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Review

The Application of Biomedicine in Chemodynamic Therapy: From Material Design to Improved Strategies

1
State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, National Innovation Platform for Industry-Education Integration in Vaccine Research, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, Xiamen 361102, China
2
College of Ocean Food and Biological Engineering, Jimei University, Xiamen 361021, China
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Bioengineering 2023, 10(8), 925; https://doi.org/10.3390/bioengineering10080925
Submission received: 28 June 2023 / Revised: 26 July 2023 / Accepted: 27 July 2023 / Published: 3 August 2023
(This article belongs to the Special Issue Nanosensors and Nanomodulators in Cancer Therapies)

Abstract

:
Chemodynamic therapy (CDT) has garnered significant interest as an innovative approach for cancer treatment, owing to its notable tumor specificity and selectivity, minimal systemic toxicity and side effects, and absence of the requirement for field stimulation during treatment. This treatment utilizes nanocatalytic medicines containing transitional metals to release metal ions within tumor cells, subsequently initiating Fenton and Fenton-like reactions. These reactions convert hydrogen peroxide (H2O2) into hydroxyl radical (•OH) specifically within the acidic tumor microenvironment (TME), thereby inducing apoptosis in tumor cells. However, insufficient endogenous H2O2, the overexpressed reducing substances in the TME, and the weak acidity of solid tumors limit the performance of CDT and restrict its application in vivo. Therefore, a variety of nanozymes and strategies have been designed and developed in order to potentiate CDT against tumors, including the application of various nanozymes and different strategies to remodel TME for enhanced CDT (e.g., increasing the H2O2 level in situ, depleting reductive substances, and lowering the pH value). This review presents an overview of the design and development of various nanocatalysts and the corresponding strategies employed to enhance catalytic drug targeting in recent years. Additionally, it delves into the prospects and obstacles that lie ahead for the future advancement of CDT.

1. Introduction

Cancer, as a major public health problem, causes approximately 10 million deaths worldwide every year due to its high incidence rate and mortality [1]. However, for patients with early-stage (stage I/II) cancer, traditional cancer treatments such as surgery, chemotherapy, and radiotherapy are less effective and have unavoidable side effects [2,3,4]. Therefore, the development of innovative and effective cancer therapies with improved efficacy and fewer side effects is both urgent and challenging.
Reactive oxygen species (ROS) is a general term for a class of chemically active molecules or ions with high oxidation activity, including hydrogen peroxide (H2O2), superoxide anion (O2), hydroxyl radical (•OH) and singlet oxygen (1O2), peroxy hydroxyl radical (•OOH), etc., which plays an important role in various physiological processes of biological systems [5]. A large number of studies have shown that the overgenerated ROS could break the redox hemostasis and cause a series of biochemical reactions, such as decreased mitochondrial membrane potential, DNA breakage, cytoskeleton contraction, chromatin condensation, etc., leading to cancer cells death [6,7]. Since cancer cells are more sensitive to ROS levels, ROS generation is considered to be an effective way to kill tumor cells selectively.
Currently, the applications of ROS-based tumor therapies mainly including photodynamic therapy (PDT), chemodynamic therapy (CDT), and sonodynamic therapy (SDT) have attracted significant attention from researchers [8,9]. Among these treatment modalities, various methods can generate excessive ROS. In PDT treatment, the photosensitizer generates ROS under the action of near-infrared irradiation, and the local ROS burst promotes cell apoptosis. The cavitation effect, sonoluminescence, and piezoelectric effect are the main mechanisms of ROS generation in SDT. At the same time, there are other ways to increase ROS levels in tumors. For instance, Wang et al. reported a kind of ultrathin two-dimensional metal-organic framework (Cu-TCPP), which was endowed with selectively producing 1O2 in the tumor microenvironment for tumor therapy [10]. Firstly, the acidic H2O2 peroxidized the tetrakis(4-carboxyphenyl) porphyrin (TCPP) ligand, and then it was reduced to peroxyl radicals under the action of peroxidase (POD)-like nanosheets and Cu2+. Finally, a spontaneous recombination reaction based on the Russell mechanism occurred to generate 1O2. In addition, Cu-TCPP also consumed glutathione (GSH) through a cyclic oxidation mechanism. Based on the above two “magic weapons”, Cu-TCPP nanosheets efficiently and selectively destroyed tumors.
CDT, proposed by Bu and co-workers in 2016, has emerged as a fascinating research area in recent years. This is primarily due to its remarkable specificity and selectivity for tumors, minimal systemic toxicity and side effects, and the absence of a requirement for field stimulation during treatment [11,12]. All the facts demonstrated that CDT not only had the potential to enhance the efficacy of cancer treatment but could also be used for bacterial infection treatments [13]. Generally, CDT utilizes peroxidase-like catalysis, metallic catalysis, or Fenton and Fenton-like reactions to significantly enhance intracellular ROS. Herein, transitional metal-based nanocatalytic medicines containing some metal ions (e.g., Fe, Cu, Mn, Co, V, Pd, Ag, Mo, Ru, W, and Ce) are utilized to release metal ions in tumor cells and then trigger Fenton and Fenton-like reactions to convert H2O2 into •OH with higher toxicity in an acidic tumor microenvironment (TME), thus inducing the death of tumor cells [14]. However, the performance of CDT is limited by some natural factors, which makes it difficult to be widely applied. Firstly, there are insufficient endogenous H2O2 in tumors with a content of 50–100 µmol L−1, which is insufficient to meet the ideal CDT therapeutic efficiency [15]. Secondly, the produced oxidative •OH could be captured and neutralized by the overexpressed reducing substances in the TME, such as GSH and hydrogen sulfide (H2S), resulting in an unsatisfactory therapeutic efficiency [16,17]. Thirdly, the weak acidity (pH 6.5–7.0) of solid tumors is not suitable for Fenton and Fenton-like reactions, which are required to be remodeled to provide more suitable reaction conditions [18]. Up to now, a variety of nanozymes and strategies have been designed and developed in order to solve these problems (Scheme 1) [12,19]. This review aims to provide an overview of the design and development of different types of nanozymes as well as strategies to improve CDT in recent years. Finally, the opportunities and challenges for the future development of CDT are also discussed to promote clinical translation.

2. Fenton/Fenton-like Reagent

Nowadays, the research into efficient nanozymes for Fenton and Fenton-like reactions has attracted extensive attention due to the wide application of CDT in cancer therapy. The choice of nanomaterials (iron-based materials, copper-based materials, and other metal-based materials) is crucial because of the irreplaceable role of catalysts in Fenton and Fenton-like reactions.

2.1. Iron-Based Fenton Reagent

In recent years, many nanozymes containing catalytically active ions have been designed based on the Fenton reaction and the Fenton-like reaction. So far, iron-based materials have been widely used in the biological field and have shown excellent biosafety and biocompatibility [20,21]. Various iron-based nanomaterials have been extensively studied to enhance the efficacy of CDT, such as ferroferric oxide (Fe3O4) [22], ferrous disulfide (FeS2) [23], ferric oxide (Fe2O3) [24], Fe-metal organic frameworks (Fe-MOFs) [25], and Fe-doped nanoagents [26]. A Fenton reaction is often catalyzed by Fe2+ or Fe3+, which decomposes H2O2 to produce radical •OH, resulting in the destruction of lipids, proteins, and DNA. The reactions (Equations (1) and (2)) are shown below:
Fe2+ + H2O2 → Fe3+ + •OH + OH
Fe3+ + H2O2 → Fe2+ + •OOH + H+
As one of the most classical H2O2-responsive nanozymes, Fe3O4 nanoparticles become an effective POD-like enzyme with the Fe2+/Fe3+ redox cycle. As the reaction site of nanozymes, Fe2+ on the surface of Fe3O4 nanoparticles reacted with the overexpressed H2O2 in TME to produce •OH, which was then converted to Fe3+ in the oxidized state, leading to severe tumor damage. In this reaction process, the oxidation property of the generated •OOH was lower than that of the generated •OH, and the rate of the generated •OH was relatively faster [27,28]. For instance, Du et al. successfully constructed kinds of hollow Fe3O4 mesocrystals to realize the high level of •OH in the tumor region and a low expression of heat shock proteins, resulting in a self-enhanced antitumor efficacy between magnetic hyperthermia and CDT [29]. The therapeutic efficiency of nanomaterials was greatly restricted due to the low iron loading and cumbersome releasing route. Polydopamine (PDA) has been widely studied as a CDT agent owing to its high biocompatibility and radical scavenging strong chelation with Fe2+. Recently, Xiao et al. prepared a multifunctional hybrid nanozyme (PDA/Fe3O4), which was retained in infected sites via an external magnet (Figure 1a) [30]. PDA with redox-active catechol moieties supplied oxygen with electrons to produce H2O2, which was then decomposed by decorated ultrasmall Fe3O4 to generate more •OH. Surprisingly, PDA/Fe3O4 was equipped with simultaneous H2O2-self-sufficient •OH generation and GSH depletion to improve the CDT efficacy. In another work, Luo et al. synthesized a novel nanoplatform of Fe3O4@PDA@BSA-Bi2S3 nanoparticles via the amidation between the carboxyl and amino groups to promote the efficiency of Fenton reaction in cancer cells [31]. In this system, the Fe3O4 nanoparticles were not only capable of triggering Fenton reactions to generate highly •OH from the innate H2O2 in the TME but were also employed as the magnetic resonance imaging (MRI) contrast agent for the precise cancer diagnosis. Specifically, PDA promoted the long-term Fenton reactions and tumor apoptosis by preventing oxidation of Fe3O4, which reacted with intracellular H2O2 to produce •OH and further suppressed tumor growth. Moreover, computed tomography (CT) contrast was also enhanced due to the significant X-ray attenuation coefficient of Bi2S3, enabling the simultaneous CDT and PDT treatment of tumors. On the other hand, this also contributed to the regulation of the CDT treatment process, minimizing the biotoxicity and improving diagnostic and therapeutic capabilities. Eventually, the present study demonstrated a novel and viable approach for synthesizing composite theranostic nanoplatforms.
In addition to Fe3O4, other iron-based materials are also endowed with superb Fenton reaction catalysis. For instance, Wu et al. developed hollow porous carbon-coated FeS2 (HPFeS2@C) nanocatalysts for triple-modal imaging-guided synergistic tumor starvation therapy (ST), photothermal therapy (PTT), and CDT [32]. Interestingly, glucose oxidase (GOx) in the multifunctional nanocatalysts reacted with glucose in the TME to increase the H2O2 concentration, which improved the production of •OH. Meanwhile, tannic acid (TA) was effectively released for reducing Fe3+ to Fe2+ under near-infrared (NIR) laser exposure, thereby accelerating the Fenton reaction. In addition, the photothermal effect induced by NIR lasers also increased the catalytic efficiency. Furthermore, our group reported a phthalocyanine-iron-based complex FeS2@PcD, program-regulated by the dual factors of gluconic acid (H+) and H2O2 in the TME (Figure 1b) [33]. After the efficient internalization into cancer cells, FeS2@PcD reacted with excessive H+ to generate Fe2+. Fe2+ then catalyzed intracellular H2O2 to produce •OH for CDT and simultaneously generate Fe3+ for further MRI as well as activating the released building block PcD (Figure 1c). Interestingly, the nitrogen atom on the DPA group of PcD specifically chelated Fe3+, thereby recovering fluorescence and sonosensitizing activity. Moreover, in vitro data showed that the fluorescence intensity of FeS2@PcD increased 52.21-fold, resulting from the programmable response, whereas the signal of the H+ or H2O2 univariate factor was almost unchanged (Figure 1d). Moreover, FeS2@PcD combined with ultrasound irradiation had a significant inhibitory effect on HepG2 tumor-bearing mice tumor, with an inhibition rate of 87.15% (Figure 1e). In summary, our work achieved precise sonodynamic and chemodynamic therapies, providing a novel strategy for CDT-related clinical research. To date, dihydroartemisinin (DHA) has been regarded as a drug candidate for cancer therapy. This mechanism was based on the breakdown of weak endoperoxide bridges by Fe2+ to produce toxic ROS, which resulted in facilitating H2O2-mediated Fenton reactions to generate abundant ROS for effective CDT [34]. Xu et al. prepared an antibacterial nanoagent Fe2O3@DHA@MPN (FDM) for dual-augmented NIR and DHA antibacterial CDT [35]. As the core, α-Fe2O3 mesoporous nanorods provided both efficient DHA transport and an additional source of Fe2+ used for enhanced CDT. Furthermore, metal-polyphenol networks (MPN) shells released DHA in response to the microenvironment and led to the release of TA and Fe3+ simultaneously due to bacterial infection. Consequently, TA reduced Fe3+ to Fe2+ under NIR laser exposure, which was favorable for H2O2-mediated CDT as well as DHA-mediated CDT.
Figure 1. (a) The mechanism underlying the effects of PDA/Fe3O4 hybrid nanozymes as an enhanced CDT agent for bacterial elimination. Reproduced with permission [30]. Copyright 2021, WILEY–VCH. (b) Fabrication and programmable mechanism of the FeS2@PcD. (c) The action process of FeS2@PcD in HepG2 cells for sono/chemodynamic therapies. (d) Fluorescence intensity of FeS2@PcD in the presence of H+ and H2O2. (e) Curves showing HepG2 tumor volumes in mice treated with FeS2@PcD–mediated SDT. Data were expressed as mean ± SD, n = 5, ** p < 0.01, *** p < 0.001, **** p < 0.0001, analysed by Student’s t test. Reproduced with permission [33]. Copyright 2023, Elsevier Ltd.
Figure 1. (a) The mechanism underlying the effects of PDA/Fe3O4 hybrid nanozymes as an enhanced CDT agent for bacterial elimination. Reproduced with permission [30]. Copyright 2021, WILEY–VCH. (b) Fabrication and programmable mechanism of the FeS2@PcD. (c) The action process of FeS2@PcD in HepG2 cells for sono/chemodynamic therapies. (d) Fluorescence intensity of FeS2@PcD in the presence of H+ and H2O2. (e) Curves showing HepG2 tumor volumes in mice treated with FeS2@PcD–mediated SDT. Data were expressed as mean ± SD, n = 5, ** p < 0.01, *** p < 0.001, **** p < 0.0001, analysed by Student’s t test. Reproduced with permission [33]. Copyright 2023, Elsevier Ltd.
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Recently, MOFs, which are composed of metal ions and organic ligands, have attracted increasing attention in catalysis, energy storage, separation, and cancer therapy [36,37]. Owing to the large pore surfaces, good biodegradability, and biocompatibility, MOFs were widely used as nanoplatforms for drug delivery. Therein, Fe-MOFs (like MIL-101) showed an efficient catalytic effect as a Fenton nanocatalyst. For instance, Chen et al. prepared photosensitizer-integrated nanoagents of MIL-101(Fe)@TCPP for implementing the combined PDT and CDT [38]. In this system, the MIL-101(Fe) MOF transformed endogenous H2O2 into •OH via Fe ion-catalyzed Fenton reaction, resulting from the intrinsic POD-mimicking activity of MIL-101(Fe)@TCPP. Moreover, the photosensitizer TCPP was covalently connected with MIL-101(Fe) through amide bonds, leading to in situ 1O2 evolution at the tumor region under light irradiation and amplifying ROS-induced oxidative damage. Similarly, Yin et al. successfully synthesized a cascade biomimetic nanoplatform of CPPO@Fe-porphyrin-MOF@Cancer cell membrane-GOD (C1@M@C2G) by loading harbors bis(2-carbopentyloxy-3,5,6-trichlorophenyl) oxalate (CPPO) into the Fe-porphyrin-MOF nanoparticle, which was further coated with the cancer cell membrane and grafted GOD on the surface (Figure 2a) [39]. After accumulating in the tumor site, GOD-catalyzed glucose oxidation activated the therapy of starvation, thereby consuming the local glucose and further generating H+ and H2O2, further greatly decreasing the pH of the microenvironment and promoting the massive generation of •OH for efficient CDT. Simultaneously, CPPO, as an energetic reagent, reacted with some other H2O2 to form high energy states, which excited porphyrin photosensitizers and produced 1O2 for PDT in situ. Overall, this work combined CPPO-induced PDT, Fenton reaction-based CDT, and GOD-catalyzed ST to synergistically enhance cancer therapy with effective cascade catalysis, and also broaden anticancer pathways.
Additionally, due to properties such as prominent molecular recognition ability and accurate addressability of nucleic acids, DNA-based hydrogels have outstanding advantages in controlling the release of encapsulated cargoes for controlled drug delivery [40,41,42]. Wang et al. prepared a kind of MOF-biomineralized DNA nanosphere (Fe-DNA@ZIF-8) via cascade reactions to implement the intracellular H2O2 level for enhanced CDT (Figure 2b) [43]. Fe-DNA was composed of Fe2+ and DNA molecules by coordination-driven self-assembly, which was then coated by zeolitic imidazolate framework-8 (ZIF-8) for mineralization. At the same time, GOx was encapsulated into ZIF-8 to further form Fe-DNA/GOx@ZIF-8. After being endocytosed by tumor cells, Fe-DNA and GOx were released in the acidic condition, providing Fe2+ and Fe3+ to activate the Fenton reaction and catalyzing glucose into H2O2 to enhance CDT effectiveness. In addition, multimetallic alloy nanostructures demonstrated higher catalytic activity than monometallic components owing to the electronic coordination effect, leading to its wide application. For example, Jana et al. fabricated a trimetallic (Pd, Cu, and Fe) alloy nanozyme (PCF-a NEs) with dynamic active-site synergism, which depleted intracellular overexpressed GSH and reduced the cellular self-defense antioxidant mechanism [44]. PCF-a NEs had the synergistic peroxidase-like property to promote •OH in the presence of Cu and Fe, thus boosting the effectiveness of CDT. This work pointed to the potential for using alloy nanozymes for tumor-specific treatments mediated by external stimulus.
To improve the application of iron-based nanoparticles for efficacious CDT, an effective method was to accelerate the conversion efficiency of Fe2+ and Fe3+. The low indirect band-gap (1.2–1.8 eV) of MoS2 made it an effective co-catalyst for the Fenton reaction, which converted Fe(III) into Fe(II). For example, our group synthesized gallic acid (GA)-modified MoS2 nanosheets coated with high Fe(III) (MoS2@GA-Fe), which were used for photoacoustic (PA) imaging and MRI-guided combined cancer treatment integrating •OH and H2S (Figure 2c) [45]. Firstly, GA-Fe(III) reacted with overexpressed GSH to produce GA-Fe(II), which promoted the generation of •OH in the TME. Moreover, after Mo (IV) was oxidized to Mo (VI), S-Mo-S was destroyed, exposing active sites for further reaction cycles and converting unsaturated sulfur atoms to H2S with selective cytotoxicity to cancer cells. Additionally, PA imaging for BALB/c nude tumor-bearing mice after intravenous injection of MoS2@GA-Fe showed that the signal of the tumor area was enhanced and remained for 24 h, resulting from the structure-based enhanced permeability and retention (EPR) effect (Figure 2d,e). Thus, the TME-responsive “Fenton Nanoreactor” was used as a promising nanomedicine to treat cancer or other diseases and improve patient health.
Figure 2. (a) Schematic representation of the fabrication procedure of C1@M@C2G NSs and their working mechanism of CL–induced PDT, Fenton reaction–based CDT, and GOD–mediated ST. Reproduced with permission [39]. Copyright 2021, Royal Society of Chemistry. (b) Scheme of Fe–DNA/GOx@ZIF–8 for enhanced CDT. Reproduced with permission [43]. Copyright 2021, Elsevier Ltd. (c) Theranostic mechanism of the MoS2@GA–Fe NPs for PA/MR imaging–guided HCC treatment. (d) The PA images and (e) intensity of tumor–bearing mice after intravenous injection with MoS2@GA-Fe. Reproduced with permission [45]. Copyright 2021, Elsevier Ltd.
Figure 2. (a) Schematic representation of the fabrication procedure of C1@M@C2G NSs and their working mechanism of CL–induced PDT, Fenton reaction–based CDT, and GOD–mediated ST. Reproduced with permission [39]. Copyright 2021, Royal Society of Chemistry. (b) Scheme of Fe–DNA/GOx@ZIF–8 for enhanced CDT. Reproduced with permission [43]. Copyright 2021, Elsevier Ltd. (c) Theranostic mechanism of the MoS2@GA–Fe NPs for PA/MR imaging–guided HCC treatment. (d) The PA images and (e) intensity of tumor–bearing mice after intravenous injection with MoS2@GA-Fe. Reproduced with permission [45]. Copyright 2021, Elsevier Ltd.
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2.2. Copper-Based Fenton-like Reagent

In addition to ferrous iron ions, other transition metal ions like Cu2+ also have catalytic effects in Fenton and Fenton-like reactions. As a potential alternative to Fe-based nanomaterials, Cu-based nanomaterials have found a variety of applications in many CDT research fields. Cu-catalyzed Fenton-like reactions occur in neutral and very mild acidic conditions, which are less violent than that of Fe-catalyzed Fenton reactions [46]. Moreover, the valence transition between Cu2+ and Cu+ is usually accompanied by depletion of the excessive GSH in the TME, enhancing the production of •OH to achieve highly efficient CDT [47]. Hence, Cu-based nanomaterials have been extensively employed as Fenton reagents, such as copper sulfide (CuS), copper oxide (CuO), Cu-based MOF, and Cu-doped nanoagents [48,49,50,51]. The Cu-based catalytic reactions (Equations (3) and (4)) are shown below.
Cu+ + H2O2 → Cu2+ + •OH + OH
Cu2+ + H2O2 → Cu+ + •OOH + H+
More and more attention has been paid to CuS nanoparticles because of their low toxicity, their ability to penetrate into biological tissues after being stimulated by NIR light, and their PA and Fenton-like properties [52,53,54]. For instance, Kong and co-workers reported a smart biomimetic enzyme system of CuGP/G, which was composed of the CuS nanoparticle, generation 5 poly (amidoamine) (G5) dendrimer, and GOD for the combination of CDT and PTT (Figure 3a) [55]. Specifically, CuS cores with Fenton-like catalysts were entrapped by positively charged G5, which simultaneously bonded to the negatively charged GOD via electrostatic interactions as a carrier. Additionally, H2O2 was produced by GOD to generate •OH in the sequential Fenton-like reaction, resulting in efficient tumor treatment. Moreover, the Michaelis–Menten kinetic curve demonstrated that the Michaelis–Menten constant (Km) was 3.75 × 10−3 M, and the maximum reaction velocity (Vm) was calculated at 3.6 × 10−7 M s−1 after incorporating GOD with CuGP (Figure 3b,c), compared to a Fe3O4-GOD system with the Km of 10.93 × 10−3 M and the Vm of 4.22 × 10−8 M s−1, indicating that the Fenton-like catalytic activity of CuGP/G was better than the Fe3O4-GOD-based system [56]. Nevertheless, CuS was usually trapped by the endothelial reticular system or rapidly cleared by the kidney, resulting in poor accumulation in tumors. To efficiently transport CuS to tumor cells, Li et al. used macrophages to phagocytose large supramolecular aggregates of CuS for the specific-release nanomedicines in the tumor region (Figure 3d) [57]. The supramolecular aggregates were composed of CuS nanoparticles, which were capped by β-cyclodextrin (β-CD) and ferrocene (Fc), respectively, and self-assembled via β-CD-Fc host–guest interactions. Since macrophages were attracted to tumor tissue with inflammatory properties, nanomedicines were successfully delivered through macrophages and then the β-CD-Fc host–guest pair were dissociated by the oxidation of ferrocene, inducing the disassemble of CuS aggregates into small CuS nanoparticles for further photothermal-enhanced CDT. This work proposed a feasible strategy for specific cancer therapy and new insights into new cell-based medicine carriers.
CuO nanoparticles have aroused great interest in recent years, benefiting from the large surface area, reactive morphology, high catalytic reusability, and superb chemical and thermal stability [58,59]. As mentioned earlier, the rate of •OH production was relatively faster relative to •OOH in Cu-mediated CDT. As a representative CuO-based Fenton-like nanocatalyst in CDT, Jiang et al. reported the synthesis of semiconductor CuO and MoS2 nanoflowers to construct MoS2-CuO heteronanocomposites through a two-step hydrothermal method (Figure 4a) [60]. MoS2-CuO heteronanocomposites were then loaded with bovine serum albumin (BSA) and immunoadjuvant imiquimod (R837) on its surface to further form MoS2-CuO@BSA/R837 (MCBR) nanoplatforms, which had an excellent ability to eliminate the primary tumor and release tumor-associated antigens (TAAs). In this system, CuO responded to overexpressed H2O2 in tumor cells and produced a mass of •OH through Fenton-like reactions. The reactions were further improved by the effect of MoS2 due to its high photothermal conversion efficiency. And more importantly, MCBR released TAAs under 808 nm NIR laser irradiation, which combined with R837 to act as an immune-stimulating adjuvant to boost dendritic cells maturation and the release of effector T cells from the lymph node. Consequently, this work achieved an efficient and tumor-specific therapy, providing a meaningful paradigm for future clinical applications. In another study, Xiao et al. prepared an intelligent nanoplatform of CuO2@mPDA/DOX-HA (CPPDH) with self-sufficient H2O2 and GSH depletion for the synergistic chemotherapy, PTT, and CDT (Figure 4b) [61]. The surface of CuO2 nanospheres was decorated with mesoporous polydopamine (mPDA) with seed-mediated microemulsion and further loaded with doxorubicin (DOX) via π-π stacking. Moreover, the obtained CuO2@mPDA/DOX was constructed by hyaluronic acid (HA) using electrostatic adsorption to finally acquire CPPDH. After entering the intracellular HA environment, CuO2 was released to generate Cu2+ and H2O2 triggered by the acidic environment. The Cu2+ was then reduced to Cu+ by GSH, and subsequently Cu+ reacted with intracellular H2O2 to produce massive •OH for enhanced CDT. Interestingly, CPPDH had excellent targeting ability to tumor cells resulting from the specific binding affinity of HA, whose bonds overexpressed CD44 receptor in the tumor region. Furthermore, the nanoparticles were endowed with a superb effect of PTT due to the strong NIR absorption capacity of PDA, and the light-to-heat conversion efficiency was calculated as 38.39%, which was significantly higher than that of reported photothermal reagents like AuNRs@SiO2 (20.8%) [62], MS-BSA (21.8%) [63], and Au-Cu9S5 nanoparticles (37%) [64].
In addition to the use of CuS and CuO, Cu-MOF also exhibited superb catalytic performance to achieve highly efficient CDT. For example, Tian et al. reported a nanoplatform integrating vitamin K3 into the MOF-199(Cu) to implement a CDT-mediated tumor therapy [65]. The hollow structures derived from MOFs have the virtue of drug loading and delivery with outstanding mass transfer and loading capacity. In a recent study, Cheng et al. proposed a strategy to incorporate Cu2+ into the precursors of ZIF-90 to form the Cu+/2+ mixed-valence hollow porous structure (Cu/Zn-MOF) through heating treatment, and then Cu/Zn-MOF was integrated with Mn2+/MnO2 using manganese(II) acetylacetonate(Mn(acac)2) to construct a mixed-metal and mixed-valence (Cu+/2+/Mn2+/4+) structure, which was finally loaded by the photosensitizer indocyanine green (ICG) to prepare ICG@Mn/Cu/Zn-MOF@MnO2 (Figure 4c,d) [66]. After being endocytosed by tumor cells, Cu2+ and MnO2 oxidized GSH to generate a great mass of ROS and Cu+ and produced Mn2+, which was used to “turn on” MRI. Subsequently, the obtained Cu+ and Mn2+ catalyzed H2O2 to produce •OH for effective CDT via the Fenton-like reaction and O2 through a synergistic catalytic effect to relieve the hypoxia for the enhanced PDT. Then, the aggregated ICG in the system was not only employed for photothermal imaging (PTI) with excellent photothermal capacity, but also achieved “turn on” fluorescence imaging (FLI) after its release in tumor cells. Irradiated with a single 808 nm NIR, ICG@Mn/Cu/Zn-MOF@MnO2 exhibited an obvious temperature increase with an excellent photothermal conversion efficiency of 30.1% and converted the O2 generated in situ into 1O2 for enhancing the effect of PDT. ICG@Mn/Cu/Zn-MOF@MnO2 was expected as a versatile platform of PTI/FLI/MRI trimodality imaging due to the high photothermal conversion, ICG release capability, and the generation of Mn2+ that responded to TME.
Figure 4. (a) Schematic illustration of the therapeutic mechanisms of MoS2–CuO@BSA/R837 nanoplatforms for synergistic PTT/CDT/immunotherapy. Reproduced with permission [60]. Copyright 2021, Elsevier Ltd. (b) Schematic illustration of the synthesis of CPPDH and the schematic diagram of the therapeutic mechanism. Reproduced with permission [61]. Copyright 2021, American Chemical Society. (c) Schematic illustration of the synthesis of ICG@Mn/Cu/Zn–MOF@MnO2. (d) The scheme of therapeutic mechanism for PTI/FLI/MRI–guided ROS–augmented synergistic PTT/PDT/CDT. Reproduced with permission [66]. Copyright 2021, WILEY–VCH.
Figure 4. (a) Schematic illustration of the therapeutic mechanisms of MoS2–CuO@BSA/R837 nanoplatforms for synergistic PTT/CDT/immunotherapy. Reproduced with permission [60]. Copyright 2021, Elsevier Ltd. (b) Schematic illustration of the synthesis of CPPDH and the schematic diagram of the therapeutic mechanism. Reproduced with permission [61]. Copyright 2021, American Chemical Society. (c) Schematic illustration of the synthesis of ICG@Mn/Cu/Zn–MOF@MnO2. (d) The scheme of therapeutic mechanism for PTI/FLI/MRI–guided ROS–augmented synergistic PTT/PDT/CDT. Reproduced with permission [66]. Copyright 2021, WILEY–VCH.
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2.3. Other Metal-Based Fenton-like Reagents

In addition to Fe-and Cu-based Fenton reagents, other metals have also been used in Fenton and Fenton-like reactions, such as Mn [67], Ti [68], Ag [69], Pt [70], V [71], and Ru [72]. For Mn-based Fenton reagents, manganese oxide (MnOx) triggers the generation of oxygen, a unique behavior that alleviates the hypoxia of TME, making it the most commonly used Mn-based Fenton nanomaterial in biological applications [73]. Moreover, as a classical Fenton-like reagent, MnOx can enhance CDT effectiveness by depleting intracellular GSH. Meanwhile, Mn2+ has been demonstrated as an effective contrast agent for tumor T1-weighted magnetic resonance imaging (T1-MRI), and it also has excellent PTI, photoacoustic imaging (PAI), and ultrasound imaging capabilities [74,75,76].
In a recent study, Xiao and co-workers reported kinds of macrophage membrane-coated polymer nanogels (MPM@P NGs), which were co-loaded with MnO2 nanoparticles and cisplatin to achieve specific targeted chemotherapy and CDT (Figure 5a) [77]. In this nanoplatform, redox-responsive poly (N-vinylcaprolactam) nanogels containing disulfide bond (S-S) cross-linkers were disintegrated in TME to specifically release cisplatin and consume GSH to enhance CDT. Furthermore, MnO2 simultaneously consumed the highly concentrated endogenous GSH to promote the production of •OH, and the produced Mn2+ catalyzed the decomposition of H2O2 to generate ROS for tumor apoptosis and was also employed for T1-MRI (Figure 5b). In addition, the outer macrophage membrane enabled the polymer nanogels to penetrate the blood–brain barrier (BBB) due to the overexpressed macrophage-1 antigen, integrin α4, and β1 on the surface for effective glioma targeting. Consequently, this nanoplatform represented a feasible way to enhance MRI-guided synergetic antitumor effect. To realize more accurate cancer imaging and effective treatment, Wang et al. employed poly(lactic-co-glycolic acid) (PLGA) nanoparticles with porous structure as templates to prepare hollow MnO2 (HMnO2) shells in situ, which were further utilized to deliver bufalin and then cloaked with platelet membrane (Figure 5c) [78]. Bufalin and platelet modification were able to inhibit cancer angiogenesis, block cancer cell growth, and improve tumor targeting mediated by specific binding of P-selectin to the CD44 receptor of cancer cells. Moreover, under conditions of acidic tumor pH and relatively high GSH concentration, HMnO2 nanoparticles were rapidly degraded to allow the controlled release of bufalin, while Mn2+ was obtained for magnetic resonance monitoring and further targeted chemotherapy and CDT.
Recent reports have especially shown that multicomponent metallic composites improved activity and selectivity compared to single components, which was called the “synergetic catalytic effect” [79,80]. Zhou et al. synthesized cerium peroxide with good stability and then in situ doped Fenton-type metallic peroxides (Fe2+, Cu2+, Mn2+, Ce4+, Cr3+, etc.) to successfully prepare cerium peroxide matrix (M-CeOx) as a novel Fenton-type bimetallic peroxide nanomaterial [81]. Interestingly, the results of 3,3′,5,5′-tetramethylbenzidine (TMB) assays exhibited that the maximum absorbance increase of TMB increased 40–60-fold at pH 7.0 in the presence of M-CeOx, suggesting that the relatively high pH stimulated the generation of •OH and M-CeOx had excellent catalytic performance. In this prepared M-CeOx, 10% doping of Mn had much higher catalyst efficiency, and Mn-CeOx represented superb anticancer activity at the relatively high pH, due to the in situ self-generated H2O2 supplement and the multimetal-mediated synergistic-enhanced catalytic activity. In addition, in a recent work by Wu’s group, a novel type of organosilica hybrid micelles (Mn3O4@PDOMs-GOD) was designed and constructed by co-loading Mn3O4 and GOD for enhanced ST and CDT [82]. After the entry of Mn3O4@PDOMs-GOD in the tumor cells, GOD effectively depleted glucose and produced a large amount of H2O2 at the same time. Under the condition of acidic TME, H2O2 was decomposed into O2 by Mn3O4, breaking the vicious cycle of hypoxia and simultaneously enhancing the GOD-mediated ST effect through the regeneration of H2O2. Meanwhile, Mn3O4 also reacted with overexpressed GSH to release Mn2+, thereby converting the increased H2O2 into highly toxic •OH. Eventually, the Mn3O4@PDOMs-GOD nanosystem exhibited excellent cascade catalytic performance in the TME, which endowed it with a superior ability of sustained and stable delivery of O2 and H2O2 in situ. Overall, the novel type of organosilica hybrid micelles was a promising approach to improve the efficiency of O2-dependent ST and H2O2-dependent CDT.

3. Different Strategies to Improve CDT Performance

Although CDT has unique advantages over cancer treatments, its wide application in vivo is still limited by factors such as harsh Fenton reaction conditions, complex physiological environment, and limited reaction efficiency. Accordingly, to tackle the main obstacles existing in CDT, several strategies have been proposed to change this dilemma in the past few years. In general, the strategies to improve CDT performance are as follows: (1) CDT efficacy is improved by generating more H2O2; (2) oxidative stress at the tumor cells is enhanced by decreasing the reducing substances amount; and (3) CDT efficiency is improved by reducing the pH value.

3.1. Increasing H2O2 Level

The concentration of H2O2 plays an important role in the efficiency of CDT. In response to the limitation of endogenous H2O2 deficiency in the tumor region, an earlier approach was to directly deliver exogenous H2O2 into the body [83]. For example, Li et al. prepared a PLGA polymersome to encapsulate H2O2 into a hydrophilic core for direct delivery of exogenous H2O2 [84]. However, supplementing H2O2 from an external source had a risk of leakage and was difficult to implement. Therefore, several approaches for production in situ of endogenous H2O2 have been designed to overcome the limitation of H2O2 insufficiency in the tumor cells, such as the application of H2O2-related enzymes, metal peroxides, and photocatalysts.
GOx, which was able to specifically oxidize β-D-glucose into H2O2 and H+, was ideal for increasing tumor acidity and H2O2 level [85]. Zhang et al. synthesized an adenosine triphosphate (ATP)-responsive autocatalytic Fenton nanoagent (GOx@ZIF@MPN) for tumor therapy (Figure 6a) [86]. The nanoagents had cores which were formed by GOx and then incorporated with ZIF and MPN shells. Interestingly, the MPN shell was decomposed into TA and Fe3+ by the overexpression of ATP existing in the tumor cells, resulting in the exposure of internal GOx. Subsequently, the GOx consumed endogenous glucose to generate abundant H2O2. And TA then reacted with Fe3+ to produce Fe2+, which converted H2O2 to •OH and finally exerted good antitumor efficacy. It is widely known that GOx, as an aerobic enzyme, cannot efficiently catalyze the production of H2O2 in situ due to the hypoxic condition of cancer cells. To address this situation, Feng et al. employed MnO2 as an oxygen donor to compose core-shell structured nanoplatform Fe5C2-GOD@MnO2, which generated O2 through the weakly acidic TME-specific response, thereby enhancing the process of GOx to catalyze the production of H2O2 from glucose and O2 (Figure 6b) [87]. Tao et al. designed a new CDT nanosystem of RBC@Hb@GOx that effectively overcame the restriction of BBB by using GOx to elevate H2O2 concentration at the tumor site for the treatment of glioblastoma multiforme. Specifically, hemoglobin (Hb) and GOx were combined as an alternative synthetic Fenton catalyst and then encapsulated with red blood cell (RBC) membranes to achieve longer retention time and less immunogenic responses.
ROS-regulated nanozymes, such as superoxide dismutase (SOD) and POD, are employed to regulate intracellular and extracellular ROS concentrations. Hence, materials possessing SOD-like or POD-like enzyme activity are extensively utilized to enhance the level of ROS in TME [88,89]. In a study by Sang and her collaborators, the nanoparticle zeolitic imidazole framework-67 (ZIF-67) was constructed by assembling cobalt ions with 2-methylimidazole [90]. Subsequently, small-molecule inhibitor 3-amino-1,2,4-triazole (3-AT) and COOH-PEG-COOH were modified on the surface of ZIF-67 to fabricate the final product PZIF67-AT. PZIF67-AT with SOD-like activity could break the homeostasis of H2O2 and convert plenty of O2•− into H2O2. At the same time, the small molecule inhibitors released in the acidic microenvironment effectively inhibited the activity of catalase (CAT) and reduced the self-consumption of H2O2. In a separate study, Dong et al. constructed a nanozyme with tunable multi-enzymatic activities named PHMZCO-AT, which was composed of a hollow mesoporous Mn/Zr-doped CeO2 and 3-AT (Figure 6c) [91]. The nanozyme PHMZCO-AT, with enhanced SOD-like and POD-like activities, as well as inhibited CAT-like activity, allowed more H2O2 to participate in the Fenton reaction, thereby generating massive hydroxyl radicals to induce tumor cells apoptosis and death.
In addition to the SOD-like activity materials, cisplatin and β-Lapachone have also been demonstrated to be involved in affecting the related enzymes responsible for the generation of H2O2. For example, cisplatin was an extensively used broad-spectrum chemotherapy drug for cancer therapy. It was reported that nicotinamide adenine dinucleotide phosphate (NADPH) oxidase existing in cancer cells could be specifically activated by cisplatin and, subsequently, an O2 molecule was converted into O2•− after accepting an electron provided by the oxidation of NADPH, which was further catalyzed by SOD to produce the final H2O2 [92]. Ren et al. utilized this mechanism to design and synthesize the nanodrug of PTCG, which was composed of phenolic platinum (IV) prodrug, epigallocatechin-3gallate, and copolymer (PEG-b-PPOH) [17]. The study demonstrated that activated cisplatin was employed to increase the intracellular H2O2 level obviously via a cascade reaction in vitro and in vivo. Moreover, β-Lapachone, a new antitumor drug, was catalyzed by NAD(P)H: quinone oxidoreductase1 (NQO1) to generate H2O2 [93]. For instance, Wang et al. combined β-Lapachone, iron oxide nanoparticles, and camptothecin (CPT) to form pH- and H2O2-dual-responsive nanoplatform LaCIONPs (Figure 6d) [94]. The research indicated that β-Lapachone could generate large amounts of H2O2 through tumor-specific NAD(P)H: NQO1 catalysis. Interestingly, the product H2O2 not only participated in the Fenton reaction but also specifically activated the release of camptothecin from LaCIONPs for chemotherapy.
Figure 6. (a) Schematic illustration of the synthesis of GOx@ZIF@MPN and its detailed therapeutic mechanisms for synergetic CDT and ST. Reproduced with permission [86]. Copyright 2018, American Chemical Society. (b) Schematic illustration of the therapeutic mechanisms of Fe5C2–GOD@MnO2. Reproduced with permission [87]. Copyright 2018, American Chemical Society. (c) The action mechanism of PHMZCO–AT nanozymes. Reproduced with permission [91]. Copyright 2021, WILEY–VCH. (d) The detailed therapeutic mechanisms of LaCIONPs for chemo/chemodynamic combination therapy. Reproduced with permission [94]. Copyright 2019, WILEY–VCH.
Figure 6. (a) Schematic illustration of the synthesis of GOx@ZIF@MPN and its detailed therapeutic mechanisms for synergetic CDT and ST. Reproduced with permission [86]. Copyright 2018, American Chemical Society. (b) Schematic illustration of the therapeutic mechanisms of Fe5C2–GOD@MnO2. Reproduced with permission [87]. Copyright 2018, American Chemical Society. (c) The action mechanism of PHMZCO–AT nanozymes. Reproduced with permission [91]. Copyright 2021, WILEY–VCH. (d) The detailed therapeutic mechanisms of LaCIONPs for chemo/chemodynamic combination therapy. Reproduced with permission [94]. Copyright 2019, WILEY–VCH.
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Metal peroxides were conventionally composed of metal ions and peroxo groups. Previous studies have shown that metal peroxides, especially in acidic solutions, more easily react with H2O to generate H2O2, which makes them more suitable for tumor therapy through the acidic TME response [95]. Meanwhile, with the rapid development of nanotheranostic technology in recent years, many nanostructured metal peroxides have been designed and fabricated for biomedical research and have achieved good therapeutic outcomes [49,96,97,98]. As a highly biocompatible metal peroxide, calcium peroxide (CaO2) was rapidly hydrolyzed in the acidic TME to produce O2 and H2O2 while releasing large amounts of Ca2+. The production of H2O2 not only strengthened the effect of CDT, but also caused the abnormal function of intracellular calcium channels, which eventually led to calcium overload-mediated cell necrosis. In addition, to prevent the disintegration of CaO2 during blood circulation in vivo, Shen et al. utilized pH-responsive ZIF-90 as a protective layer to encapsulate CaO2 (Figure 7a) [99]. CaO2@ZIF-Fe/Ce6@PEG was co-synthesized by Fe2+ and photosensitizer chlorin e6 (Ce6). CaO2@ZIF-Fe/Ce6@PEG achieved structural disassembly in the weakly acidic TME, and the exposed CaO2 was further hydrolyzed to produce O2 and H2O2, which enhanced Ce6-mediated PDT and Fe2+-induced CDT. HA, another material that prevents the breakdown of CaO2 during circulation, has been widely used as a tumor-targeting delivery carrier due to its good biocompatibility, biodegradability, and specific binding ability to CD44 receptors [100]. Meanwhile, HA exhibited strong affinity to CaO2 and Fe3O4 based on the coordinating properties of carboxyl groups with Ca2+ and Fe3+. Therefore, Han et al. prepared CaO2-Fe3O4@HA nanoparticles utilizing HA as a stabilizer and tumor-targeting block to deliver CaO2 (Figure 7b) [101]. In addition, there are several other metal peroxides that have shown the ability to generate H2O2. For instance, ZnO2 nanoparticles generated exogenous H2O2 and Zn2+ under the weakly acidic TME, and the generated Zn2+ could further promote the generation of endogenous O2•− and H2O2 after entering cancer cells [96,97].
In the fields of energy and the environment, artificial photocatalysis is a common approach to produce H2O2. In order to apply the approach of photocatalytic synthesis of H2O2 to tumor treatment, it urgently needed to be considered that the low efficiency of existing photocatalysts to generate H2O2 under the low oxygen condition, as well as the critical characteristic of the tumor microenvironment (pO2 ≤ 5 mmHg), retrained its application. Therefore, Ma et al. proposed a C5N2 photocatalyst with a conjugated C=N chain by Schiff base reaction for stable and sufficient H2O2 production in both hypoxic and normoxic conditions (Figure 7c) [102]. The results showed that the CB/VB position of C5N2 was downshifted remarkably due to the reinforced delocalization of π-electrons, which contributed to a favorable CB and VB band position for H2O2 photosynthesis in kinetics and thermodynamics (Figure 7d). Encouragingly, the H2O2 production rate of C5N2 was 1550 μmol L−1 per hour, which was approximately 298 times higher than that of traditional g-C3N4 (5.2 μmol L−1 per hour), indicating that C5N2 had high photocatalytic H2O2 production performance (Figure 7e). Since H2O2 did not have a direct strong killing effect on cancer cells, the original C5N2 was exfoliated into nanosheets by ultrasonication, and then Fe3+ was doped into C5N2 nanosheets to achieve effective CDT. Overall, this finding proposed a promising approach for improving CDT efficiency.

3.2. Decreasing the Level of Reducing Substances

The high expression of GSH in tumor cells hinders the production of ROS, further weakening the antitumor effect of CDT owing to the balance of oxidation and reduction being broken in the presence of high-level GSH in the TME. Therefore, downregulation of GSH in the TME was required to enhance the effectiveness of CDT.
One strategy for eliminating GSH was to deplete the existing GSH in tumor cells. Metals in the oxidized state were the most commonly used oxidants in existing GSH consumption because they could directly interact with GSH and consume it rapidly [103,104]. For instance, Chen et al. designed carrier-free Fe(III)-artemisinin (ART)-coordinated nanoparticles (Fe(III)-ART NPs) via coordination-driven self-assembly for self-enhanced MRI-guided CDT (Figure 8a) [105]. After cellular endocytosis, Fe(III)-ART NPs decomposed in an acidic and redox environment of endo/lysosomes to release Fe3+ and ART. The Fe3+ was then reduced to Fe2+ by intracellular GSH, catalyzing the endoperoxide of ART to generate toxic C-centered free radicals for efficacious CDT. Moreover, significant toxicities were detected in A549 cells co-incubated with Fe(III)-ART NPs. In vitro studies demonstrated that after being treated with 200 μg mL−1 Fe(III)-ART NPs for 24 h, the cell viability decreased to 34%, resulting from DNA damage and lipid and protein oxidation (Figure 8b). In addition, FLI was performed using ICG-labeled Fe(III)-ART NPs. The experiment showed that signals at the tumor site were detected within 8 h and maximized at 48 h. Furthermore, T2-weighted MRI signals in tumors were significantly enhanced at 32 h after intravenous administration of Fe(III)-ART NPs, proving that Fe(III)-ART NPs successfully accumulated in tumor cells (Figure 8c). Notably, the free radical generation process of Fe(III)-ART NPs was without reliance on pH or endogenous H2O2, thereby breaking through the bottlenecks of traditional CDT. Carbon dots (CDs) are small fluorescent carbon nanoparticles less than 10 nm in diameter, and have high chemical stability, luminescence, and broadband optical absorption. Existing studies have shown that CDs easily and rapidly formed iron-containing nanoparticles with Fe3+ and then quench the fluorescence. Subsequently, GSH continues to react with the nanoparticles to restore fluorescence while oxidizing into GSSG. In this way, GSH in the tumor region was consumed, and CDs-based GSH FLI was realized for further cancer therapy [106,107]. In recent work, Li et al. combined fluorescence-imaging CD and Fe3+ to produce a TME stimuli-responsive therapeutic nanodrug (Fe-CD) for FLI of glutathione depletion and tumor therapy (Figure 8d) [108]. After the entry of Fe-CD into the tumor cells, Fe-CD reacted with GSH and then released Fe3+, which not only acted as a quencher but was also an important factor in enhanced CDT. In this process, GSH was converted to GSSG, while Fe3+ was simultaneously reduced to Fe2+, making CDT more efficient. Moreover, this important process was also monitored by enhancing the fluorescence intensity of Fe-CD. In vitro data showed little change in GSH content when the A549 cells were treated with CD. However, when treated with Fe-CD, GSH content was significantly reduced, by 31.8%, due to the introduction of Fe3+, suggesting that Fe-CD had a significant GSH consumption potential (Figure 8e). In addition, this process restored the bright fluorescence of CD, while the reduction of intracellular GSH content was qualitatively indicated by the increase of fluorescence intensity.
The other strategy for more effectively eliminating GSH was to inhibit the synthesis of GSH utilizing chemical inhibitors. However, the use of inhibitors was limited by their high toxicity to normal cells and short half-life. In order to overcome these shortcomings and more effectively eliminate GSH in the tumor, Huang et al. synthesized a multistage GSH exhaustion nanomedicine, named TDMH (TP/2-DG @HMnO2@HA), to achieve high-efficiency CDT (Figure 9a) [109]. HA, which was modified on the surface of nanoparticles, enhanced tumor recognition by binding to the CD44 receptor on tumor cells. After HMnO2 entered the TME, it underwent a redox reaction with GSH to generate Mn2+ and GSSG, thereby quickly depleting the original GSH in the tumor. The generated Mn2+ catalyzed the formation of •OH from H2O2 in the presence of bicarbonate (HCO3), which was abundant in the physiological medium. On the other hand, TP and 2-DG were released due to the collapse of the HMnO2 framework. Notably, the released TP targeted Nrf2 (nuclear factor (erythroid-derived 2)-like 2)/SLC7A11, thereby preventing de novo synthesis of GSH. As a commonly used glycolysis inhibitor, 2-DG blocked ATP production in the glycolytic pathway, which provides energy for tumor cells. Consequently, these reaction processes enabled multistage GSH depletion and amplified differences in the susceptibility of tumor cells and normal cells to oxidative stress.
High endogenous H2S expression is unique to the colon cancer tumor microenvironment compared to other tumor types [110]. As such, it is the target of many colon cancer treatments. The reducing capacity of endogenous H2S (currently 0.3–3.4 mM) in colon cancer is much stronger than that of GSH [111]. Hence, the efficacy of CDT in colon cancer is limited by endogenous H2S, which has a strong reducing ability and can scavenge the generated hydroxyl radicals. To solve the problem, Liu et al. synthesized H2S-activated CuFe2O4 nanoparticles using the characteristic that H2S could react with metal oxides and accelerate the valence transformation of Fenton or Fenton-like reagents for efficacious CDT of colon cancer (Figure 9b) [112]. Firstly, CuFe2O4 nanoparticles reacted with endogenous H2S in situ in the TME, leading to the depletion of endogenous H2S in colon cancer. Meanwhile, Cu9Fe9S16 nanoparticles with strong NIR absorption were obtained by CuFe2O4, which were used as photothermal-enhanced CDT agents and intelligent PAI reagents (Figure 9c,d). In addition, parts of Cu2+ and Fe3+ in CuFe2O4 nanoparticles were reduced to Cu+ and Fe2+ by endogenous H2S to form hydroxyl radicals via Fenton or Fenton-like reactions. Eventually, CuFe2O4 had a wide range of promising applications in anticancer drug delivery for colon cancer.
Figure 9. (a) The therapeutic mechanisms of TDMH nanomedicine. Reproduced with permission [109]. Copyright 2022, American Chemical Society. (b) The action mechanism of CuFe2O4 nanoparticles in cancer cells. (c) Thermal imaging of different groups under 808 nm laser irradiation. (d) Corresponding PA signals of HCT116 tumor-bearing mice. Reproduced with permission [112]. Copyright 2021, Elsevier Ltd.
Figure 9. (a) The therapeutic mechanisms of TDMH nanomedicine. Reproduced with permission [109]. Copyright 2022, American Chemical Society. (b) The action mechanism of CuFe2O4 nanoparticles in cancer cells. (c) Thermal imaging of different groups under 808 nm laser irradiation. (d) Corresponding PA signals of HCT116 tumor-bearing mice. Reproduced with permission [112]. Copyright 2021, Elsevier Ltd.
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3.3. Lowering pH Value

The pH range of the TME was between 6.5 and 7.0, while the optimal pH for Fenton reactions ranged from 2 to 4 [113]. Since the high pH value inhibited the decomposition of nanomaterials and the release of metal ions with catalytic activity, lowering the pH value of TME could effectively improve the catalytic efficiency of the Fenton reaction and enhance the therapeutic efficiency of CDT. In general, introducing exogenous acids or other substances was an efficient and common approach to regulating the pH of the TME. GOx was able to oxidize glucose to H2O2 and H+, which effectively increased the acidity and hydrogen peroxide in the tumor region, thus improving the efficiency of CDT treatment [85]. For instance, Liu et al., for the first time, designed a ternary pillar[6]arene-based nanocatalyst (GOx@T-NPs) employing pillar[6]arene and ferrocene via host–guest interactions to realize the combination of chemotherapy, ST, and CDT (Figure 10a) [114]. After being internalized and endocytosed by cancer cells, the intratumoral glucose was catalyzed by GOx@T-NPs into H+ and H2O2, thereby reducing the pH value inside cancer cells and further achieving high toxicity toward tumor cells. Meanwhile, overexpressed GSH in tumors was consumed by disulfide bonds of GOx@T-NPs, inducing the massive •OH production and the simultaneous release of the antitumor drug CPT. Li et al. reported a cascade catalytic nanoplatform (GOx-NCs/Fe3O4) for antibacterial CDT toward Escherichia coli (Figure 10b) [115]. Specifically, GOx-NCs/Fe3O4 was constructed by loading GOx onto the surface of covalent-assembled polymer capsules (NCs) through electrostatic interactions, which was successfully achieved to efficiently encapsulate Fe3O4 and immobilize GOx. Furthermore, GOx was oxidized into H2O2 in the presence of glucose, increasing in H+ concentration. After that, H2O2 was converted into •OH triggered by Fe3O4 nanoparticles through the Fenton reaction, thereby destroying the lipoproteins of the bacterial cell wall and causing the death of pathogens. The results of plate counting showed that GOx-NCs/Fe3O4 represented much higher inhibition efficiency compared with GOx and GOx-NCs, demonstrating its potential for efficient antimicrobial activity (Figure 10c). As a result, this strategy demonstrated that GOx-NCs/Fe3O4 improved the efficacy of the Fe3O4-mediated and GOx-introduced CDT for antibacterial applications.
However, the uncontrollable reaction between GOx and glucose during blood circulation could cause damage to normal tissue, so Shi et al. synthesized an acidity-unlocked nanoplatform (FePt@-FeOx@TAM-PEG) in order to selectively produce ROS within tumors while remaining silent in normal tissue (Figure 11a) [116]. Since FePt@FeOx@TAM-PEG had a hydrophobic shell, it remained silent in blood and normal tissues. After reaching the tumor area, FePt@FeOx@TAM-PEG was decomposed and further reacted with H2O2 to generate •OH due to the pH-responsive transition from hydrophobic to hydrophilic tamoxifen (TAM). Notably, TAM, an anti-estrogen drug, inhibited mitochondrial complex I and further triggered the adenosine monophosphate-activated protein kinase signaling pathway. This process promoted the decomposition of glucose and the accumulation of lactic acid, which increased the acidity of the cancer cells, thus overcoming the limitations of the weak acidity of the tumor. The increased intracellular acidity boosted the release of Fe2+ and Fe3+ from FePt@FeOx nanoparticles, thereby accelerating the H2O2 degradation and enhancing the antitumor potential of the nanoplatform. Therefore, the problem of insufficient CDT efficiency and potential side effects on normal cells have been effectively solved by the design of the nanodrug.
Carbonic anhydrase IX (CA IX) is a pH-regulating enzyme overexpressed on the cell membrane of most hypoxic tumors and can catalyze the reversible hydration of CO2 to generate H2CO3 and H+, participate in tumor extracellular acidosis, and accelerate tumor metastases [117]. CA IX inhibitors (CAI) inhibit extracellular HCO3/H+ formation, leading to intracellular glycolytic H+ accumulation. Inspired by this, Zuo et al. designed and constructed kinds of hollow mesoporous ferric oxide (HMFe) nanocatalysts (MM@HMFe@BS), which were camouflaged by macrophage membrane as well as loaded with CAI to decrease intracellular pH in the TME for self-amplified CDT (Figure 11b) [118]. The camouflage of macrophage cell membrane enabled the nanocatalysts to have immune evasion ability and recognize tumor endothelium cells and cancer cells via α4/VCAM-1 interaction, further promoting tumor chemotactic aggregation. After the efficient internalization into cancer cells, MM@HMFe@BS was specifically degraded to release HMFe and 4-(2-aminoethyl) benzene sulfonamide (BS). Interestingly, the released HMFe not only acted as a highly active atom-exposing Fenton agent to enhance CDT but was also used with high-efficiency MRI to monitor the biodistribution and treatment progress of MM@HMFe@BS. With the specific release of the CAI, CA IX was inhibited by BS, thus inducing intracellular H+ accumulation to accelerate the Fenton reaction. Dong and co-workers reported a multifunctional nanosystem of TPI@PPCAI to remodel the TME and reinforce the in situ Fenton reaction, which was composed of the inner TPI micelles-loading iron-oxide nanoparticles (IONs) and the outer poly (dopamine-co-protocatechuic acid) (PDA-PA, PP) coating modified with the CAI [119]. Firstly, 4-(2-aminoethyl) benzenesulfonamide, a CA IX inhibitor, inhibited the overexpressed CA IX, thus leading to intracellular acidification. Next, the PP coating was degraded, triggered by the acidification and NIR irradiation, resulting in the disintegration of the inner micellar structure to further release TPGS-PPh3 and IONs. Research showed that TPGS-PPh3, as the endogenous ROS amplifier, was able to target the mitochondria and then interfere with the function, thereby increasing the intracellular ROS basal level for Fenton reactions [120,121,122]. Additionally, based on the good photothermal conversion performance of PDA, the temperature of TPI@PPCAI nanoparticles solution increased by more than 15 °C and reached 46.5 °C at a concentration of 0.5 mg mL−1 after NIR irradiation for 8 min, indicating that TPI@PPCAI had good photothermal performance to enhance Fenton catalytic efficiency and improve the efficiency of CDT.
Jiang et al. synthesized a nanomedicine of FeCNB with high catalytic activity in acidic/neutral conditions, which overcame the limit of firm acidity required for the traditional Fenton reaction (Figure 11c) [123]. The nanomedicine FeCNB was composed of a Fe/Fe3C core and mesoporous graphite carbon shell modified by biotin to realize effective CDT by improving the efficiency of the Fenton reaction in acidic/neutral conditions. Specifically, graphitic carbon received electrons from Fe0 via a reduction reaction based on the principle of galvanic cells. Meanwhile, Fe0 in FeCNB as a reducing agent was oxidized to Fe2+, thus consuming H2O2 to produce •OH in neutral and acidic environments. Moreover, the experimental results confirmed that the photothermal conversion efficiency of FeCNB was 31.4% with 808 nm laser irradiation, revealing that it had an efficient photothermal conversion function to achieve effective PTT. This work offered a new perspective to remodel the pH in the TME for the development of ideal CDT nanomedicine.
Figure 11. (a) The therapeutic mechanisms of FePt@–FeOx@TAM–PEG. Reproduced with permission [116]. Copyright 2021, WILEY–VCH. (b) Schematic diagram of the therapeutic mechanisms of MM@HMFe@BS nanomaterials in vivo. Reproduced with permission [118]. Copyright 2022, American Chemical Society. (c) Schematic illustrations of the construction and the therapeutic mechanism of FeCNB [123]. Copyright 2022, Elsevier Ltd.
Figure 11. (a) The therapeutic mechanisms of FePt@–FeOx@TAM–PEG. Reproduced with permission [116]. Copyright 2021, WILEY–VCH. (b) Schematic diagram of the therapeutic mechanisms of MM@HMFe@BS nanomaterials in vivo. Reproduced with permission [118]. Copyright 2022, American Chemical Society. (c) Schematic illustrations of the construction and the therapeutic mechanism of FeCNB [123]. Copyright 2022, Elsevier Ltd.
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4. Conclusions and Future Directions

Cancer has remained a major killer that endangers human life and health. However, traditional cancer treatment techniques such as chemotherapy, radiotherapy, and surgery suffer from poor treatment efficiency, large toxic side effects and easy recurrence, and metastasis, which limit their application in the clinic. Many researchers have focused on exploring more efficient and simpler cancer treatments with important clinical value. Based on Fenton/Fenton-like reactions, CDT is attracting increasing attention as a catalyst-driven modality for cancer therapy because of its remarkable specificity and selectivity for tumors, minimal systemic toxicity and side effects, and the absence of a requirement for field stimulation during treatment. So far, many studies have reported that a large number of metal-based nanocatalytic medicines have been developed to initiate in situ Fenton or Fenton-like reactions in tumor cells, while various nanomaterials have also been used to modulate the tumor microenvironment to improve the therapeutic efficiency of CDT and achieve better tumor treatment effects. Here, Table 1 shows commonly used metal-based catalysts and their applications in biomedicine.
However, CDT is still in its early stages. More research is needed for the clinical translation of CDT, as several important scientific questions need to be addressed. Typical questions are listed below. (1) The target activity of anticancer medicines needs to improve. Metal-based compounds are widely utilized to enhance the performance of CDT based on Fenton and Fenton-like reactions. However, the targeted delivery via the EPR effect is limited, so modifying the surface of nanoparticles for active targeting to recognize tumors selectively could be considered. (2) It is also an urgent issue to reduce the toxic side effects of CDT. Some of these metal ions remain in vivo after therapy, which has potential side effects on the body. Hence, it is necessary to improve the catalytic efficiency of the catalyst and to deepen its ADME (absorption, distribution, metabolism, and excretion) performance study. (3) New smart combinatorial therapeutic nanosystems with high therapeutic efficiency need to be developed. The efficiency of most nanocatalytic therapies depends largely on the tumor microenvironment. The H2O2 and reductive substances levels, and the pH value in the TME, greatly restrict the efficiency of CDT. Moreover, regulation of the CDT treatment process is also extremely important. Therefore, smart combinatorial therapeutic nanosystems with diagnostic and therapeutic capabilities capable of modulating the tumor microenvironment are a future prospect [28,126]. (4) The efficacy of a single treatment is limited. The further development and design of CDT-induced combination cancer therapies will, to some degree, overcome the shortcomings of CDT, which has a stronger therapeutic performance than any single therapy or their theoretical combinations, such as CDT-PTT, CDT-PDT, CDT-ST, CDT-chemotherapy, CDT-SDT, and CDT-immunotherapy. For example, the Fenton and Fenton-like reactions in CDT are used to produce large amounts of •OH in combination with immunotherapy, and the Russell mechanism in CDT is used to produce a number of 1O2 to overcome the deficiencies of photodynamic therapy.
CDT is a fascinating research frontier that still requires further development. It is recommended to develop more metal-based and metal-free CDT nanomaterials and to improve the targeting and biological safety of these drugs. At the same time, metal-based nanocatalytic medicines are more likely to progress to the clinical stage, due to their multimodal diagnostic and therapeutic capabilities combined with advanced diagnostic methods like CT imaging and MRI. These nanomedicines could accurately diagnose diseases in real-time while simultaneously providing treatment. Moreover, the ability to monitor the therapeutic effect and adjust the dosage regimen during treatment enables optimal therapeutic outcomes and promotes the application of CDT nanomaterials in clinical transformation [126,127]. Additionally, an in-depth understanding and exploration of the anticancer pathways of CDT at the genetic and molecular levels are needed, which would help deepen the understanding of the anticancer mechanism of CDT and lead to the design of more effective agents.

Author Contributions

Conceptualization, D.L., P.W. and G.L.; writing—original draft preparation, B.C. and D.L.; resources, C.L. and B.C.; data curation, Z.Z.; project administration, D.L. and P.W.; writing—review and editing, D.L., P.W. and G.L.; supervision, G.L. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by the Major State Basic Research Development Program of China (2017YFA0205201), the National Natural Science Foundation of China (NSFC) (81925019, 81901876 and U1705281), the Fundamental Research Funds for the Central Universities (20720190088 and 20720200019), and the Program for New Century Excellent Talents in University, China (NCET-13-0502).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data are contained within the article.

Conflicts of Interest

The authors declare no conflict of interest.

Abbreviations

reactive oxygen speciesROS
hydrogen peroxideH2O2
superoxide anionO2
hydroxyl radical•OH
singlet oxygen1O2
peroxy hydroxyl radical•OOH
photodynamic therapy PDT
chemodynamic therapyCDT
sonodynamic therapySDT
tetrakis(4-carboxyphenyl) porphyrinTCPP
peroxidasePOD
glutathioneGSH
tumor microenvironmentTME
hydrogen sulfideH2S
ferroferric oxideFe3O4
ferrous disulfideFeS2
ferric oxideFe2O3
Fe-metal organic frameworksFe-MOFs
polydopaminePDA
magnetic resonance imagingMRI
computed tomographyCT
starvation therapyST
photothermal therapyPTT
glucose oxidaseGOx
glucose oxidaseGOD
tannic acidTA
near-infraredNIR
gluconic acidH+
dihydroartemisininDHA
metal-polyphenol networksMPN
bis(2-carbopentyloxy-3,5,6-trichlorophenyl) oxalateCPPO
zeolitic imidazolate framework-8ZIF-8
gallic acidGA
photoacousticPA
enhanced permeability and retentionEPR
copper sulfideCuS
copper oxideCuO
bovine serum albuminBSA
immunoadjuvant imiquimodR837
tumor-associated antigensTAAs
mesoporous polydopamine mPDA
doxorubicinDOX
hyaluronic acidHA
generation 5 poly (amidoamine)G5
Michaelis–Menten constantKm
velocityVm
β-cyclodextrinβ-CD
ferroceneFc
indocyanine greenICG
photothermal imagingPTI
fluorescence imagingFLI
manganese oxideMnOx
T1-weighted magnetic resonance imaging T1-MRI
photoacoustic imagingPAI
blood–brain barrierBBB
poly(lactic-co-glycolic acid)PLGA
hollow MnO2HMnO2
cerium peroxide matrixM-CeOx
3,3′,5,5′-tetramethylbenzidineTMB
adenosine triphosphateATP
hemoglobinHb
red blood cell RBC
superoxide dismutaseSOD
zeolitic imidazole framework-67ZIF-67
3-amino-1,2,4-triazole3-AT
catalaseCAT
nicotinamide adenine dinucleotide phosphateNADPH
quinone oxidoreductase1NQO1
camptothecinCPT
calcium peroxideCaO2
chlorin e6Ce6
artemisininART
carbon dotsCDs
bicarbonateHCO3
tamoxifenTAM
carbonic anhydrase IXCA IX
CA IX inhibitorCAI
hollow mesoporous ferric oxideHMFe
4-(2-aminoethyl) benzene sulfonamideBS
iron-oxide nanoparticlesIONs
poly (dopamine-co-protocatechuic acid)PP

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Scheme 1. Schematic illustration of design of Fenton/Fenton–like reagent and strategies to improve CDT performance. Image for Fe–based Fenton’s regent: reproduced from publication of Li, D. et al. with permission, Copyright 2023, Elsevier Ltd. Image for Cu–based Fenton–like’s regent: reproduced from publication of Jiang, F. et al. with permission, Copyright 2021, Elsevier Ltd. Image for other metal–based Fenton–like’s regent: reproduced from publication of Xiao, T. et al. with permission, Copyright 2021, American Chemical Society. Image for lowering pH value: reproduced from publication of Dong, K. et al. with permission, Copyright 2022, Elsevier Ltd. Image for decreasing the level of GSH and H2S: reproduced from publication of Li, J. et al. with permission, Copyright 2022, Elsevier Ltd. Image for increasing H2O2 level: reproduced from publication of Shen, J. et al. with permission, Copyright 2021, WILEY-VCH.
Scheme 1. Schematic illustration of design of Fenton/Fenton–like reagent and strategies to improve CDT performance. Image for Fe–based Fenton’s regent: reproduced from publication of Li, D. et al. with permission, Copyright 2023, Elsevier Ltd. Image for Cu–based Fenton–like’s regent: reproduced from publication of Jiang, F. et al. with permission, Copyright 2021, Elsevier Ltd. Image for other metal–based Fenton–like’s regent: reproduced from publication of Xiao, T. et al. with permission, Copyright 2021, American Chemical Society. Image for lowering pH value: reproduced from publication of Dong, K. et al. with permission, Copyright 2022, Elsevier Ltd. Image for decreasing the level of GSH and H2S: reproduced from publication of Li, J. et al. with permission, Copyright 2022, Elsevier Ltd. Image for increasing H2O2 level: reproduced from publication of Shen, J. et al. with permission, Copyright 2021, WILEY-VCH.
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Figure 3. (a) Synthetic route of CuGP/G. (b) The Michaelis–Menten kinetic curve and (c) Lineweaver–Burk plotting curve that indicate the catalytic activity of CuGP/G with the addition of GOD. Reproduced with permission [55]. Copyright 2020, WILEY–VCH. (d) Preparation of the supramolecular aggregates composed of CD–CuS and Fc–CuS and its action mechanism of tumor-targeted PTT/CDT. Reproduced with permission [57]. Copyright 2021, Royal Society of Chemistry.
Figure 3. (a) Synthetic route of CuGP/G. (b) The Michaelis–Menten kinetic curve and (c) Lineweaver–Burk plotting curve that indicate the catalytic activity of CuGP/G with the addition of GOD. Reproduced with permission [55]. Copyright 2020, WILEY–VCH. (d) Preparation of the supramolecular aggregates composed of CD–CuS and Fc–CuS and its action mechanism of tumor-targeted PTT/CDT. Reproduced with permission [57]. Copyright 2021, Royal Society of Chemistry.
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Figure 5. (a) Schematic synthetic process of macrophage membrane–moated and the therapeutic mechanisms of MPM@P NGs for MRI–guided combination chemotherapy/CDT. (b) T1–weighted MR images of the orthotopic glioma before injection and after intravenous injection of PM@P NGs or MPM@P NGs. Reproduced with permission [77]. Copyright 2021, American Chemical Society. (c) Schematic synthetic process of PLTM–HMnO2@Bu NPs and the schematic illustration of the therapeutic mechanisms for in vivo MRI–monitored combination chemotherapy/CDT. Reproduced with permission [78]. Copyright 2020, Elsevier Ltd.
Figure 5. (a) Schematic synthetic process of macrophage membrane–moated and the therapeutic mechanisms of MPM@P NGs for MRI–guided combination chemotherapy/CDT. (b) T1–weighted MR images of the orthotopic glioma before injection and after intravenous injection of PM@P NGs or MPM@P NGs. Reproduced with permission [77]. Copyright 2021, American Chemical Society. (c) Schematic synthetic process of PLTM–HMnO2@Bu NPs and the schematic illustration of the therapeutic mechanisms for in vivo MRI–monitored combination chemotherapy/CDT. Reproduced with permission [78]. Copyright 2020, Elsevier Ltd.
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Figure 7. (a) The therapeutic mechanisms of pH–responsive CaZFCP for enhanced CDT/PDT. Reproduced with permission [99]. Copyright 2021, WILEY–VCH. (b) The action mechanism of CaO2–Fe3O4@HA NPs in vivo. Reproduced with permission [101]. Copyright 2019, American Chemical Society. (c) The synthesis of C5N2 photocatalyst via Schiff base reactions. (d) CB/VB positions of photocatalysts reported by C5N2 et al. (e) Photocatalytic generation of H2O2 by C5N2 or g-C3N4 in water. Reproduced with permission [102]. Copyright 2022, WILEY–VCH.
Figure 7. (a) The therapeutic mechanisms of pH–responsive CaZFCP for enhanced CDT/PDT. Reproduced with permission [99]. Copyright 2021, WILEY–VCH. (b) The action mechanism of CaO2–Fe3O4@HA NPs in vivo. Reproduced with permission [101]. Copyright 2019, American Chemical Society. (c) The synthesis of C5N2 photocatalyst via Schiff base reactions. (d) CB/VB positions of photocatalysts reported by C5N2 et al. (e) Photocatalytic generation of H2O2 by C5N2 or g-C3N4 in water. Reproduced with permission [102]. Copyright 2022, WILEY–VCH.
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Figure 8. (a) The therapeutic mechanisms of Fe(III)–ART NPs. (b) The viability of A549 cells treated with Fe(III)–ART NPs. Data were expressed as mean ± SD, n = 3, ns: no significance, * p < 0.05, ** p < 0.01, analysed by Student’s t test. (c) T2–weighted MR imaging of A549 tumor-bearing mice. Reproduced with permission [105]. Copyright 2020, Elsevier Ltd. (d) The synthesis of Fe–CD and its action mechanism in cancer cells. (e) GSH content of A549 cells treated with CD and Fe–CD. Reproduced with permission [108]. Copyright 2022, Elsevier Ltd.
Figure 8. (a) The therapeutic mechanisms of Fe(III)–ART NPs. (b) The viability of A549 cells treated with Fe(III)–ART NPs. Data were expressed as mean ± SD, n = 3, ns: no significance, * p < 0.05, ** p < 0.01, analysed by Student’s t test. (c) T2–weighted MR imaging of A549 tumor-bearing mice. Reproduced with permission [105]. Copyright 2020, Elsevier Ltd. (d) The synthesis of Fe–CD and its action mechanism in cancer cells. (e) GSH content of A549 cells treated with CD and Fe–CD. Reproduced with permission [108]. Copyright 2022, Elsevier Ltd.
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Figure 10. (a) The therapeutic mechanisms of GOx@T–NPs. Reproduced with permission [114]. Copyright 2021, American Chemical Society. (b) The synthesis of Gox–NCs/Fe3O4 and its antibacterial action mechanism. (c) Plate coating results. con, Control.((a) glucose; (b) NCs; (c) GOx (10 μg mL−1) without glucose; (d,e) GOx–NCs (10 μg mL−1) and GOx–NCs/Fe3O4 (GOx: 10 μg mL−1; Fe3O4: 50 μg mL−1) without glucose; (f,g) GOx (5 μg mL−1and 10 μg mL−1) incubated with glucose; (h,i) GOx–NCs (5 μg mL−1 and 10 μg mL−1) incubated with glucose; (j) Gox–NCs/Fe3O4(GOx: 5 μg mL−1 and Fe3O4: 25 μg mL−1) and (k) GOx–NCs/Fe3O4 (GOx: 10 μg mL−1 and Fe3O4 50 μg mL−1) incubated with glucose). Reproduced with permission [115]. Copyright 2021, Royal Society of Chemistry.
Figure 10. (a) The therapeutic mechanisms of GOx@T–NPs. Reproduced with permission [114]. Copyright 2021, American Chemical Society. (b) The synthesis of Gox–NCs/Fe3O4 and its antibacterial action mechanism. (c) Plate coating results. con, Control.((a) glucose; (b) NCs; (c) GOx (10 μg mL−1) without glucose; (d,e) GOx–NCs (10 μg mL−1) and GOx–NCs/Fe3O4 (GOx: 10 μg mL−1; Fe3O4: 50 μg mL−1) without glucose; (f,g) GOx (5 μg mL−1and 10 μg mL−1) incubated with glucose; (h,i) GOx–NCs (5 μg mL−1 and 10 μg mL−1) incubated with glucose; (j) Gox–NCs/Fe3O4(GOx: 5 μg mL−1 and Fe3O4: 25 μg mL−1) and (k) GOx–NCs/Fe3O4 (GOx: 10 μg mL−1 and Fe3O4 50 μg mL−1) incubated with glucose). Reproduced with permission [115]. Copyright 2021, Royal Society of Chemistry.
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Table 1. Summary of various Fenton nanocatalysts for enhanced chemodynamic therapy.
Table 1. Summary of various Fenton nanocatalysts for enhanced chemodynamic therapy.
CategoryCDT AgentOther Drugs/MaterialsBiological
Model
Ref.
Fe-based nanocatalystsHollow Fe3O4 mesocrystals-4T1 tumor-bearing mice[29]
Fe3O4PDAS. aureus-infected mice[30]
Fe3O4PDA and BSA-Bi2S3HT29 tumor-bearing mice[31]
FeS2hollow porous carbon, GOx and TAHeLa tumor-
bearing mice
[32]
FeS2PcDHepG2 tumor-bearing mice[33]
Fe2O3dihydroartemisinin and metal-polyphenol networksS. aureus-infected mice[35]
MIL-101(Fe)TCPP231 tumor-bearing mice[38]
Fe-porphyrin-MOFCPPO, cancer cell membrane, and GOx4T1 tumor-bearing mice[39]
Fe-DNAGOx and ZIF-84T1 tumor-bearing mice[43]
PdCuFe alloyDOPA-PIMA-PEG4T1 tumor-bearing mice[44]
GA-Fe(III)MoS2HepG2 tumor-bearing mice[45]
Cu-based nanocatalystsCuSgeneration 5 poly (amidoamine) and GOD4T1 tumor-bearing mice[55]
CuSβ-cyclodextrin, ferrocene, and macrophagemelanoma-bearing mice[57]
MoS2-CuOBSA and R837CT26-bearing mice[60]
CuO2mesoporous polydopamine, DOX, and HA4T1 tumor-bearing mice[61]
MOF-199(Cu)vitamin K34T1 tumor-bearing mice[65]
Mn/Cu/Zn-MOF@MnO2ICGU87 tumor-bearing mice[66]
BSA-CuFeS2-4T1 tumor-bearing mice[124]
Cu2-xSe-GOD4T1 tumor cell membrane4T1 tumor-bearing mice[50]
Mn-based nanocatalystsMnO2macrophage membrane, PVCL-NH2, and cisplatinC6 glioma-bearing mice[77]
Hollow MnO2bufalin and platelet membraneH22 tumor-bearing mice[78]
Mn-CeOx-4T1 tumor-bearing mice[81]
Mn3O4GOD and organosilica hybrid micellesSMMC-7721 tumor-bearing mice[82]
Hollow MnCO3Ce6-PEGHeLa tumor-
bearing mice
[125]
Ag-based nanocatalystsAgNPs–TAMRA-DNAgraphene oxideHeLa and LO2 cell lines[69]
PDA: polydopamine; GOx: glucose oxidase; TA: tannic acid; TCPP: tetrakis(4-carboxyphenyl) porphyrin; CPPO: bis(2-carbopentyloxy-3,5,6-trichlorophenyl) oxalate; ZIF-8: zeolitic imidazolate framework-8; DOPA-PIMA-PEG: dopamine and polyethylene glycol decorated poly(isobutylene-alt-maleic anhydride); GOD: glucose oxidase; BSA: bovine serum albumin; R837: immunoadjuvant imiquimod; DOX: doxorubicin; HA: hyaluronic acid; ICG: indocyanine green; PVCL: poly (N-vinylcaprolactam); Ce6: chlorin e6.
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Cheng, B.; Li, D.; Li, C.; Zhuang, Z.; Wang, P.; Liu, G. The Application of Biomedicine in Chemodynamic Therapy: From Material Design to Improved Strategies. Bioengineering 2023, 10, 925. https://doi.org/10.3390/bioengineering10080925

AMA Style

Cheng B, Li D, Li C, Zhuang Z, Wang P, Liu G. The Application of Biomedicine in Chemodynamic Therapy: From Material Design to Improved Strategies. Bioengineering. 2023; 10(8):925. https://doi.org/10.3390/bioengineering10080925

Chicago/Turabian Style

Cheng, Bingwei, Dong Li, Changhong Li, Ziqi Zhuang, Peiyu Wang, and Gang Liu. 2023. "The Application of Biomedicine in Chemodynamic Therapy: From Material Design to Improved Strategies" Bioengineering 10, no. 8: 925. https://doi.org/10.3390/bioengineering10080925

APA Style

Cheng, B., Li, D., Li, C., Zhuang, Z., Wang, P., & Liu, G. (2023). The Application of Biomedicine in Chemodynamic Therapy: From Material Design to Improved Strategies. Bioengineering, 10(8), 925. https://doi.org/10.3390/bioengineering10080925

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