Yang, G.; Qi Lim, W.; Gu, L.; Qian, C.; Wang, H.; Guo, Z.; Chen, H.; et al. Self-assembled single-atom nanozyme for enhanced photodynamic therapy treatment of tumor. Nat. Commun. 2020, 11, 357. [Google Scholar] [CrossRef] [PubMed] [Green Version]
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Scheme 1. Graphical representation of the present review.
Scheme 1. Graphical representation of the present review.
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Figure 1. The properties of various nanozymes and their advantages over enzymes.
Figure 1. The properties of various nanozymes and their advantages over enzymes.
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Figure 2. Schematic representation of POD mimetic assay.
Figure 2. Schematic representation of POD mimetic assay.
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Figure 3. Mechanism of nanomaterials mediated photodynamic therapy.
Figure 3. Mechanism of nanomaterials mediated photodynamic therapy.
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Figure 4. Peroxidaselike Fe3O4 nanocomposite (FCCP) nanoplatform for photo-induced cancer theranostics. Reproduced with permission from [63].
Figure 4. Peroxidaselike Fe3O4 nanocomposite (FCCP) nanoplatform for photo-induced cancer theranostics. Reproduced with permission from [63].
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Figure 5. Schematic illustration of CMH NPs for synergetic chemo-photodynamic tumor therapy. Image was reproduced with permission from reference [69].
Figure 5. Schematic illustration of CMH NPs for synergetic chemo-photodynamic tumor therapy. Image was reproduced with permission from reference [69].
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Figure 6. Schematic representation of photothermal-enhanced nanozymatic mediated cancer therapy on viruslike Fe3O4@Bi2S3 nanozymes. Image was reproduced with permission from reference [101].
Figure 6. Schematic representation of photothermal-enhanced nanozymatic mediated cancer therapy on viruslike Fe3O4@Bi2S3 nanozymes. Image was reproduced with permission from reference [101].
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Figure 7. Schematic illustration of Ce6 loaded Ruthenium incorporated metal organic framework-based single atom nanozyme (OxgeMCC-r SAE) in PDT. (a) Schematic representation of the fabrication of Ru-based single atom nanozyme. (b,c) are molecular structure and H2O2 decomposition mechanisms of Ru-based nanozyme. (d) Schematic representation of in vivo ROS mediated catalytic therapy on OxgeMCC-r SAE. Image was reproduced with permission from reference [112].
Figure 7. Schematic illustration of Ce6 loaded Ruthenium incorporated metal organic framework-based single atom nanozyme (OxgeMCC-r SAE) in PDT. (a) Schematic representation of the fabrication of Ru-based single atom nanozyme. (b,c) are molecular structure and H2O2 decomposition mechanisms of Ru-based nanozyme. (d) Schematic representation of in vivo ROS mediated catalytic therapy on OxgeMCC-r SAE. Image was reproduced with permission from reference [112].
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Table
Table 1. Recent reports on POD-based nanozyme-mediated cancer phototherapeutics.
Table 1. Recent reports on POD-based nanozyme-mediated cancer phototherapeutics.
S. No.NanozymeEnzyme Mimetic PropertiesApplicationRef.
1Au2Pt-PEG-Ce6POD, CATChemodynamic therapy/phototherapy[83]
2SFO nanozymePOD, CATSynergistic phototherapy[84]
3Cu2MoS4 (CMS) loaded with GOxCAT and GPOD activitiesCDT/starvation/photo/immunotherapy[85]
4ZIF-8 NPs coated with Ce6 and Cyt cPOD, CATPDT and protein therapy[86]
5Au-Ag@HA NPPODRadiation/nanozyme/Ag+ combined therapy[87]
6Au@HCNsPOD and OXDEnzyme catalytic-PTT[88]
7ABTS@PAH-CNtsPODPTT[89]
8PB-Ft NPsPODChemo-PTT via ROS production[90]
9PCN-224-PtPOD, CATPDT[91]
10AgPd@BSA/DOXPODROS/hyperthermia/chemotherapy[92]
11FeΙΙΙ-doped C3N4 nanosheetsPODMRI guided PDT[93]
12MIONzyme-GOxPOD and GOxROS induced damage[94]
13PDAC NPsPODPTT/CDT/CHT combination therapy[95]
14GQD-SPNsPODPTT enhanced cancer catalytic therapy[96]
15FeN200@GOx@MPODcombinational therapeutic approach (UTMD and enzyme)[97]
16Co9S8 NDsPODPTT/PDT[98]
Abbreviations: chlorin e6 (Ce6); polyethylene glycol (PEG); SnFe2O4 (SFO); Au-Ag@HA NP; gold nanoparticle core with a porous hollow carbon shell nanospheres (Au@HCNs); PEGylated CMS@GOx; zeolitic imidazolate framework-8 (ZIF-8); dual lock-and-key type activatable nanotherapeutic platform (ABTS@PAH-CNts), 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS); ceria nanocubes (CN); Prussian blue-modified ferritin nanoparticles (PB-Ft NPs); bovine serum capped bimetallic silver palladium nanoparticles loaded with doxorubicin (AgPd@BSA/DOX); iron oxide-based nanozymes loaded with glucose oxidase (MIONzyme-GOx); polydopamine (PDA) and ammonium bicarbonate (NH4HCO3) coated and doxorubicin (Dox) loaded hollow cerium oxide (CeO2) NPs (PDAC NPs); graphene quantum dots/semiconducting polymer nanocomposites (GQD-SPNs); ultrasound-targeted microbubble destruction (UTMD); chemotherapy (CHT); Fe-Metal organic framework-based nanozyme (FeN); chemodynamic therapy (CDT); cobalt sulfide nanodots (Co9S8 NDs).
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Thangudu, S.; Su, C.-H. Peroxidase Mimetic Nanozymes in Cancer Phototherapy: Progress and Perspectives. Biomolecules 2021, 11, 1015. https://doi.org/10.3390/biom11071015

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Thangudu S, Su C-H. Peroxidase Mimetic Nanozymes in Cancer Phototherapy: Progress and Perspectives. Biomolecules. 2021; 11(7):1015. https://doi.org/10.3390/biom11071015

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Thangudu, Suresh, and Chia-Hao Su. 2021. "Peroxidase Mimetic Nanozymes in Cancer Phototherapy: Progress and Perspectives" Biomolecules 11, no. 7: 1015. https://doi.org/10.3390/biom11071015

APA Style

Thangudu, S., & Su, C. -H. (2021). Peroxidase Mimetic Nanozymes in Cancer Phototherapy: Progress and Perspectives. Biomolecules, 11(7), 1015. https://doi.org/10.3390/biom11071015

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