Nanocatalytic Medicine of Iron-Based Nanocatalysts

Abstract

Open AccessCCS ChemistryMINI REVIEW1 Feb 2021Nanocatalytic Medicine of Iron-Based Nanocatalysts Peilei Liu, Minfeng Huo and Jianlin Shi Peilei Liu State Key Laboratory of High Performance Ceramics and Superfine Microstructure, Shanghai Institute of Ceramics, Chinese Academy of Sciences, Shanghai 200050 Center of Materials Science and Optoelectronics Engineering, University of Chinese Academy of Sciences, Beijing 100049 Google Scholar More articles by this author , Minfeng Huo *Corresponding authors: E-mail Address: [email protected] E-mail Address: [email protected] State Key Laboratory of High Performance Ceramics and Superfine Microstructure, Shanghai Institute of Ceramics, Chinese Academy of Sciences, Shanghai 200050 Center of Materials Science and Optoelectronics Engineering, University of Chinese Academy of Sciences, Beijing 100049 Google Scholar More articles by this author and Jianlin Shi *Corresponding authors: E-mail Address: [email protected] E-mail Address: [email protected] State Key Laboratory of High Performance Ceramics and Superfine Microstructure, Shanghai Institute of Ceramics, Chinese Academy of Sciences, Shanghai 200050 Center of Materials Science and Optoelectronics Engineering, University of Chinese Academy of Sciences, Beijing 100049 Google Scholar More articles by this author https://doi.org/10.31635/ccschem.020.202000519 SectionsAboutAbstractPDF ToolsAdd to favoritesDownload CitationsTrack Citations ShareFacebookTwitterLinked InEmail Iron can be found in all mammalian cells and is of critical significance to diverse cellular activities within human bodies. Widespread applications and the underlying chemical and biological fundamental explorations of iron-based nanomaterials, especially on the biomedical frontiers, have attracted growing interests most recently in the community. In this review, we focus on the catalytic performance of iron-based nanomaterials (termed as nanocatalysts, abbreviated as NCs) and their nanocatalytic biomedical applications in Fenton nanocatalytic therapeutics, nanocatalytic oxygenation-enabled therapeutics, and nanocatalytic peroxidation-enabled biodetections. Fabrication methodologies of the iron-based NCs are also summarized along with their applications. Representative therapeutic performance against malignant tumors, Alzheimer’s disease (and other pathological abnormalities), and nanocatalytic-based biodetection are discussed. Finally, future development prospects of the iron-based NCs are surveyed, aiming to deliver a brighter future for iron-based NCs in nanocatalytic medicine. Download figure Download PowerPoint Introduction Iron is the chemical element with atomic number 26. It is by mass the fourth most common element in the Earth’s crust and can be found in most meteorites and ores.1 Iron is also an indispensable trace elements in the human body, accounting for 0.005% of the body weight of adults. Biological iron is dominantly found in hemoglobin and myoglobin inside the human body, where iron is responsible for oxygen transport throughout the whole plasma.2,3 Iron is also necessary for numerous cellular functions such as peroxide degradation and ribonucleotide reduction because iron is the indispensable fundamental cofactor for several enzymes, specifically for maintaining their cellular activities.4–6 Despite the prominent role of iron in physiological homeostasis, iron also plays critical roles in diverse pathological abnormalities. For instance, anemia is the most common disease induced by iron deficiency (characterized by the reduction of red blood cells), causing cardiac arrhythmia and delayed development.7,8 Anemia can be clinically treated by oral/intravenous administration of iron-containing agents such as ferric gluconate and iron sucrose, combined with erythropoiesis-stimulating agents. One of the major diseases caused by iron overload is hemochromatosis.9 This disease can lead to prominent iron accumulation in heart, liver, pancreas, and gonads, subsequently inducing oxidative damage of these tissues. Clinical treatments of hemochromatosis include phlebotomy and/or frequent administration of desferrioxamine mesylate.10 The biological functions of iron in cancer development remain one of the most controversial and complicated of topics.11 Numerous reports have shown that a high-iron diet may substantially increase the risk of colorectal cancer, suggesting the carcinogenic role of iron.12 In contrast, iron therapy (administration of iron) has also been demonstrated to be able to treat cancer with high efficacy.1,11 These findings evidence a double-edged sword effect of iron in cancer therapeutics. The dual roles of intracellular iron mainly originate from its diverse physiological and chemical properties. Fortunately, the endeavors of researchers are gradually unveiling the biological features of iron, and iron-based NCs are attracting increasing attention in the field of nanomedicine. Based on advances in nanoscience and nanotechnology, a number of iron-based NCs have been fabricated, contributing to biomedical advances, especially in tumor therapy.13,14 Depending on varied chemical conditions and substrates, the functionalities of iron-based NCs mainly rely on the catalytic performance of the iron species.15 Under an acidic environment, H2O2 can be reduced into hydroxyl and peroxyl radicals catalytically by iron species, specifically by ferrous ions (Fe2+), via Fenton chemistry. Within cells, this reaction can simultaneously induce prominent oxidative stresses. The massive production of hydroxyl radicals intracellularly can eventually lead to cell apoptosis.16,17 While under physiological pH conditions, several iron-based NCs can display catalase-like activities (by ferric species), catalyzing H2O2 disproportionation into oxygen and water.15 Such an antioxidative chemical reaction is fundamental to the intracellular elimination of peroxides and oxygenation as well. Alternatively, in the presence of a peroxidase substrate such as 3,3′,5,5′-tetramethylbenzidine (as hydrogen donor), peroxidase-mimicking iron-based NCs can effectively catalyze peroxides (typically H2O2) into water and dehydrogenated peroxidase substrate.18 Peroxidase-like catalytic reactions are especially popular among applications to biodetection and theranostic diagnosis.19,20 These reaction mechanisms constitute the catalytic basis of iron-based NCs in biomedical applications. In this review, we will focus on the diverse nanocatalytic medical applications of synthetic iron-based NCs in the category of Fenton nanocatalytic therapeutics, nanocatalytic oxygenation therapeutics, and nanocatalytic peroxide detection, based on the specific catalytic reaction mechanisms enabled by different iron species of the NCs. Prospects in biomedical applications for iron-based NCs will also be surveyed (Figure 1). Figure 1 | Summative scheme of the rational designs and applications of Fe-based NCs of different catalytic mechanisms.NCs, nanocatalysts. Download figure Download PowerPoint Fenton Chemistry-Enabled Nanocatalytic Therapy Fenton chemistry refers to the chemical fundamentals of Fenton or Fenton-like reactions that were initially proposed by British chemist Fenton in 1894,21 who found that ferrous species can act as the catalyst to reduce hydrogen peroxides to highly oxidative hydroxyl radicals in acidic conditions. The reaction can be accelerated in two steps, resulting in a total decomposition reaction of two hydrogen peroxide molecules to hydroxyl radical, hydroperoxyl radical, and water, catalyzed by Fe2+/Fe3+ (eqs 1 and 2).22 Kinetic studies showed that the rate constants for the two major reactions of Fenton chemistry are approximately 70 and 0.001–0.01 M−1 s−1, respectively, indicating that the ferrous regeneration step was rate-determining. The generated hydroxyl radicals are extremely reactive and efficient in the oxidative degradation of organic contaminants, enabling their popular applications in the area of wastewater treatment.23–25 Fe 2 + + H 2 O 2 → Fe 3 + + · OH + OH − k 1 ≍ 70 M − 1 s − 1 (1) Fe 3 + + H 2 O 2 → Fe 2 + + HO 2 · + H + k 2 ≍ 0.001 ∼ 0.01 M − 1 s − 1 (2) Fenton reaction is also frequent within all types of cells due to the existence of intracellular H2O2 and free ferrous ions. Intracellularly generated hydroxyl radicals harbor multiple functionalities for cell signaling and homeostasis.26 For instance, serving as the cell messenger for extensive cellular activities and functionalities,27–29 these radicals can not only signal cell proliferation and differentiation processes, but also the apoptosis pathways to accomplish cell metabolism.30,31 Pathological accumulation of hydroxyl radicals may lead to the oxidative damage of a broad spectrum of biomacromolecules, including DNA, proteins, and cell membranes, hence to cell destruction.32,33 The apoptosis mediated by hydroxyl radicals has inspired researchers to design highly selective and efficient cancer therapeutic modalities with satisfactory biocompatibility. Notably, mild acidity (pH values 6.0–7.0), a mark of the tumor microenvironment (TME), is a result of the intracellular balance between the carbonates and the excessive accumulation of the glycolysis product—lactate.34,35 In addition, tumor cells have been demonstrated to produce H2O2 at the micromolar level through superoxide dismutase-based enzymatic reactions.36 These features collectively contribute to the tumor-specific catalytic environment of Fenton catalytic reaction to generate highly toxic hydroxyl radicals within tumors rather than in normal cells/tissues, guaranteeing the therapeutic selectivity and biocompatibility. Most recently, nanocatalytic tumor therapy based on the intracellular Fenton reactions of iron NCs has emerged. As the dominant catalytically active species, iron plays a major role in Fenton reactions, and the rational design and fabrication of iron-based NCs are of great importance. According to the catalytic environment of the iron species, the constructed therapeutic NCs can be further classified as homogeneous or heterogeneous. For homogeneous Fenton reaction-based nanocatalytic tumor therapy, iron therapeutic NCs have been designed to generate mobile ferrous species in the aqueous medium in response to the mildly acidic TME, which catalyzes the Fenton chemical reaction for hydroxyl radical production, ultimately leading to cell apoptosis. Meanwhile, in heterogeneous Fenton reaction-based nanocatalytic tumor therapy, iron species have been covalently bonded or coordinated in a solid phase (nanoparticles [NPs]). Despite the absence of free ferrous ions, the chemically coordinated iron species on the surface of a heterogeneous catalyst can catalyze the generation of hydroxyl radicals in the presence of H2O2, followed by the desorption of the reaction product from the surface.37,38 In the following sections, typical iron-based NCs for homogeneous and heterogeneous nanocatalytic tumor therapies will be reviewed and discussed. Homogeneous iron-based NCs Iron NPs Iron NPs are highly reactive and can be readily oxidized into free ferrous ions in acidic aqueous solution (eq 3). So-called nanoscale zero-valent iron (nZVI) particles have been extensively used for the degradation of organic contaminants with high efficacy.39–40 Fe 0 ( s ) + 2 H 2 O ( aq ) → Fe 2 + ( aq ) + H 2 ( g ) + 2 OH − ( aq )(3) However, nZVI particles have an extremely high tendency to aggregate, decreasing the catalytic reactivity over time.41,42 Furthermore, due to the uncontrolled particle size and the high susceptibility to oxidation in the aqueous phase, nZVI particles are not expected to be suitable for in vivo nanocatalytic therapeutics. Therefore, researchers have made efforts on the synthesis of monodispersed stable nZVI. A pyrolysis strategy is one of the common methods to prepare monodispersed nZVI. In earlier research, nZVI was synthesized by one-pot thermal decomposition of Fe(CO)5 in the presence of weak oxidant—oleylamine.43 The prepared nZVI possessed excellent monodispersity, with an average hydrodynamic diameter of ∼15.2 nm, and its surface was controllably oxidized into an amorphous iron oxide layer for the protection of the inner iron core. Recently, our group has proposed a novel approach to synthesize amorphous iron NPs (AFeNPs) that outperform their nanocrystalline counterparts in catalytic Fenton activity.44 The AFeNPs, synthesized by Zhang et al.44 via a hubble-bubble approach, can effectively release ferrous species upon the challenge of weakly acidic aqueous solution. This approach utilizes the amphiphilic block copolymer F-127 to constrain the iron precursor within limited space, thereby hindering the long-range diffusion of iron atoms and the subsequent growth and crystallization of the AFeNPs. The authors have prepared of the AFeNPs (7–10 nm) without the need for harsh conditions. AFeNPs are extremely reactive in completely releasing Fe2+ in weakly acidic condition (pH = 6.5), while they are relatively inert in the neutral conditions in normal tissues. As a result, these NPs were particularly active and selective in homogeneous nanocatalytic tumor therapy for tumor destruction and inhibition. The Fenton reaction activity of AFeNPs is dependent on the acidity of the TME; however, the acidic extracellular fluid could also degrade tumor extracellular matrix and accelerate tumor invasion and metastasis.45,46 To combat this scenario, Chen et al.47 reported a combinational therapeutic strategy based on the AFeNPs (Figure 2a). They introduced a carbonic anhydrase IX inhibitor (CAI) onto AFeNPs to inhibit the tumorous-overexpressed carbonic anhydrase IX (CA IX). CA IX is an integral plasma membrane protein capable of catalyzing CO2 and H2O into HCO3− and H+. Inhibition of the CA IX could simultaneously result in decreased extracellular acidity and increased intracellular acidity. As verified by an in vivo antimetastasis experiment on bilateral MB231 tumor xenograft-bearing nude mice, [email protected] has been shown to inhibit tumor growth significantly (Figure 2b) and prevent tumor invasion and metastasis effectively (Figure 2c). It has been demonstrated by in vivo toxicity experiments that [email protected] shows high biosafety. The visceral organ pathological sections, weight profiles, and blood biochemical parameters of mice evidence the nontoxicity of [email protected] In conclusion, [email protected] possesses both tumor growth inhibition and antimetastasis capabilities by catalyzing intratumoral Fenton reaction and rebuilding the acidic TME. These functionalities were constructed by exploiting the performance of AFeNPs in generating reactive oxygen species (ROS), and the modification of their surfaces, providing feasible approaches to design various biofunctional nanomedicines for the therapeutics of malignant tumors or other diseases. Figure 2 | (a) Schematic illustrations of the preparation and therapeutic concept of [email protected] (b) Tumor growth curves of bilateral MB 231 tumor-xenografted nude mice with intravenous or intratumoral injection of different AFeNPs. (c) In vivo fluorescence imaging of bone metastasis of mice after indicated treatments. Reprinted with permission from ref 47. Copyright 2019 Wiley-VCH Verlag GmbH & Co. KGaA. AFeNPs, amorphous iron NPs; CAI, carbonic anhydrase IX inhibitor. Download figure Download PowerPoint Iron oxide NPs Iron oxide NPs (IONPs) are traditional Fenton catalysts that have been explored in research frontiers such as environmental science48,49 and enzyme-linked immunosorbent assay (ELISA)-based biodetection.18,50 IONPs can be prepared via various synthetic methods including sol–gel, coprecipitation, and hydrothermal.51–53 The performance of IONPs is sensitive to their size, shape, composition, and structure, which can be tuned by applying different synthetic routes. With a chemical composition of Fe2O3 or Fe3O4, IONPs have been demonstrated to display both heterogeneous Fenton reactivity and homogenous Fenton reactivity under different conditions. In a typical paradigm, our group designed a biodegradable mesoporous silica-based NC with glucose oxidase (GOx) and ultrasmall Fe3O4 IONPs encapsulated inside, termed as GOx-Fe3O4@DMSNs NCs (GFD NCs).54 The intravenously injected GFD NCs could accumulate in tumor tissue by a pathway such as enhanced permeability and retention (EPR),55 and catalyze the oxidation of intracellular glucose to produce hydrogen peroxide, enabling the Fe3O4-based Fenton catalytic chemistry to generate hydroxyl radicals in the acidic TME, and ultimately inducing the apoptosis of the tumor cells. This work has pioneered nanocatalytic tumor therapy, aiming to selectively destroy tumor cells/tissues in response to the catalytically active TME.14 Notably, several clinically applied IONPs have been confirmed to possess anticancer ability. For instance, ferumoxytol (Feraheme, FH), a Food and Drug Administration (FDA)-approved drug for the treatment of iron deficiency anemia, consist of superparamagnetic and bioactive IONPs coated with carbohydrates.56 The core of FH contains 5874 iron atoms with a mixture of ferrous and ferric species. Therefore, FH NPs are particularly suitable to initiate and maintain prominent Fenton catalytic activity. In a recent study by Trujillo-Alonso et al.,57 it has been found that a majority of leukemia cell lines belong to low-iron-exporting phenotypes, as characterized by the low expression of SLC40A1 (ferroportin). This would specifically enable iron therapy (administration of FH) by inducing an iron-overloaded circumstance with bursts of ROS generation. The authors have confirmed that low-ferroportin-expressed leukemia cell lines were substantially sensitive to FH treatment in 48 h. The percentage of leukemic blasts in different murine tissues sampled from mice treated with 6 mg kg−1 FH was significantly lower than that of other groups. In conclusion, based on the Fenton chemistry triggered by the IONPs, these NCs provided a novel therapeutic schedule against tumors. In addition, the ferromagnetism of IONPs has been utilized for magnetic hyperthermia58–60 and magnetic resonance (MR) imaging,61–63 illuminating promising application prospects for cancer theranostics. Layered double hydroxide Iron-based Fenton therapeutic NCs can also be designed into layered structures. Layered double hydroxide (LDH) is a type of layered ionic solid consisting of metal hydroxides with intercalated anions or intercalated electronegative molecules, represented by the formula [M2+1−xM3+x(OH)2]z+An−z/n·mH2O, in which M2+ and M3+ are metal cations (i.e., Mg2+, Ca2+, Fe2+, and Fe3+) in the host layers; An− are exchangeable anions intercalated in the interlayer by a weak bond.64 As a consequence of the abundant interlayer space and the peculiar metal-anion connection, LDHs can be synthesized into diverse compounds with various organic/inorganic anions, NPs, and genes.65–67 Limited by their poor thermostability, a majority of LDHs were prepared via one-step precipitation without further thermal treatments, leading to less-controlled composition and growth of LDH particles.68 Other methods including microwave irradiation and electrodeposition have also been developed.68–70 Typical LDHs tend to degrade to biologically friendly substances under pathological acidic conditions, accompanied by the release of the loaded cargos. These specific properties enable LDHs to be high-performance drug carriers that could synergize promisingly with nanocatalytic medicine. In a typical paradigm, Cao et al.71 have synthesized polyethylene glycol-conjugated, ferrous ion-containing two-dimensional (2D) ultrathin LDH monolayer nanosheets (PEG/Fe-LDH) via a solvent-free bottom-up approach. When the NPs were administrated and delivered into specific tumor cells/tissues, the layered PEG/Fe-LDH easily disintegrated to produce Fe2+ effectively. By catalyzing the dissociation of intratumoral H2O2 molecules, cytotoxic hydroxyl radicals could be generated rapidly by the intracellular Fenton catalytic reaction for tumor destruction (Figure 3a). The pH responsiveness of PEG/Fe-LDH in generating hydroxyl radicals had been revealed by electron spin resonance (ESR) spectra. Negligible catalytic activity under neutral pH conditions could be observed, whereas much elevated catalytic activities were verified under an acidic environment (Figure 3b). By intracellular staining with a ROS-sensitive fluorescence probe (2′,7′-dichlorofluorescin diacetate), the generation of cytotoxic hydroxyl radical species was confirmed inside the 4T1 tumor cells in vitro (Figure 3c). During in vivo experiments, PEG/Fe-LDH also suppressed tumor growth in xenograft-bearing mice with low-dose nanomedicine injection. Furthermore, the biosafety performance of PEG/Fe-LDH was evaluated in healthy Balb/c mice, implying that there is no significant in vivo toxicity during the 30 days of treatment. Figure 3 | (a) Schematic illustration of the preparation of PEG/Fe-LDH nanosheets and the mechanism schematics of nanocatalytic cancer therapy. (b) ESR spectra of PEG/Fe-LDHs in the presence of H2O2 under different pH conditions using 5,5-dimethyl-1-pyrroline N-oxide as a spin trap. (c) Confocal microscopic image of ROS probe-stained 4T1 tumor cells treated with PEG/Fe-LDHs and H2O2. Reprinted with permission from ref 71. Copyright 2018 Wiley-VCH Verlag GmbH & Co. KGaA. PEG/Fe-LDH, polyethylene glycol-conjugated, ferrous ion-containing 2D ultrathin LDH monolayer nanosheets; ESR, electron spin resonance; ROS, reactive oxygen species. Download figure Download PowerPoint Heterogeneous iron-based NCs Unlike homogeneous iron-based NCs, iron species within heterogeneous iron-based NCs are physically stable in the solid framework and thereby cannot be released as free iron species. The Fenton catalytic performance of these heterogeneous iron-based NCs is specifically dependent on the catalytic reactivity of the conjugated iron species in decomposing H2O2 to hydroxyl radicals. Recent years have witnessed the development and biomedical application (including Fenton therapeutics) of several typical heterogenous iron-based NCs, for example single iron atom NCs, metal–organic frameworks (MOFs), and covalent iron conjugates.72–75 The research advances of these iron-based NCs will be summarized and discussed in following section. Single iron atom NCs Single-atom catalysts (SACs) outperform their bulk counterpart catalysts in mass-specific catalytic activity due to their high atomic utilization efficiency and the abundant atomically disperse active catalytic sites.76,77 The main challenge in the preparation of SACs is to prevent metal–metal aggregation during synthesis and subsequent posttreatments.37 To address this crucial issue, several synthetic strategies for SACs have been proposed and developed, including framework-based pyrolysis,78 wet chemistry,79 and atomic layer deposition.80 Considering iron-enabled Fenton NCs, heterogeneous Fenton performance is especially attractive thanks to their high catalytic efficacy and recycle ability. Our group has pioneered the biomedical applications of SACs.81 PEGylated single-atom Fe-containing NCs (PSAF NCs) have been designed and fabricated via an “isolation-pyrolysis” approach to efficiently catalyze the in situ heterogeneous Fenton reaction within the TME (Figure 4a). As seen from the transmission electron microscopy (TEM) image of SAF NCs, uniform dodecahedral nanoparticulate geometry with isolated single atomic iron sites could be manifested (Figure 4b). During the in vivo tumor-inhibiting investigation, the tumor growth profiles of 4T1 xenografts injected with PSAF NCs intravenously or intratumorally were significantly reduced as compared with the control group injected with saline (Figure 4c); moreover, an obvious near-infrared (NIR) radiation-triggered temperature increase could be observed in 1 min, which confirmed the effect of photothermal treatment (Figure 4d). It is noted that within the therapeutic period, the relative tumor inhibition rates remain at a high level (>40%), revealing high therapeutic potential owing to the high biocompatibility. Furthermore, the authors have proposed a possible reaction mechanism for the heterogeneous Fenton process based on density functional theory. The Fe-N4 site confined in the SAF NCs matrix has been revealed to be the catalytically active site, on which H2O2 molecules could be readily absorbed with an adsorption energy of −0.26 eV, followed by homolysis of a H2O2 molecule on the single iron site into a desorbed hydroxyl radical and a remaining absorbed hydroxyl group. Such a hydroxyl group can hardly desorb from the single iron site due to the high binding energy (2.85 eV) under pH neutral conditions and at ambient temperature, thus poisoning the single iron site of the SAF NCs. Alternatively, under acidic TME, the binding energy could be much diminished by proton attack on the hydroxyl group, forming a water molecule without significant energy barrier to desorption, thereby recovering the Fe-N4 heterogeneous catalytic sites on SAF NCs (net investment: 0.31 eV).81 This work provides experimental and theoretical understandings of the catalytic chemistry of single iron atomic catalysts, favoring the exploration of novel heterogeneous Fenton NCs, and the more detailed catalytic fundamentals. Figure 4 | (a) Schematic illustration of isolation-pyrolysis approach to synthesize SAF NCs. (b) TEM image of SAF NCs. Inset: Selected area electron diffraction of the NPs. (c) In vivo tumor development curves of the xenografts of mice treated with saline or PSAF NCs by intravenous and intratumoral injections. Values are presented as means ± SD (n = 5 per group). *p < 0.05, **p < 0.01. (d) Infrared digital photographs of mice when exposed to NIR irradiation during the in vivo animal experiment. Reprinted with permission from ref 81. Copyright 2019 American Chemical Society. (e) Schematic illustration revealing that the ApFA can be internalized into tumors and tumor cells through EPR effect and size reduction-facilitated deeper penetration. Reprinted with permission from ref 89. Copyright 2019 Elsevier Inc. PSAF NCs, PEGylated single-atom Fe-containing nanocatalysts; TEM, transmission electron microscopy; NPs, nanoparticles; NIR, near-infrared; ApFA, aptamer-ferrocene assembly; EPR, enhanced permeability and retention. Download figure Download PowerPoint In addition to the cancer therapeutics, the high catalytic activity of SAF NCs has also enabled their application in bacterial elimination.82 In a recently published work, SACs with isolated iron catalytic sites were synthesized, and their in vitro antibacterial and in vivo anti-infection performances were investigated in detail.83 Under a physiological H2O2 concentration, single iron atoms can catalyze the heterogeneous Fenton reaction at high reaction rates to produce hydroxyl radicals, as confirmed by prominent peroxidase-like activity. When combined with the NIR laser-induced photothermal effect, SAF NCs significantly suppressed the propagation of Escherichia coli and Staphylococcus aureus bacterial infection at wounds of mice and promoted wound healing. In summary, SACs with single iron atomic catalytic sites can enable prominent heterogeneous Fenton therapeutics against cancer and bacterial infection, with high catalytic efficiency and guaranteed biocompatibility. Covalent iron conjugates Ferrocene is a typical covalent iron conjugate in which iron is sandwiched by two parallel cyclopentadiene rings, featuring strong hydrophobicity.84 However, hydrophobic ferrocene [Fe(Cp)2] can be transformed into hydrophilic Fe(Cp)2+ by a radical generation reaction with H2O2 through Fenton chemistry.85–87 For instance, ferrocene conjugates with Tamoxifen have been designed for targeted breast cancer treatment.88 Together with the targeting function of Tamoxifen against the oestrogen ERα receptors, which are abundantly expressed in MCF-7 breast cancer cell