Advances in metal-organic framework-derived single-atom catalysts for biomedicine

Abstract

As a alternative for natural enzymes, nanozymes has shown enzyme-like activity and selectivity in the field of various kinds of biomedical application, which has attracted considerable research interest. Recently, single-atom catalysts (SACs) have been extensively studied due to their similar active centers, coordination environment and better stability to natural enzymes. Metal-organic frameworks (MOFs) have been demonstrated as highly promising precursors for the synthesis of various types of SACs. MOF-derived SACs can not only significantly enhance the catalytic activity, but also improve the selectivity of nanozymes due to tunable coordination environment and structure, thereby receiving widespread attention in biomedicine. This review provided an overview of the preparation strategies for MOF-derived SACs, and then detailed the latest research progress of the SACs in the biomedical field for cancer, antibacterial, antioxidation and biosensors. Finally, the challenges and potential future opportunities of MOF-derived SACs in biomedical applications are proposed.

Headnote

ABSTRACT

As a alternative for natural enzymes, nanozymes has shown enzyme-like activity and selectivity in the field of various kinds of biomedical application, which has attracted considerable research interest. Recently, single-atom catalysts (SACs) have been extensively studied due to their similar active centers, coordination environment and better stability to natural enzymes. Metal-organic frameworks (MOFs) have been demonstrated as highly promising precursors for the synthesis of various types of SACs. MOF-derived SACs can not only significantly enhance the catalytic activity, but also improve the selectivity of nanozymes due to tunable coordination environment and structure, thereby receiving widespread attention in biomedicine. This review provided an overview of the preparation strategies for MOF-derived SACs, and then detailed the latest research progress of the SACs in the biomedical field for cancer, antibacterial, antioxidation and biosensors. Finally, the challenges and potential future opportunities of MOF-derived SACs in biomedical applications are proposed.

Keywords:

Biomedicine

MOF-Derived

SAC nanozymes

Catalytic mechanisms

1. Introduction

Biomedicine is an interdisciplinary subject developed by medicine, life science, and biology in recent years. The primary task is to use biological and engineering techniques to investigate and address life science problems, especially in medicine [1,2]. Natural enzymes, as biological catalysts, play vital roles in many chemical and biological reactions due to their high selectivity for substrates and excellent catalytic efficiencies [3,4]. However, their high costs, poor stabilities, and time-consuming production methods have prompted researchers to seek novel and promising candidates [5,6]. As artificial enzymes, nanozymes show enzyme-like activity and regulate their active sites with the unique physicochemical nature of nanomaterials [7,8], thereby enhancing the stability and robustness to harsh conditions. Since the discovery of peroxidase mimetics in Fe3O4 nanoparticles in 2007 in 2007 [9], several functional nanomaterials, including noble metals [10–13], transition metal oxides [14,15], carbon [16,17], single-atom catalysts (SACs) [18–21], and metal-organic frameworks (MOFs) [22–27], have been identified to mimic natural enzymes. Benefiting from the unique properties of nanomaterials and natural enzymes, nanozymes have also shown great potential for application in clinical medicine [28,29], biotechnology [30,31], diagnosis [32,33], biosensors [34–36], environmental remediation [37–39], therapeutics [40,41] and tissue engineering [42].

Although nanozyme catalysts have shown promise in nanocatalytic medicine, there is still potential toxicity originating from the metal atom in the catalysts [43]. Particularly, the metal atoms released from nanomaterials enter healthy organs, which is toxic to normal cells and eventually leads to cell death, hampering clinical application of the nanomaterials [44]. To address these problems, the design and synthesis of nanomaterials enabling maximum utilization efficiency for the metal atoms may be the best way to address the toxic effects. Since the first SAC was reported in 2011 by Zhang [45], SACs have been widely used in homogeneous catalysis (e.g., oxygen reduction [46,47], oxygen evolution [48], hydrogen evolution [49] and CO2 reduction [50]), energy conversion (Li–S batteries [51], Zn-air batteries [52]), organic synthesis [53] and environmental governance [54–56] owing to their exceptional atom utilization, well-defined electronic structures and high selectivity. Due to the relatively low metal concentrations, SACs have also been applied to biomedical applications because of their nontoxic properties and excellent catalytic capabilities. MOFs are newly discovered porous polymers synthesized by combining organic linkers and metal ions or clusters. Due to their high surface area and well-defined porosity, MOFs are considered the ideal support for anchoring SAC [3,28]. In the last decade, MOF-derived SACs have shown great promise in mimicking natural enzymes for enzymatic reactions [57,58]. Several reviews have discussed the preparation of various SACs, as well as advances in catalyzing versatile reactions such as disease treatments (cancer treatment), antibacterial processes (wound healing), antioxidation and biosensors, laying the foundation for biomedical applications [59–61]. Unfortunately, the effects of the carbon-based supports, metal loadings and coordination environments of SACs on catalytic activity are rarely discussed, and they play key roles in determining the catalytic performance in biomedical applications. In addition, efficient synthetic methods, advanced characterization techniques and the underlying catalytic mechanism needs to be further studied.

In this review, we provide an overview of the recent advances in the field of MOF-derived SACs for biomedical applications and detail the preparations of SACs and the crucial factors affecting the activities of SACs. Four different biomedical applications will be detailed, including cancer treatments, antibacterial, antioxidation and biosensors. Finally, we discuss the future of rational design and preparation of SACs and hope that this review will contribute the development of SACs and promote their use in biomedical applications.

2. MOF-derived single-atom catalysts Atomically dispersed SACs have recently considered as some of the most explored catalysts in biomedicine due to their superior catalytic activities and preeminent selectivity that exceed those of their nanosized counterparts [62]. A literature survey showed that the isolated metal atoms in SACs were usually supported on a porous nitrogen-doped carbon, where a metal atom was coordinated with four N atoms to form an M ° N4 (M 1/4 Fe, Cu, Zn, etc.) single site [63–65]. Subsequently, SACs with axial traction coordination structures (FeN4O1 [66], FeN4Cl [67], FeN5 [58], etc.) and unsaturated coordination structures (FeN3 [68], Co–N2 [69], CuN3 [70], MoSA-N3-C [71] etc.) have been reported. An overview of the synthetic methods shows that several synthetic strategies, such as high-temperature pyrolysis method, wet chemistry method, sacrificial templates and photocatalytic reduction, have been developed to synthesize various SACs [72]. In particular, high-temperature pyrolysis is widespreadly employed as a universal approach for preparing SACs due to its simple operation and ready availability of the precursors (e.g., MOFs, polymers, metal-containing complexes and small molecules). Because of their mesoporous structures, MOFs are the most often used NC sources for the preparation of various SACs with M-N-C moieties. As shown in Fig. 1a and b, the metal ions are first incorporated into the cage or pores of the MOF during the crystallization process and then pyrolyzed at high temperature (800–1000 -C) under an inert protect atmosphere [71,73]. During the pyrolysis process, the MOF precursor prevented the metal atoms from migrating and agglomerating, which produced M-N-C catalysts with individual M ° N active sites. Another strategy is to use MOF-derived carbon as a carrier for adsorbing metal salts and undergo a second annealing process to form atomically dispersed SACs [74,75] (Fig. 1c and d). The morphologies, pore structures, coordination environments, specific surface areas, metal loadings, and active site densities vary with the synthetic method. A comprehensive understanding of the nature of SACs is required to enhance their catalytic performances. In the past decade, the characterization of SACs has been significantly advanced owing to the development of modern characterization techniques such as aberration-corrected high-angle annular dark-field scanning transmission electron microscopy (AC HAADF-STEM), X-ray absorption near-edge spectroscopy (XANES) and extended X-ray absorption fine structure spectroscopy (EXAFS). With AC HAADF-STEM, isolated single metal atoms supported on porous carbon can be observed directly. Furthermore, XANES and EXAFS can provide more detailed information on SACs, offering a deeper understanding of the bonding, mode oxidation states, and coordination environment. Therefore, these characterization techniques provide great support for the development of high-performance SACs.

Although great achievements have been made in homogeneous electrocatalysis and energy storage, research on the use of SACs in the biomedical field is in its infancy. Recently, many efforts have been put into the design and biomedical application of Fe–N–C, Cu–N–C, Zn–N–C, etc., catalysts. Considerable efforts have been devoted to developing efficient SACs by (i) adjusting the coordination environment of the central metal atoms to enhance intrinsic activity [71,76,77]; (ii) increasing the density of active single atoms [73]; and (iii) regulating the morphological structure of the carbon carrier to facilitate mass transport [78]. These factors are closely related to the types of precursors, synthetic methods, pyrolysis temperature/time and post-treatment process. By using advanced characterization techniques, the key factors that affect catalyst performance have been adjusted at the atomic level, providing great promise for use in the biomedical field.

3. Applications in biomedicine

3.1. Cancer treatment

With high incidence and fatality rates, malignant tumors have become one of the important diseases that threaten human health and lead to human death [79]. At present, traditional chemotherapy, radiotherapy and surgical resection still play key roles in tumor treatment. Targeted therapy and immunotherapy have received widespread attention, and significant progress has been made in clinical practice. Meanwhile, nanocatalytic therapy based on organic or inorganic nanomaterials has also been applied [80]. However, the complex environments of tumor sites often lead to treatment failure, such as hypoxia, an important feature of solid tumors and a cause of radiotherapy resistance and poor prognosis. To overcome the hypoxic environments of tumors, Muhammad Pir et al. prepared ultra-small carbon dot-supported single-atom iron nanozymes (Fe-CDs) by controlling the single Fe active site coordinated with C and N atoms. The Fe-CDs exhibited multiple enzyme-mimicking properties and acted as a drug-free nanomedicine that modulated the tumor microenvironment by regulating the reactive oxygen species and lysosome-mediated autophagy, which provided a new targeted strategy for the successful treatment of glioblastoma (GBM) in cancer therapy. Wang et al. [81] developed a porphyrin-like MOF with single atom Fe(III) centers (P-MOF), which had a Fe-TCPP complex (TCPP 1/4 tetrakis (4-methoxycarboxyphenyl) porphyrin) and edge-sharing Zr6 clusters as nodes, leading to a large one-dimensional open channel with an average diameter of 3.7 nm and a high specific surface area of 1062 m2 g°1 . Due to the rich Fe SAC sites, the P-MOF catalyst showed good catalytic activity in regulating the hypoxic tumor microenvironments of HeLa cell tumors in mice, showing great promise for photoacoustic imaging (PAI).

Huo et al. [57] prepared Fe single-atom nanozymes (SAF NCs) with Fe atoms dispersed on porous N-doped carbon by pyrolysis of Fe(acac)3@ZIF-8 NP precursors at 800 -C under an Ar atmosphere (Fig. 2a). XANES analysis showed the Fe–N4 moieties in isolated single iron atom catalytic sites on SAF NCs. (Fig. 2b). Combining the SAF NCs with PEGylation resulted in an excellent localized heterogeneous Fenton reaction for efficient nanocatalytic tumor therapy. As shown in Fig. 2c, by imaging tumor cells stained with C11-BODIPY after treatment with the PSAF NC catalyst and H2O2. It was found that significant damage to the cell membrane resulted in the death of the cells exposed to high levels of LPO stress. In addition to the Fenton reaction-generated •OH, lipid peroxidation (LPO) was a concomitant side process because α-tocopherol is fat-soluble (Fig. 2d). DFT results revealed that the PSAF NC catalysts effectively catalyzed the heterogeneous Fenton reaction (Fig. 2e). The images of dissected tumors revealed that after treatment with the PSAF NC nanocatalysts, the tumor volumes in mice were greatly reduced, and the dead area was enlarged, indicating a good therapeutic outcome for the use of PSAF NC catalysts with malignant tumors. (Fig. 2f). Furthermore, the tumor suppression rate for the PSAF NCs þ NIR group exceeded 150 %, while it was negligible for the NIR-only control group, verifying the effectiveness of the PSAF NCs on Fenton's catalytic therapy under photothermal acceleration (Fig. 2g). Additionally, Zhu et al. [78] reported a PEGylated Mn/PSAE single-atom enzyme with Mn–N moieties. Briefly, uniformly hollow ZIF-8 nanocubes with average particle sizes of approximately 230 nm were prepared, and Mn2þ was adsorbed by ion exchange, followed by high-temperature pyrolysis. During the pyrolytic process, the ZIF-8 nanocubes were converted into hollow N-doped carbon shells, and the Mn atoms were coordinated with N atoms to form a Mn/SAE. The Mn/PSAE exhibited significant catalytic activity in weakly acidic tumor environments and produced reactive oxygen species (ROS) that killed tumor cells. This work provided a novel strategy for developing efficient and reactive SAEs for enhanced photothermal tumor therapies.

Photothermal therapy (PTT) is a very useful treatment approach for tumors; however, overheating will unavoidably injure the normal tissues near the tumors. To address this issue, Chang et al. [82] reported a single-atom Pd nanozyme that was suitable for mild PTT enhanced by iron death. As shown in Fig. 3a, small Pd NPs were prepared and incorporated into a ZIF-8 precursor to obtain Pd@ZIF-8 composites, which were subsequently pyrolyzed under a N2 atmosphere. Transmission electron microscopy (TEM) images exhibited a polyhedral carbon structure with no metal NPs, indicating that the small Pd NPs were completely transformed into Pd SAC nanozymes (Fig. 3b). Western blots (Fig. 3c) confirmed that ferroptosis inhibited the expression of HSP, providing a new strategy for enhancing mild PTT. Furthermore, the in vivo antitumor effect was investigated. Fig. 3d displays the tumor growth curves after different treatments, and the Pd SAzyme group exhibited a significant inhibition of tumor growth compared to the PBS and 1064 nm control groups. Moreover, an obvious accumulation of LPO was observed in the Pd SAzyme irradiated with a 1064 nm laser (Fig. 3e). In addition, the cellular structures of all major organs were well organized (Fig. 3f), indicating that the Pd SAzyme exhibited good biosafety. This provided a novel opportunity for ferroptosis and Pd SAzyme-mediated mild-temperature PTT.

Although SACs have enabled great achievements in biomedicine, further improvement in the catalytic activities of SACs is challenging. One promising strategy is to develop bimetallic atom catalysts. For instance, Zhao et al. [83] designed bimetallic SACs with isolated single Fe and Co atoms supported on a N-doped carbon carrier (FeCo-DIA/NC) for efficient tumor therapy. As displayed in Fig. 4a, trimetallic FeCoZIF-8 NPs were firstly prepared by encapsulating Fe(acac)3 and Co(NO3)2 into ZIF-8. The FeCoZIF-8 NPs were coated with a thin layer of mSiOx and pyrolyzed under an Ar atmosphere to obtain FeCo-DIA/NC after the removal of the SiOx shell and the residual metal species. The TEM images showed that FeCo-DIA/NC had a porous carbon structure with abundant pores at the edges (Fig. 4b). The SAC PoD-like activity of FeCoDIA/NC was investigated with o-phenylenediamine (OPDA). As displayed in Fig. 4c, the absorbance at 420 nm continuously increased with the addition of H2O2, suggesting that FeCo-DIA/NC effectively catalyzed the production of •OH via the Fenton reaction. FeCo-DIA/NC combined with hyaluronic acid (HA) (FeCo-DIA/NC@HA) was used to target tumors.

In vitro results showed that the growth of HeLa tumors in mice treated with FeCo-DIA/NC@HA was significantly inhibited compared to the control group (Fig. 4d). Moreover, the performance of the FeCo-DIA/ NC@HA catalyst was greatly superior to those control samples, indicating that the synergistic effect of bimetallic dual active sites and HA targeted tumor tissues and catalyzed local H2O2 to generate ROS, thereby effectively inhibiting tumor growth. Flow cytometry analyses showed that the apoptosis rate of the FeCo-DIA/NC@HA þ H2O2 group was 81.6 ° 8.6 %, which was much higher than those of the SIA/NC@HA þ H2O2 group (76.2 ° 6.3 %) and Co-SIA/NC@HA þ H2O2 group (58.8 ° 18.7 %), indicating an excellent therapeutic effect (Fig. 4e). Additionally, the morphologies of the tumor cells treated with FeCo-DIA/NC@HA þ H2O2 showed the characteristics of apoptosis (Fig. 4f). Finally, a pathological analysis suggested that the developed FeCo-DIA/NCs had good biocompatibility (Fig. 4g).

Compared to the frequently reported M ° N4 moiety, an axial traction strategy improved the performance of SACs. For example, Xu et al. [58] presented the preparation of a Fe SAzyme catalyst containing Fe–N5 sites supported by ZIF-derived porous N-doped carbon by a melamine-mediated pyrolysis method. Firstly, ZIF-8 was used as the NC precursor and coated with an inorganic SiO2 shell, followed by high-temperature pyrolysis. After removing the SiO2 shell, a porous N-doped carbon framework with high specific surface area was obtained. Next, melamine, a N-rich carbon support and absorbed Fe ions were mixed and then subjected to a second high-temperature pyrolysis to obtain Fe SACs with FeN5 moieties, and the FeN4 SAzyme was prepared via a similar procedure but without melamine (Fig. 5a). The TEM image in Fig. 5b shows that the FeN5 SAzyme maintained its polyhedral morphology with the planes partially collapsing due to confinement by the SiO2 shell. Fig. 5c shows that the FeN5 SAzyme showed much higher peroxidase-like activity than MCS (Fe-free species). Furthermore, the fluorescence of the FeN5 SAzyme at 435 nm was enhanced by the presence of H2O2 compared with other control samples (Fig. 5d). With the addition of isopropanol (•OH quencher), the peak intensity decreased sharply, verifying that the FeN5 SAC accelerated the decomposition of H2O2 to produce •OH. DFT results revealed that, compared to the FeN4 SAzyme, the FeN5 SAzyme was more effective in the adsorption of H2O2 molecules and the generation of •OH (Fig. 5e). Compared with the MCS and FeN4 counterparts, when the concentration was 200 μg mL°1 , the killing effect of the FeN5 catalyst with 4T1 cells was greatly improved, and the cell viability rate decreased to 41.8 % (Fig. 5f). In addition, photographs of the tumors showed that tumor growth was significantly inhibited after FeN5 treatment, indicating that the FeN5 SAzyme had a superior antitumor effect (Fig. 5g). This work offers new horizons for the synthesis of high-performance nanozymes.

3.2. Antibacterial: wound healing

Disruption of the relationships among bacteria and the host cells in the living body leads to a variety of infectious or contagious diseases [84]. For example, the most common cause of wound septicaemia is infection by Staphylococcus aureus, and various types of tuberculosis are caused by Mycobacterium tuberculosis [85]. The prevalence and incidence of bacterium-induced diseases are increasing annually, and our current antimicrobial treatments still involve the use of antibiotics, which will create drug resistance problems and limit clinical application. Recently, many newly designed nanomaterials and nanozymes were investigated for the detection and treatment of bacterial infections enabling wound disinfection and healing [86]. MOF-derived single-atom nanozymes or catalysts are increasingly used as antimicrobials due to their high atom utilization rates, clear catalytic sites and high catalytic selectivity [87].

As shown in Fig. 6a, Pan et al. [17] synthesized monodisperse mesoporous carbon nanospheres with porphyrin-like zinc centers (PMCS) via a mSiO2 confined pyrolysis strategy. Briefly, ZIF-8 nanoparticles were coated by a thin layer of mSiO2 to obtain ZIF-8@mSiO2, followed by high-temperature pyrolysis and etching. During the pyrolysis process, the mSiO2 physical barrier prevented aggregation of the nanoparticles and promoted the formation of porous structures in the PMCS. The PMCS particles showed sizes of approximately 140 nm and the physical barrier formed on the surface prevented aggregation and maintained most of the internal porosity of the precursor. The PMCS exhibited rapid transport of the nanoparticles and improved permeability and retention (EPR) effect in vivo, thus showing good biocompatibility. Therefore, the uses of the PMCS in photothermal therapy (PTT) and sonodynamic therapy (SDT) as a stabilizer photosensitizer, photothermal agent and sonosensitizer were further explored. Specifically, Pan further reported that a combination of the PMCS and ultrasound (US) produced a cavitation effect to enhance the efficiency of SDT, which killed tumor cells and inhibited tumor growth (6b-c). Additionally, Wang et al. [76] confirmed that during the PTT process, the PMCS improved the necrosis or apoptosis of tumor cells under near-infrared laser irradiation, and the tumors of nude mice regressed rapidly. Subsequently.

In addition, the potential of the PMCS for use as an antibacterial monatomic nanoenzyme for wound treatment has been discovered [88]. The PMCS had Zn–N4 active site (Fig. 6d) and showed excellent peroxidase-like activity, which could catalyze the decomposition of H2O2 to produce •OH, thereby initiating oxidation and cell death. In vitro experiments, the PMCS reduced the population of Pseudomonas aeruginosa in the presence of H2O2 (Fig. 6e), indicating its destruction of the bacterial cell membranes, induction of programmed death, and a growth inhibition rate as high as 99.87 %. In a mouse model for wound infections, the PMCS provided effective wound healing after 6 days of treatment, which was significantly faster than the normal healing rate, and there was no significant toxicity toward organ tissues (Fig. 6f).

Recently, Yang et al. [89] reported Fe-SACs in which the Fe atoms were the catalytic centers, and they showed OXD-like activity and catalytic photothermal antibacterial activity. Meanwhile, synergistic catalytic therapy and photothermal therapy (PTT) accelerated the destruction of biofilms and improved the antibacterial ability of the gram-positive strain methicillin-resistant Staphylococcus aureus (MRSA), showing great potential for treating multidrug-resistant bacteria. To increase the density of the active sites, Huang et al. [90] developed FeN5 SA/CNF single-atom nanozymes that mimicked cytochrome P450. Firstly, Fe-phthalocyanine (FePc) coated with the Zn-based MOF (FePc@Zn-MOF) was used as a precursor. During the pyrolysis process, the FeN4 was generated by decomposition of FePc@Zn-MOF precursors and also coordinated with the pyridinic N species in the organic N-containing ligands to form more thermodynamically stable dispersed FeN5/C sites (FeN5 SA/CNF) (Fig. 7a and b). The FeN5 sites showed activities similar to that of cytochrome P450 with oxidation reactions that reduced O2 to H2O (Fig. 7c). The enzymatic activity (OXD) of the Fe–N5 catalyst was approximately 17 times that of the Fe–N4 catalyst (Fig. 7d). Accordingly, the sequence of OXD-like activity was similar to OXD activity (Fig. 7e). DFT calculations revealed that O2 adsorption in the first step was the key step enabling the transfer of electrons from the active center to the adsorbed intermediate. In vitro antibacterial experiments showed that, compared with the control group, the ulcers of FeN5 SA/CNF-treated mice were significantly relieved, and wound healing was accelerated after 4 days of treatment (Fig. 7f and g).

In addition to developing Zn and Fe SACs, Cu SACs also exhibited enzyme-like activities. Wang et al. [91] developed a pyrolysis-etching-adsorption-pyrolysis strategy to prepare Cu single-atom catalysts (Cu SASs/NPCs). As shown in Fig. 8a, the ZIF-8 precursors were first pyrolyzed at 920 -C for 5 h to obtain NPCs and then processed in 3 M HCl. Subsequently, Cu2þ-sodium dicyandiamide/melamine-NPC (Cu2þ-DCDA/MA-NPC) was synthesized by adsorbing Cu ions onto NPC, followed by mixing with sodium dicyandiamide and melamine in a mixed solvent of isopropanol and water. The resulting Cu SASs/NPC were obtained by pyrolyzing the Cu2þ-DCDA/MA-NPC precursor at 650 -C for 2 h. The as-prepared Cu SASs/NPCs was consisted of porphyrin Cu–N4 active sites, which were uniformly distributed on the porous nitrogen-doped carbon support (Fig. 8b). The antibacterial activity of the Cu SASs/NPCs was manifested by concentration-dependent peroxidase-like catalytic activity and NIR absorption capacity, which showed synergistic antibacterial effects on ROS production, GSH consumption and photothermal killing via surface collapse and morphological damage to bacteria (Fig. 8e and f). As a result, the efficacy of combination therapy with PTT catalytic therapy on E. coli and MRSA was significantly enhanced, resulting in significantly reduced bacterial activity (Fig. 8c and d). In an in vivo model, Cu SASs/NPCs activated with H2O2 and NIR had a significant bactericidal effect, which stopped the spread of MRSA pathogens in wounds and helped wound healing (Fig. 8g and h). Furthermore, the excellent biosafety increased its potential for use in biomedical applications.

To achieve better performance, a combination of MOF-derived SACs and other physical means provides promise. For example, Huo et al. synthesized iron single-atom catalysts encapsulated in nitrogen-doped carbon (SAF NCs) through an "encapsulated-pyrolysis" strategy. The obtained SAF NCs exhibited excellent peroxidase-like properties and produced striking antibacterial effects with both gram-negative E. coli and gram-positive S. aureus bacterial cells in vitro. Moreover, with the help of NIR laser irradiation (808 nm), the local hyperthermic effect of the SAF NCs accelerated wound healing in mice and showed a stronger sterilization effect, indicating promise for infection control by the SAF NCs in vitro [92]. In addition to infrared heating, ultrasound (US) is also a good external choice for antibacterial therapy. Feng et al. developed a bifunctional sonosensitizer composed of a Zn SAC (g-ZnN4) and MoS2 quantum dots (QD). With US irradiation, the g-ZnN4-MoS2 showed antibacterial efficiencies of up to 99.58 % with methicillin-resistant Staphylococcus aureus (MRSA), which enabled bone marrow regeneration and inhibited inflammation through acoustic ion therapy to alleviate osteomyelitis [22].

These SACs or nanozymes contained different active sites and exhibited excellent peroxide or oxidase-like activity with bactericidal efficacy. Furthermore, these SACs also work synergistically with other treatments (e.g., as PTT photosensitizers) to accelerate wound healing. Therefore, they show good prospects in the treatment of diseases caused by pathogenic bacteria, providing new treatment ideas and methods.

3.3. Antioxidation

Oxidative stress plays an increasingly crucial role in various kinds of diseases, and its impact on diseases is mainly manifested in two ways. On the one hand, the reactive substances (such as ROS and reactive nitrogen species (RNS)) produced during oxidative stress act on biological macromolecules, which could cause cellular oxidative damage, leading to death or functional abnormalities. On the other hand, redox homeostasis in the body is damaged, and abnormal redox signaling occurs, thereby affecting normal physiological functions [93,94]. Therefore, it is of great significance to develop highly efficient antioxidants that can prevent or reduce the production of ROS and RNS.

Currently, some SACs have been found to exhibit antioxidant effects by mimicking antioxidant enzymes in the body, which protect cells from oxidative stress and constitute an effective class of ROS scavengers [59]. For instance, Cao et al. reported N-doped carbon-supported Co/PMCS SAC prepared via direct pyrolysis of a bimetallic MOF (Co-doped ZIF-8). The as-prepared Co/PMCS showed SOD-like activity and effectively eliminated O2 .° and H2O2 by mimicking the roles of CAT and GPx. Additionally, the active Co-porphyrin centers were involved in redox cycling, and the formation of nitroso-metal complexes to eliminate ROS/RNS was dose dependent. Furthermore, the Co/PMCS also reduced proinflammatory factors while eliminating RONS to reduce oxidative stress levels, showing great potential as.

an antioxidant for sepsis management [64]. Lately, Lu et al. [95] reported a facile and large-scale production of Fe–N/C SACs with Fe–N4 moieties anchored on the carbon framework; these were prepared by pyrolysis of host-guest Fe-TPP⊂rho-ZIF complex precursors (Fig. 9a). The Fe–N/C SACs had highly dense and dispersed Fe atoms with loadings of up to 3.8 wt%, so they displayed efficient catalytic activity and robust stability in catalyzing oxygen reduction, and the activity was significantly higher than that of Pt/C (Fig. 9b and c). More importantly, the Fe–N/C SACs exhibited a range of enzymatic-like activities, such as those of peroxidases, oxidases, and catalases, among which the glutathione peroxidase-like activity was positively correlated with the concentration and reduced the absorption of H2O2 at 340 nm (Fig. 9d and e). Next, pretreatment with the Fe–N/C SACs reduced the increase in fluorescence intensities of β-lapachone (β-Lap) and Rosup-stimulated HeLa cells (Fig. 9f and g), indicating a decrease in ROS production. This confirmed that the Fe–N/C SACs successfully cleared ROS in HeLa cells to regulate the level of oxidative stress while exhibiting low cytotoxicity; this broadened the range of biomedical applications [96]. Ma et al. reported another Fe-related SAC with Fe–N4 sites supported on N-doped porous carbon (Fe–SAs/NC), exhibiting good catalase (CAT) and superoxide dismutase (SOD) activities and effectively functioning as antioxidant enzymes. As a result, the Fe–SAs/NC was very effective in removing ROS from cells and protecting the cells from oxidative stress. Additional cell experiments showed that the Fe–SAs/NC significantly inhibited ROS production by β-Lap in HeLa cells, indicating its antioxidant potential [97].

3.4. Biosensors

Biosensing platforms have shown good prospects for use in the medical field, and they effectively monitor drugs, biomolecules and metabolites in clinical samples (such as body fluids and serum) to aid the diagnoses of diseases, the detection of pathogens and monitoring of treatment processes, especially with the detection of biomarkers to quickly identify clinical diseases [98–100]. MOF-derived SACs have been used in biosensing applications and showed good application prospects based on their low detection limits, high sensitivities and selectivities, good reproducibilities and stabilities, and good biocompatibilities [101, 102]. Many SACs have been used to detect a variety of analytes, such as acetylcholine (AChE), H2O2, alkaline phosphatase (ALP), and acetylcholine (ACh), via colorimetric and electrochemical sensing [103]. For example, Shi and co-workers [104] used a Rh single-atom nanoenzyme (Rh SAzymes) to detect dynamic changes in the ascorbic acid in human saliva with a low detection limit (0.26 μM) and an excellent stability (>28 days). In addition, the obtained sensor shows significant selectivity with a signal of 1.5 mM AA and has a low interference response ratio (<_4.96 %) due to the uniform structure of the Rh sites.

SACs with high catalytic activities are used to generate ROS to enhance chemiluminescence (CL) biosensing. Ouyang et al. [105] synthesized a water-soluble Co single-atom catalyst (Co SAC) with abundant labelled functional groups for biometrics. Because the Co SACs showed high Fenton-like activity and produced considerable singlet oxygen (1 O2) to catalyze the lumino-H2O2 CL reaction, they could be used for CL immunoassays of cardiac troponin I (cTnI). The generation of the Co SACs were based on the HSAB principle to provide a Co/Fe bimetallic organic skeleton, which were carried out with the hot solvent method and without high-temperature calcination, so the operation was relatively simple (Fig. 10a and b). The Co SACs were composed of C, O, FE and Co; the Co content was 0.2 wt %, and it exhibited complete monoatomic dispersion and increased the specific surface area (Fig. 10c). Therefore, the Co SACs showed a significant difference in enhanced CL emission compared to that of Fe MIL-53 (1349.3-fold vs. 1.8-fold) (Fig. 10e). Meanwhile, the CL of the Co SACs depended on the pH, especially for the pH range 8–9, where it was the strongest (Fig. 10f). As shown in Fig. 10b, the detection of cTnI by the Co SACs involved labelling it with antibodies to establish a CL immunoassay (CLIA) method. The results showed that the response of the Co SACs to CL increased with increasing concentration of the cTnI (Fig. 10g), and the detection limit (LOD) for cTnI was 3.3 pg mL°1 , which was significantly lower than those of other signal probes, indicating high sensitivity and favorable selectivity. This method was also satisfactory for the detection of serum samples, indicating that the CLIA method based on Co SACs has good application prospects.

The use of nanozymes in biosensing with single-atom catalysts is increasing, usually by simulating enzyme-like activity to detect substances in vivo [106]. Wu et al. [107] prepared Cu–N–C SAzymes with specific peroxidase-like activity and further constructed a cascade reaction system (ACC system) to track acetylcholine (ACh) by combining acetylcholinesterase and choline oxidase with these SAzymes. As shown in Fig. 11a, KCl templates were first incorporated into a mixture of Cu(NO3)2 and 2-MeIm, followed by high-temperature pyrolysis and acid washing to obtain Cu–N–C SAzymes. SEM images (Fig. 11b) showed that there were a lot of N-doped carbon nanosheets in the Cu–N–C SAzymes. The Cu content in the Cu–N–C was measured to be 5.1 wt % with ICP‒ OES. Cu is an important component, and in response to 3,30 ,5,50 -tetramethylbenzidine (TMB), the Cu–N–C exhibited a significant absorbance peak at 652 nm, while N–C did not (Fig. 11c). Therefore, due to the high concentration of single-copper active sites, the Cu–N–C SAzymes tracked ultralow amounts of H2O2, so the ACC system detected Ach and showed a limit of detection (LOD) of 1.24 μM. In addition, it was also used in the detection of organophosphorus pesticides (OP) with an LOD of 0.60 ng mL°1 . Thus, detection of the ACC system was not affected by interferents (Fig. 11d), indicating excellent selectivity and high sensitivity of the ACC system. Furthermore, Chen et al. reported activity screening of the AChE with a Fe/Bi two-site single-atom nanozyme with oxidase (OXD)-like activity, which was also detected with a cascade system based on integration of the AChE and nanozyme, and the detection limit was as low as 1 x 10°4 mU mL°1 [37]. In addition, Li et al. [108] reported MOF-derived homometallic C-CoM-HNCs, which showed OXD-like activity and were used for biological detection of AChE and exhibited similar ultralow detection limits.

Jiao et al. [109] also used KCl template strategy to prepare an Fe–N–C SAzymes containing dense FeN4 sites, and these exhibited POD-like activity, mainly for the detection of intracellular H2O2. As shown in Fig. 11f and g, the KCl templates were mixed with iron (III) nitrate and a dimethylimidazole (MI) methanol solution. Subsequently, the precursor composites were pyrolyzed at 750 -C and acid washed to obtain Fe–N–C SAzymes with Fe contents of up to 13.5 wt%; Fe had the same coordination structure found in horseradish peroxidase (HRP) and an ultrathin nanosheet structure (Fig. 11g). Subsequently, the intrinsic activity of Fe–N–C SAzymes was exhibited with the chromogenic reaction of 3,30 ,5, 50 -tetramethylbenzidine (TMB), 2,20 -biazo (3-ethylbenzothiazolin-6-sulfonic acid) (ABTS), and 1,2-diaminobenzene (OPD) (Fig. 10h). In addition, the Fe–N–C SAzymes showed a stronger EPR signal due to the production of more •OH, which was accompanied by a change in the pH (Fig. 11i). The Fe–N–C SAzymes also showed excellent selectivity and sensitivity in the H2O2 detection, and the detection speed was positively correlated with the H2O2 concentration (Fig. 11j). Next, Chen et al. found that Fe–N/C SACs mimicked OXD activity and were used for alkaline phosphatase activity screening in combination with ascorbic acid 2-phosphate (AAP), and the detection limit was as low as 0.02 U/L. The ΔA652 value of ALP further demonstrated that the developed Fe–N/C/TMB/AAP sensor system has satisfactory selectivity towards ALP detection [110]. Moreover, Zhou et al. synthesized a Fe–N–C single-atom nanoenzyme (Fe-SAzyme) with POD-like activity, which demonstrated excellent anti-interference ability and selectivity for galactose detection and was used for quantitative colorimetric detection of galactose and might be a clinical treatment for galactose miaemia [111]. Another Fe–N–C SAN synthesized by Niu et al. also showed POD-like activity in the detection of butyrylcholinesterase (BChE) [112]. In addition, several heterogeneous molybdenum single-atom nanozymes (named MoSA-Nx-C) prepared by Wang et al. showed high POD-like activity and substrate specificity and can now be used to detect xanthine in biological samples [71].

Early diagnosis of cancer has been a major problem, and effective detection of biomarkers could be used to diagnose cancer and save treatment time. SACs also have good prospects in this area. Tang et al. [113] synthesized a dual-signal electrochemiluminescence (ECL) immune sensor for detecting carbohydrate antigen 125 (CA125) and human epithelial protein 4 (HE4) markers of ovarian cancer, which improved the accuracy for early diagnosis of ovarian cancer by detecting both markers simultaneously. This immunosensor was composed of the cathodoluminescent group Cu SAC/NC-CdS QDs-HE4 Ab2 and the anodic luminescent group Eu MOF@Isolu-Au NPs-CA125 Ab2. The cathodoluminescence carrier was composed of two parts: one was Cu SAC/NC obtained by high-temperature pyrolysis, and the surface was smooth with diamond-shaped dodecahedra and the other part contained CdS quantum dots prepared by hot reflow soldering. Then, these two parts were combined via electrostatic interactions to obtain the cathode emitter (Fig. 12a–c). The anodic luminescent group was produced by attaching negatively charged Isolu-Au NPs to the surfaces of Eu MOF nanospheres, and the synergistic effect between them enhanced the ECL signal, reaching the highest value at 460 nM (Fig. 12d). Finally, the cathode and anode were assembled together to obtain a dual-signal ECL sensor. The response mechanism of the sensor to the ECL reaction might involve ROS produced by Cu SAC/NC to induce photon emission at the cathode and anode (Fig. 12e), while the Eu MOFs and CdS QDs produced a larger ECL signal. In the property analyses, the signal intensity of the ECL immunosensor to different concentrations of CA3 and HE125 increased linearly over the range 0.005–500 ng mL°1 (Fig. 12f), and the limits of detection for CA3 and HE125 were 0.37 and 1.58 pg mL°1 , respectively, which were much better than those of other sensors. In addition, in the presence of other antigens, the system exhibited good selectivity and reproducibility for CA125 and HE4, and the signal changes under different conditions were less than 5 % (Fig. 12g), which was of practical significance for real serum samples. Another MOF-derived Fe–N–C SAzyme reported by Sun et al. [34] was combined with DNA to obtain Apt/Fe–N–C SAzymes. The Apt/Fe–N–C SAzymes showed peroxidase-like catalytic activity and recognition ability. These SAzymes could be utilized for complexing with HepG2 cells, enabling colorimetric detection of cancer cells. This work combined nanoenzymes with DNA technology to provide a new path for the development of SACs.

In addition to the detection of macromolecules in vivo, SACs can also detect the presence of drug molecules. For example, Liu et al. [114] synthesized a hollow porphyrin Zr-based MOF (HPCN-222) carrier by stably dispersing Pt single atoms to obtain PtHPCN-222 SACs. The PtHPCN-222 SACs were used as an electrochemical sensor to detect levodopa in serum samples with a detection limit of 3 nM. This method of monitoring drug molecules can observe changes in the drugs in the human body at any time to enable more effective treatment measures for patients, which is very important in clinical practice. In addition, the sensor also has superior interference immunity and selectivity, with electrochemical signals remaining unaffected in environments with 1000x common inorganic interfering ions and 10x and 100x different organic interfering ions. However, in addition to the excellent performance of SACs, the biomarkers of diseases also must be updated so that SACs can be more widely used in disease diagnoses [101].

4. Conclusions and prospects

In this review, we summarize the recent application of MOF-derived SAC nanozymes in biomedical applications., especially in the fields of tumor therapy, antibacterial activity, antioxidant activity and biosensing. Compared to natural enzymes, SAC nanozymes have attracted extensive research attention because of their low costs, highly efficient enzyme-like activities, and tunable physicochemical properties. Additionally, we detailed the synthesis and applications of MOF-derived SACs, and the catalytic mechanisms for various SACs were highlighted. Despite the great achievements made in preparation, characterization and mechanistic understanding, the biomedical use of SACs is still unsatisfactory. Thus, rational design and precise syntheses of advanced MOF-derived SAC nanozymes and exploration of their applications in biomedicine are the key issues to be considered in future development.

(1) Rational design of MOF-derived SACs. MOF precursors with high specific surface areas and tunable porosities are some of the most promising materials with which to anchor single atoms. In general, mixtures containing ZIF-8 NPs and a metal salt were pyrolyzed to prepare various SACs with polyhedral structures. To improve the performance of the SACs, MOF-derived SACs with unique structures, such as hollow structures, three-dimensional ordered structures, nanowires, and nanosheets, should be developed to enhance their potential for application in biomedicine. For instance, a hollow N-doped carbon has a larger volume in which to load drugs than a solid carbon support. In addition, since Fe-, Cu-, Zn-, Co-, Au-, Ag-, Pt-, and Pd-based SAzymes have been extensively reported so far, more metal centers need to be carefully considered and evaluated.

(2) Precise regulation of the active sites. It is well known that SACs with different coordination structures play key roles in therapies; however, there are still many challenges to controllable preparation of SACs with different coordination structures. On the one hand, it is necessary to precisely regulate the coordination numbers of the SACs and investigate the structure-activity relationship between the coordination number and the activity. On the other hand, in addition to N atoms, other heteroatom atoms, including S, P, B, F, Br, and I, may be ideal choices to coordinate single atom metals and mimic the active centers of natural enzymes.

(3) Increased metal loadings in SACs. Currently, most MOF-derived SACs are prepared by pyrolyzing a mixture of the MOF precursor and the metal salt; however, the resulting SACs typically have relatively low metal loadings (<2 wt %), which limits practical application. Engineered carbon supports, such as with heteroatom doping, defects, high porosity, and appropriate precursors, would increase the metal loadings of SACs. In addition, the ideal pyrolysis method (i.e., spaced-confined pyrolysis, multistep carbonization) could also prevent agglomeration and sintering of the metal salt precursors into NPs, thereby increasing the metal loadings of SACs.

(4) Biocompatibility and toxicity evaluations of SACs. Although nanozymes show excellent enzyme-like activities, biocompatibility and toxicity are key factors delaying practical application. In the future clinical transformation, biosafety is a crucial issue to be considered. Enhancing the biocompatibility and biodegradability of nanozyme materials will be the primary focus for future advancements and breakthroughs in this field. Furthermore, an indepth understanding of the biocompatibilities and toxicities of SACs and methods to reduce the toxicities of SACs further are urgently needed. Overall, the translation of experimental results into the clinic is a challenging task that requires many hurdles to overcome instead of staying in the laboratory research stage.

Declaration of competing interest

The authors declare no conflict of interests.

Acknowledgements

This work was financially supported by Key project of Science and Technology Department of Sichuan Province (2022YFS0086).

Sidebar

ARTICLE INFO

Received 23 October 2023; Accepted 13 December 2023

Available online 2 January 2024

Footnote

* Corresponding author. Department of Ultrasound, West China Second University Hospital, Sichuan University, Chengdu, China.

** Corresponding author. School of Materials and Energy, University of Electronic Science and Technology of China, Chengdu, 611731, China.

E-mail addresses: [email protected] (H. Luo), [email protected] (R. Wu).

References

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