English

• 1. Introduction

  Natural enzymes are indispensable in biocatalytic processes because of their unique three-dimensional structure and great substrate selectivity [1,2]. Their active sites, which consist of specific amino acid residues and metal ions, serve as catalytic centers that participate in and accelerate chemical reactions. Their complex architecture features precise active and substrate-binding sites composed of amino acids and metal atoms like Fe, Cu, Mn, and Zn, endowing them with exceptional catalytic properties [3,4]. Enzyme substrate-binding sites are highly complementary to the structure and chemical composition of the substrate, enabling accurate binding and catalysis by functional groups surrounding the active site. Moreover, the channel of the enzyme allows substrates and products to enter and exit, while the dynamic nature of the active site adapts to the substrate binding and reaction conditions.

  MOFs are inspired by natural catalysts and allow for the exact incorporation of catalytically active metal centers or functional groups. MOFs have emerged as a possible option to replicate the catalytic prowess of enzymes [5,6]. These porous crystalline materials are assembled from metal ions and organic ligands [7,8], offering a versatile platform that sets the stage for advancements in catalysis and material science. Researchers have developed MOFs as novel materials that mimic the attributes of natural enzymes, standing out among many candidate materials due to their highly tunable structure, functional versatility, and robust design ability [9,10]. High surface area of MOF increases the number of contact points with the substrate and its adjustable pore size allows selective catalysis of specific substrates [11,12]. Compared with conventional enzymes, MOFs not only exhibit superior thermal, chemical, and mechanical stability but also are characterized by their ease of recycling and reuse. Furthermore, the multifunctionality of MOFs allows for the integration of multiple catalytic active sites, effectively mimicking the synergistic catalytic effects observed in multi-enzyme systems. Post-synthetic modifications offer additional optimization of the surfaces and pores of MOFs to enhance their catalytic performance or selectivity [13].

  Although the structural properties of MOFs differ from the dynamics of enzymes, their design can incorporate flexible or deformable features [14,15], thereby mimicking the dynamic catalytic processes of enzymes to a certain extent. Such advancement positions MOFs as an ideal alternative for industrial catalysis and biomedical applications [16-19]. In recent years, MOF materials have made remarkable progress in mimicking natural enzymes [20-22]. By precisely modulating the composition, structure, and functionality of the frameworks, researchers have successfully designed a variety of porous frameworks capable of replicating the catalytic activity centers of natural enzymes. These frameworks can not only mimic the substrate recognition and binding mechanisms of natural enzymes but also achieve a catalytic conversion process like that of natural enzymes.

  The aim of this paper is to review the advances in the study of MOFs constructed to mimic natural enzymes from a chemical point of view. We will address in more detail the design principles of metal-organic frameworks, their catalytic properties and their prospects for mimicking natural enzymes in the field of brain chemistry research (Scheme 1). We expect that this review will contribute to the further development and application of the field by presenting readers with a comprehensive and in-depth perspective on the design of metal-organic frameworks that mimic natural enzymes and the present state of the field in solving brain chemistry problems.

  Scheme1

  

  Scheme1.  Types of MOF-based mimics of natural enzymes and their relevant applications in the field of brain chemistry.

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  2. MOFs mimicking natural enzymes

  MOF materials are of interest in the field of catalysis because of their ability to mimic natural enzymes and their ability to be precisely designed and synthesized to mimic the activity and selectivity of natural enzymes. Based on their distinct catalytic attributes, MOFs that imitate natural enzymes can be categorized as follows:

  2.1 MOF-based single enzyme mimicry

  2.1.1   MOFs mimicking peroxidases (POD)

  The most notable feature of peroxidase is its capability to catalyze the reduction of hydrogen peroxide (H₂O₂) or other peroxides, producing water and oxygen while oxidizing the substrate. In this process, peroxidases usually use metal ions (e.g., iron, manganese) in their active centers to transfer electrons and achieve catalysis. This review provides an extensive survey of the trajectory of peroxidase-mimetic MOFs, highlighting the pivotal developments and milestones in this field as depicted in Fig. 1 [23-34]. The exploration initially focused on common iron-based metals, broadening to encompass a variety of metals, the introduction of two-dimensional structures, and the recent surge in bimetallic systems that enhance catalytic activity, showcasing the extensive research in this domain.

  Figure 1

  

  Figure 1.  A brief development timeline for MOF-based simulation of POD. All figures are reproduced with permission. SEM of Fe-MIL-88NH₂. Reproduced with permission [23]. Copyright 2013, The Royal Society of Chemistry. SEM of MIL-53(Fe). Reproduced with permission [24]. Copyright 2013, Wiley. SEM of HKUST-1. Reproduced with permission [25]. Copyright 2014, Elsevier B.V. SEM of Fe-MIL-88A. Reproduced with permission [26]. Copyright 2016, Elsevier B.V. SEM of 2D Co-TCPP(Fe) nanosheets. Reproduced with permission [27]. Copyright 2016, Wiley. SEM of Cu-MOFs. Reproduced with permission [28]. Copyright 2017, Elsevier B.V. SEM of Ni-MOF. Reproduced with permission [29]. Copyright 2018, Elsevier B.V. SEM of 2D Fe-BTC. Reproduced with permission [30]. Copyright 2020, The Royal Society of Chemistry. SEM of Fe₃Ni-MOF. Reproduced with permission [31]. Copyright 2022, American Chemical Society. SEM of MIL-101(Fe/Co). Reproduced with permission [32]. Copyright 2022, The Royal Society of Chemistry. SEM of FeCo-MOF-H₂. Reproduced with permission [33]. Copyright 2023, The Royal Society of Chemistry and Chinese Chemical Society. SEM of Fe Co-MOF. Reproduced with permission [34]. Copyright 2024, American Chemical Society.

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  Inspired by natural enzyme activity centers, the use of MOF as a peroxidase mimic was first reported in 2013 [23]. By mimicking the active centers and catalytic mechanisms of natural enzymes, Fe-MIL-88NH₂ demonstrated high efficiency and selectivity in catalytic reactions. The schematic representation of Fe-MIL-88NH₂ catalyzing peroxidase-like activity in the tetramethylbenzidine (TMB)-H₂O₂ system is depicted in Fig. S1a (Supporting information). Fe-MIL-88NH₂ catalyzes the decomposition of H₂O₂ via the Fenton reaction between iron and H₂O₂, thereby inducing the generation of ^•OH. However, it has some drawbacks, such as its small pore size, large particle size, and the inability to be reused.

  In addition to Fe³⁺-based MOFs, studies on MOFs with other metal ions emerged shortly thereafter. In 2015, Wang et al. first reported that the copper-based metal-oxygenase HKUST-1 exhibits peroxidase-like activity, efficiently catalyzing the oxidation of TMB by H₂O₂. This study suggested that the oxidation mechanism involves the decomposition of H₂O₂ to produce hydroxyl radicals. As illustrated in Fig. S1b (Supporting information), HKUST-1 effectively catalyzes the transformation of non-fluorescent TMB into the highly fluorescent product thiochrome (TC) in the presence of H₂O₂, indicating a mechanism linked to ^•OH generation from H₂O₂ decomposition [25].

  Similarly, efficient peroxidase-like MOF materials can be crafted by modulating their size, boasting a tunable and highly ordered structure. Like other 2D nanosheets, MOF nanosheets have many exposed active sites that facilitate rapid electron transfer, which is critical for applications in gas storage, sensing, separation, and catalysis (especially organic reactions). Hu et al. synthesized ultrathin 2D Ni-MOF nanosheets with remarkable peroxidase-like activity through a simple solvothermal method, attributed to their ultra-high specific surface area and abundance of active sites [29]. As depicted in Fig. S1c (Supporting information), utilizing the Ni-MOF nanosheets as peroxidase mimics and TMB as the substrate, these nanosheets are capable of colorimetric detection of H₂O₂, demonstrating good dispersion and stability. In the presence of H₂O₂, the nanosheets rapidly catalyzed TMB to a blue product, a reaction visibly discernible to the naked eye. The high affinity of the Ni-MOF nanosheets for TMB was evident, and the assay exhibited excellent sensitivity and selectivity for H₂O₂ detection.

  In addition, in order to further improve the catalytic activity of monometallic iron-based MOFs, some bimetallic Fe-based MOF mimics, such as Fe-Co-MOF [34], Fe-Cu-MOF [35], Fe-Ni-MOF [36], and Fe-Mn-MOF [37], have been reported. They have good electronic structures and chemical properties because their bimetallic centers can produce synergistic effects. Wu et al. studied the mechanism behind the increased activity of Fe-Co-MOF-like enzymes. The peroxidase-like activity of Fe-Co-MOF is attributed to its capacity to catalyze the decomposition of H₂O₂ into hydroxyl radicals. Fe-Co-MOF can serve as a catalyst for the decomposition of H₂O₂ into ^•OH, which has potential applications in various fields. Possible mechanisms for the catalytic oxidation of TMB by Fe-Co-MOFs are described as follows. H₂O₂ is first adsorbed onto the Fe-Co-MOFs material, and then a large amount of Fe³⁺ and Co²⁺ exposed on the surface of the porous material can serve as a synergistic catalytic activity center to decompose H₂O₂ to produce a large amount of ^•OH ((1), (2), (3)). Finally, ^•OH can oxidize colorless TMB to obtain a blue ox TMB (Eq. 4). A colorimetric sensitive determination of Fe-Co based metal-organic skeleton mimicking peroxidase and its efficient degradation of aflatoxin B1 is shown in Fig. S1d (Supporting information).

  $ \mathrm{Fe}^{3+}+\mathrm{H}_2 \mathrm{O}_2 \rightarrow \mathrm{Fe}^{2+}+\mathrm{HO}_2^{\bullet}+\mathrm{H}^{+} $

  (1)

  $ \mathrm{Fe}^{2+}+\mathrm{H}_2 \mathrm{O}_2 \rightarrow \mathrm{Fe}^{3+}+{ }^{\bullet} \mathrm{OH}+\mathrm{OH}^{-} $

  (2)

  $ \mathrm{Co}^{2+}+\mathrm{H}_2 \mathrm{O}_2 \rightarrow \mathrm{Co}^{3+}+{ }^{\bullet} \mathrm{OH}+\mathrm{OH}^{-} $

  (3)

  $ \mathrm{TMB}+{ }^{\bullet} \mathrm{OH}+\mathrm{H}^{+} \rightarrow \text { oxTMB }+\mathrm{H}_2 \mathrm{O} $

  (4)

  2.1.2   MOFs mimicking oxidases (OXD)

  Oxidases are a class of enzymes that catalyze redox reactions by accepting hydrogen atoms or electrons from a substrate and transferring them to oxygen molecules. In this process, oxidizing enzymes act as bridges, which facilitate the shift of the electron from the substrate to the oxygen. As substrate molecules enter the pore of the MOF, they interact with the metal center. These interactions allow the substrate molecules to approach the metal centers so that electron transfer can occur. The pore structure of MOF takes an essential role in this process by providing a site for the interaction of the substrate molecules with the metal centers and facilitating the smooth transfer of electrons. With the transfer of electrons, the substrate molecules are oxidized while the oxygen molecules are reduced. This redox process was catalyzed by MOF, mimicking the catalytic mechanism of natural oxidases. To better understand the development history and current research trends in this field, this paper will provide a brief development timeline of MOFs-based simulation of oxidase to demonstrate the key advances and milestones in this field, as shown in Fig. 2 [38-44].

  Figure 2

  

  Figure 2.  A brief development timeline for MOF-based simulation of OXD. All figures are reproduced with permission. SEM of MVCM. Reproduced with permission [38]. Copyright 2015, The Royal Society of Chemistry. SEM of Ce-MOF. Reproduced with permission [39]. Copyright 2017, The Royal Society of Chemistry. HRTEM of Co-Mn NS. Reproduced with permission [40]. Copyright 2019, Springer. SEM of Cu-MOF. Reproduced with permission [41]. Copyright 2022, The Royal Society of Chemistry. TEM images of the Mg/NC. Reproduced with permission [42]. Copyright 2022, Elsevier B.V. FESEM of MVCM. Reproduced with permission [43]. Copyright 2022, Elsevier B.V. TEM of MVCM@β-CD. Reproduced with permission [44]. Copyright 2023, Elsevier B.V.

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  While past studies have focused only on mimicking the catalytic activity of peroxidases, pure MOFs were developed for the first time in 2015 to mimic the catalytic activity of oxidases [38]. A method developed by Zhao et al. is essentially a highly efficient in-situ partial oxidation synthesis technique, which was used for the preparation of mixed-valent-mode Ce-MOF (MVCM). Rapid synthesis of MVCM is shown in Fig. S2a (Supporting information). This strategy not only simplifies the synthesis steps and significantly improves the synthesis speed, thus realizing the efficient preparation of MVCM. Importantly, experiments showed for the first time that the prepared MVCM has an inbuilt catalytic capacity like that of oxidative enzymes. The key to this finding lies in the Ce³⁺/Ce⁴⁺ system possessed by MVCM. This system exhibits unique cycling and flipping properties in redox reactions, i.e., Ce³⁺ and Ce⁴⁺ ions can be "spontaneously" converted to each other during the reaction, thus maintaining the continuity of catalytic activity. The results show that MVCM has higher affinity and activity towards TMB, which may be attributed to the large surface area of MVCM and the π-π stacking interaction between TMB and MVCM. This means that MVCM first binds and reacts with TMB, followed by the release of the final product oxTMB.

  Inspired by the potential of cerium chemistry in colorimetric sensing and oxidative catalysis, A ceria-based MOF with 3,4-dimethylthieno [2,3-b] thiophene-2,5-dicarboxylic acid (H₂DMTDC) as ligand was synthesized by Shyam Biswas et al. in 2017 [39]. The compound's structure is depicted in Fig. S2b (Supporting information). These activated MOFs display intrinsic oxidase-like activity in an acidic NaAc buffer, rapidly oxidizing chromogenic peroxidase substrates such as TMB or 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt (AzBTS) without the need for external oxidants like H₂O₂. Based on these discoveries, a bio chromatographic platform was developed for the detection of bio thiols in NaAc buffer (pH 4.0) and human plasma. Notably, the compound's mimic oxidase catalytic activity is attributed to its redox-active cerium atoms.

  In addition, catalytic properties can be improved by modifying nanomaterials with small molecules. In 2022, researchers synthesized a novel 2D cobalt-based MOF nanocomposite, MVCM@β-CD [44]. MVCM@β-CD took advantage of altering Co ionic valence and β-cyclodextrins (β-CDs) modification to boost its oxidase catalytic activity. A colorimetric sensor, constructed using ABTS as a substrate, demonstrated the sensor's ability to specifically identify aminophenol isomers. The process of ABTS synthesis catalyzed by MVCM@β-CD and isomer differentiation is illustrated in Fig. S2c (Supporting information). The transition from 3D to 2D morphology in nanomaterials significantly induced oxidase-like activity, and further improvements were achieved by increasing the high valence ratio and modifying β-CD, indicating that these strategies effectively enhance oxidase-like activity. The oxidase mimetic activity of MVCM@β-CD was significantly enhanced by increasing the Co(Ⅲ)/Co(Ⅱ) ratio and modifying it with small molecule β-CDs. This enhancement resulted from the synergistic effect of the large specific surface area of the two-dimensional Co-MOF nanosheets, the large number of exposed active sites, the high ratio of cobalt, and the modulating effect of β-CD.

  While specific physicochemical properties of nanomaterials can modulate the activity of nanozyme, the quantitative relationship between nanomaterial structure and enzymatic activity is not well understood, largely due to the heterogeneity in composition and active sites. Building upon the established foundation of the oxidase-like capabilities of MOFs, the exploration of structure-activity relationships within these materials has become a focal point for enhancing their catalytic efficiency. The inspiration comes from metalloenzymes with clear metal coordination, Wang et al. used by a group of substituted MOFs with similar coordination to explore the relationship between structure and oxidase mimetic activity [45]. Both experimental results and density functional theory calculations have revealed a Hammett-type conformational linear free energy relationship for the MIL-53(Fe) nanozyme, in which the value of the Hammett σ m electron-withdrawing ligand increases the oxidase mimetic activity. As a result, MIL-53(Fe)-NO₂ has the strongest electron-absorbing NO₂ substituent and is 10 times more active than unsubstituted MIL-53(Fe).

  2.1.3   MOFs mimicking laccases

  Laccase is a class of copper-containing oxidases capable of oxidizing a wide range of environmentally and biologically important substrates such as polyamines, polyphenols and aryl diamines [46]. At these reactions, carbon dioxide is converted to water without producing or requiring hydrogen peroxide, making laccase an environmentally friendly catalyst. Currently, production of laccase relies mainly on fermentation, which is low yielding and costly, and the stability of laccase is weak. These porous and customizable materials offer a promising platform for the design of artificial laccase mimics. To provide a comprehensive view of the advancements in this field, the following section presents a concise timeline of the development of MOF-based laccase mimics, highlighting key milestones in their evolution and application, as depicted in Fig. 3 [47-53].

  Figure 3

  

  Figure 3.  A brief development timeline for MOF-based simulation of laccase. All figures are reproduced with permission. SEM of Cu/GMP. Reproduced with permission [47]. Copyright 2017, American Chemical Society. SEM of Cu/H₃BTC MOF. Reproduced with permission [48]. Copyright 2019, The Royal Society of Chemistry. SEM of UiO-67-Cu²⁺. Reproduced with permission [49]. Copyright 2021, Springer. SEM of Ce-MOFs. Reproduced with permission [50]. Copyright 2022, Elsevier B.V. SEM of Cu-SM-MOF. Reproduced with permission [51]. Copyright 2023, The Royal Society of Chemistry. SEM of Cu-Mn-MOF. Reproduced with permission [52]. Copyright 2024, Elsevier B.V. SEM of Cu-MOF. Reproduced with permission [53]. Copyright 2024, Elsevier B.V.

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  In 2017, the first MOF-based laccase mimicking nanozyme were introduced, suggesting that a multi-copper multicopper coordination environment may be an ideal laccase mimics, and their superior performance was experimentally demonstrated [47]. Liu et al. report a very simple but powerful laccase analogue based on guanosine monophosphate (GMP)-coordinated copper. It constitutes an amorphous MOF material with excellent laccase-like activity in converting a wide range of phenol-containing substrates, such as catechol, naphthol, hydroquinone and adrenaline. The catalytic schematic for the reaction of Cu²⁺ with GMP to form MOF is shown in Fig. S3a (Supporting information). Comparative studies showed that the activity originated from guanosine coordination rather than phosphate binding in GMP and that Cu²⁺ was essential and could not be replaced by any other metal ions. Considering the multicopper nature of Cu/GMP, it may prove to be a structural mimetic.

  Earlier laccase nanozyme were mainly focused on copper-containing materials with catalytic copper as the active center. While copper-based laccase mimetics have shown promise, the field has been expanding to include non-copper systems that can offer unique advantages and potentially surpass the limitations of traditional copper-based catalysts. Motivated by the multi-copper activity site and the Cu²⁺/Cu⁺ reduction-electron transfer pathway in natural laccase, the researchers designed a series of multivalent cerium-based metal-organic frameworks (Ce-MOFs) with mimicry comparable to that of laccase activity. The reactivity of inner cerium oxidation and reduction (Ce⁴⁺/Ce³⁺) in these Ce-MOFs is thought to mimic catalytic function and the active center of natural laccase [50]. Biomimicking strategy for constructing these multivalent Ce-MOFs as a new type of laccase nanozyme for environmental remediation is depicted in Fig. S3b (Supporting information). Compared with the naturally occurring laccase, Ce-UiO-66 and Ce-MOF-808 exhibit superior catalytic performance at the same mass concentration level. In addition, both materials showed excellent durability and reusability in catalyzing the oxidation of phenolic compounds.

  In natural laccase, the redox reactivity of polycopper clusters (Cu²⁺/Cu⁺) is essential for electron transfer from the reducing substrate to oxygen. The substrate binds to the active center of the multicopper cluster and is oxidized near the T1 copper. It then enters the T2/T3 trinuclear copper clusters via the Cys-His pathway, culminating in CO₂ reduction. Accordingly, a proposed catalytic mechanism for the oxidation of phenolic substrates (2,4-DP) by multivalent Ce-MOFs, based on Ce₆ clusters as potential active sites, involves four distinct steps: (1) Substrate binding to the Ce₆ cluster at the Ce(Ⅳ)-OH site due to hydroxyl group affinity; (2) Substrate oxidation at the Ce(Ⅳ) active site through a single electron transfer between Ce(Ⅲ) and Ce(Ⅳ); (3) Electron transfer, where bound water on the Ce₆ cluster's surface enters the transient Ce(Ⅳ) state, forming the steady-state Ce(Ⅲ); and (4) Oxygen reduction, where an unstable Ce(Ⅲ) is oxidized to Ce(Ⅳ) in the presence of an electron-deficient molecule, while oxygen is reduced to water, regenerating the catalytic Ce₆ clusters. The intrinsic redox reactivity of Ce(Ⅲ)/Ce(Ⅳ) in these multivalent Ce-MOFs establishes a structural foundation that mimics the function of multivalent copper laccases. This highlights the great potential of metal customization in the development of efficient nanozyme.

  Expanding on the principles of metal tailoring and the quest for robust aqueous stability in nanozyme, recent advancements have focused on expanding copper-based MOFs that address the limitations of traditional copper complexes. However, competitive coordination of water molecules with the central metal ion tends to affect the robustness of most MOF aqueous solutions. To address this, Cao et al. [51] synthesized copper-based porous metal oxides (MOFs) via a hydrothermal method, using copper ions and 5-(sulfomethyl)isophthalic acid (5-SMIPA) as precursors. The preparation process and structure of the resulting Cu-SM MOF are depicted in Fig. S3c (Supporting information). When compared with HKUST-1, which shares coordination and morphological similarities, the Cu-SM MOF demonstrated enhanced aqueous phase stability, particularly under alkaline conditions. This improved stability, along with higher catalytic activity under high salt concentrations and temperatures, is attributed to the lower K_m value and higher V_max value of Cu-SM MOF compared to the natural lytic enzymes and other reported mimics. Axial coordination of the dicopper center in Cu-SM MOF with oxygen on the sulfonic acid group creates a substantial spatial barrier. While HKUST-1 benefits from a three-dimensional pore structure and large surface area, potentially increasing the risk of water molecule attack, Cu-SM MOFs feature a more compact backbone structure that preserves stability and integrity.

  2.1.4   MOFs mimicking superoxide dismutase (SOD)

  SOD plays a key antioxidant role in organisms by neutralizing superoxide anion radicals, thereby preventing oxidative damage to organisms. SOD can be classified into four main types: Cu/Zn-SOD, Fe-SOD, Mn-SOD, and Ni-SOD. Of these four types, the copper-zinc type of SOD is the most widely distributed, and it is the most abundant in the cytoplasm, interstitial space, and extracellular matrix [54,55]. In the realm of nature, proteins with a high degree of programmability serve as versatile scaffolds that engender distinct microenvironments for their enzymatic active sites. These microenvironments are pivotal in dictating the specificity and efficacy of enzymatic catalysis. Drawing inspiration from this biological phenomenon, the replication of such microenvironments could unlock novel perspectives for the development of advanced catalysts, aligning with the sophistication of their natural counterparts.

  The brief development timeline of MOFs emulating oxidase enzymes, as depicted in Fig. 4 [56-60], offers a comprehensive overview of the progression in replicating the oxidase functionality of SOD. This section not only chronicles the advancements in the design of MOFs to mimic oxidase activity but also mirrors the swift growth of the intersecting domains of materials science and biocatalysis. Starting from the foundational proof-of-concept to the current era of diverse applications, MOFs have undergone significant evolution in their design paradigms and strategies for functionalization, showcasing their innovative potential.

  Figure 4

  

  Figure 4.  A brief development timeline for MOF-based simulation of SOD. All figures are reproduced with permission. SEM of MOF-818. Reproduced with permission [56]. Copyright 2022, American Chemical Society. TEM of Ce(Ⅲ)- and Ce(Ⅳ)-MOFs. Reproduced with permission [57]. Copyright 2022, American Chemical Society. TEM of Sn-PCN. Reproduced with permission [58]. Copyright 2022, American Chemical Society. SEM of Mn/Cu−C−N₂. Reproduced with permission [59]. Copyright 2023, American Chemical Society. SEM of Cu-MOF. Reproduced with permission [60]. Copyright 2023, The Royal Society of Chemistry.

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  In 2022, Wu et al. have demonstrated that the use of bimetallic MOF to mimic Cu/Zn-SOD and dynamically enhance O₂ superoxide anion scavenging activity [56]. The catalytic environment of the Cu/Zn-SOD enzyme and the architecture of MOF-818 are illustrated in Fig. S4a (Supporting information). In the native Cu/Zn-SOD, the enzymatic mechanism hinges on the histidine-assisted coordination of the Cu-Zn binuclear centers. These metal ions are anchored through the sharing of an N-terminal His61 residue. A bimetallic node-integrated MOF, designated as MOF-818, was identified for its inherent SOD-mimetic capabilities. Examination of the crystal lattice reveals that the metallic nodes in MOF-818 are paired through connections with organic counterparts at the N-terminus, akin to the active site of the Cu/Zn-SOD enzyme. This analogous bimetallic configuration endows MOF-818 with a pronounced specificity in its SOD-mimetic function. The bimetallic synergistic catalysis, spatially organized in MOF, is greatly superior to the current monometallic MOF simulations. This enhanced activity is mainly attributed to zirconium-mediated modulation of the catalytic activity center. This approach diminishes the energy threshold, facilitating the cyclic redox activity of Cu(Ⅱ) and Cu(Ⅰ), akin to the natural catalytic pathway of SOD. Moreover, these bimetallic MOF nanozyme exhibit robust stability against external perturbations and demonstrate significant promise for incorporation into biosensors, owing to the intrinsic design flexibility of the bimetallic MOF framework.

  Furthermore, innovative metal-organic framework-derived SOD mimics have emerged prominently. During the year 2023, a pair of cerium-centered metal-organic frameworks, Ce(Ⅲ)BTC and Ce(Ⅳ)BTC, were engineered to address superoxide anion neutralization and radiation shielding. These frameworks were motivated by the characteristics of endogenous SOD and nanoscale cerium oxide catalysts, focusing on the functions and structures features [57]. As shown in Fig. S4b (Supporting information), the monovalent cerium-based MOF has been designed to emulate the protective and catalytic functions of SOD while providing ionizing radiation shielding. The framework's architecture supports efficient electron transfer, enabling effective superoxide anion neutralization and radiation mitigation, positioning it as a promising candidate for applications in radiation protection and enzymatic mimicry. Like natural SOD and cerium oxide nanozymes, the SOD-like catalytic mechanism of Ce MOFs involves cycling between Ce(Ⅳ) and Ce(Ⅲ). Recent scholarly work has revealed that the SOD-mimetic function of cerium oxide nanozymes stems from the reversible binding and transformation of oxygen between the oxidation states of Ce³⁺ and Ce⁴⁺, a process analogous to that observed in natural SODs ((5), (6)). However, certain theoretical investigations have contested the feasibility of the reduction of Ce⁴⁺ to Ce³⁺ at the surface of cerium oxide, suggesting that these nanozymes are capable solely of reducing superoxide anions (O₂^•−) to H₂O₂ (Eq. 7). The subsequent oxidation of H₂O₂ is proposed to be the reaction that reverts Ce⁴⁺ back to Ce³⁺, concomitantly generating molecular O₂ (Eq. 8). Consequently, through a series of reactions with superoxide anions and hydrogen peroxide, the surface of cerium oxide is inherently restored, enabling the progressive elimination of superoxide anions.

  $ \mathrm{M}^{\mathrm{n}+} \mathrm{SOD}+\mathrm{O}_2^{\bullet-}+2 \mathrm{H}^{+} \rightarrow \mathrm{M}^{(\mathrm{n}+1)+} \mathrm{SOD}+\mathrm{H}_2 \mathrm{O}_2 $

  (5)

  $ \mathrm{M}^{(\mathrm{n}+1)+} \mathrm{SOD}+\mathrm{O}_2^{\bullet-} \rightarrow \mathrm{M}^{\mathrm{n}+} \mathrm{SOD}+\mathrm{O}_2^{\bullet-}+2 \mathrm{H}^{+} $

  (6)

  $ \mathrm{M}^{\mathrm{n}+} \mathrm{SOD}+\mathrm{O}_2^{\bullet-}+2 \mathrm{H}^{+} \rightarrow \mathrm{Ce}^{4+}+\mathrm{H}_2 \mathrm{O}_2 $

  (7)

  $ 2 \mathrm{Ce}^{4+}+\mathrm{H}_2 \mathrm{O}_2 \rightarrow 2 \mathrm{Ce}^{3+}+\mathrm{O}_2+2 \mathrm{H}^{+} $

  (8)

  Furthermore, augmenting the ratio of Ce³⁺ to Ce⁴⁺ on the surface of the material has been demonstrated to amplify the SOD-mimetic capabilities of cerium oxide nanozymes. An in-depth analysis of the influence of cerium's oxidation-reduction potential on both its SOD-like activity and the decomposition of hydrogen peroxide was conducted through the synthesis of monovalent cerium-based metal-organic frameworks, Ce(Ⅲ)BTC and Ce(Ⅳ)BTC. Among these, the Ce(Ⅳ)BTC, with a higher oxidation state, emerged as a more potent SOD-mimetic nanozymes. Electrochemical data indicated that the reduction potential of the cerium-MOFs was contingent upon the redox state of cerium. Specifically, the reduction potential of Ce(Ⅳ)BTC was positioned between the redox potentials necessary for the reduction of superoxide radicals, endowing it with a greater thermodynamic propensity to catalyze this reduction compared to Ce(Ⅲ)BTC. Meanwhile, the oxidizing nature of Ce(Ⅳ) makes Ce(Ⅳ)BTC catalytically active for H₂O₂, and the low-priced Ce(Ⅲ)BTC nanozymes hardly accelerate the decomposition of H₂O₂.

  Deeply influenced by the natural and structural mechanisms of SOD, where copper (Cu) acts as the catalytic center, Lin et al. skillfully devised a robust copper-containing metal-organic framework (Cu-MOF) [60]. This framework is crafted to emulate the role of SOD, enabling effective identification and neutralization of O₂^•− within biological contexts. In addition, given the importance of the conductivity of the electrocatalyst for the performance of electrochemical sensors, a thiophene derivative containing a conjugated double bond, 2,5-dicarboxylic acid-3,4-ethylenedioxythiophene (H₂L), was specifically chosen in this study, which allows for the smooth transfer of electrons through the lattice structure of the Cu-MOF material and thus with the Cu-ion. The biomimetic SOD-like Cu-MOF was prepared by forming a stable coordination structure with copper ions. For the inaugural application, the biomimetic SOD-analogous Cu-MOF material was utilized in the electrochemical assay for the reduction of O₂^•− both within cellular environments and in living organisms. It exhibited remarkable specificity and acute responsiveness to the detection of O₂^•−. It is especially significant to highlight that the electrochemical reduction, conducted at a potential of -0.05 V, adeptly circumvents interference from other physiological molecules that may be electrochemically reactive. This approach guarantees the precision and dependability of the detection outcomes.

  Furthermore, the SOD-mimetic capability of the Cu-MOF, notably its efficacy in neutralizing O₂^•−, significantly expands its potential for superoxide anion elimination within cancerous cells. This biomimetic material, anticipated to substitute for natural SOD across a range of applications, also paves the way for innovative concepts in the realm of functional material design and biomolecular emulation. These advancements hold immense potential for the development of biosensors, the elucidation of physiological processes, and the advancement of disease diagnostics.

  2.1.5   MOFs mimicking catalase (CAT)

  CAT is crucial in biological systems for decomposing H₂O₂ into water and oxygen, protecting cells from oxidative damage [61]. In materials science, MOFs are gaining attention for their potential as drug carriers, enhancing drug stability and bioavailability through their porosity. Like SOD, CAT neutralizes hydrogen peroxide, preventing oxidative damage. Scientists are developing MOFs to mimic CAT's catalytic capabilities. The development of MOFs that mimic CAT, as depicted in the timeline, as shown in Fig. 5 [62-66], provides a comprehensive overview of the progress in replicating the functionality of the enzyme.

  Figure 5

  

  Figure 5.  A brief development timeline for MOF-based simulation of CAT. All figures are reproduced with permission. TEM of MnTCPP–Hf–FA. Reproduced with permission [62]. Copyright 2019, American Chemical Society. SEM of MOF Eu-pydc. Reproduced with permission [63]. Copyright 2020, Elsevier B.V. TEM of Ce-MOF. Reproduced with permission [64]. Copyright 2021, Elsevier B.V. TEM of Ce-MOF. Reproduced with permission [65]. Copyright 2023, American Chemical Society. SEM of Co-MOF. Reproduced with permission [66]. Copyright 2024, Elsevier B.V.

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  Researchers, including Tang et al. [62], developed MnTCPP-Hf-FA MOF NPs to address radio resistance in hypoxic tumors by enhancing radiotherapy efficacy through the generation of reactive oxygen species and catalyzing H₂O₂ decomposition. In chemical research, a new room-temperature synthesis method for MOFs was developed by Luo et al. [63], expanding their applications. The Eu-pydc MOF, with peroxidase activity, enables the colorimetric sensing of glucose and cysteine with high sensitivity and selectivity. In cancer therapy, Lin and colleagues designed a Ce-based MOF [65], Ce-MOF, which catalyzes ATP hydrolysis in the presence of H₂O₂, inducing oxidative stress and disrupting cancer cell energy metabolism. Ce-MOF intensifies the H₂O₂/ATP feedback mechanism, promoting autophagy and cell death in cancer cells, offering a new strategy for cancer treatment.

  2.2 MOF-based multi-enzyme mimics

  At the forefront of biochemical research, multi-enzyme mimics based on MOFs are showing their unique appeal. This field skillfully combines the remarkable properties of MOF materials, such as porosity, high specific surface area, and tunability, with the efficient catalytic ability of enzymes, aiming to mimic and hopefully surpass the functions of natural enzymes in some aspects. This innovative research aims to address various challenges faced in industrial production and medical applications. Significantly, the capacity of MOFs for structural fine-tuning and precise organization positions them as optimal microenvironments for sequential reactions catalyzed by dual or multiple enzymes. Such attributes herald their substantial promise in creating nanozymes constructs that embody the functionalities of multiple enzyme mimics. This development is poised to carve out novel avenues in biochemical inquiry and technological innovation, warranting exhaustive investigation by the scientific community [67,68].

  2.2.1   Natural enzyme-MOF nanozyme tandem catalytic system

  The natural enzyme-MOF nanozyme tandem catalytic system is an advanced catalytic platform that combines the high selectivity of natural enzymes with the porous structure and tunability of MOFs. By immobilizing enzymes within the pores of MOFs, this system not only enhances the stability and reusability of the enzymes but also achieves synergistic catalysis of multi-step reactions, demonstrating significant application potential in the fields of biosensing, drug delivery, and industrial catalysis.

  In the latest research report, the researchers have proposed an innovative method that combines bionic metal-organic frameworks (HP-MOF) with natural enzymes to successfully construct a simulated multi-enzyme system for tandem catalysis [69]. This system utilizes the peroxidase-like activity of HP-PCN-224(Fe), as well as the catalytic characteristics of glucose oxidase and uricase, to develop two colorimetric sensors for the detection of glucose and uric acid, respectively. Compared with traditional free enzymes, these immobilized enzymes exhibit significant advantages in terms of pH value and thermal stability. This study not only provides a simple and efficient enzyme immobilization strategy but also builds a bridge for the synergistic action between natural enzymes and artificial analogs. By integrating the advantages of these two components, the researchers have successfully constructed powerful biocatalysts that show great potential in the fields of biosensing, biomimetic catalysis, biomedical engineering, and biofuel cells.

  In the year 2020, the scientific community engineered a multi-enzyme mimetic system through an innovative integration of glucose oxidase (Gox) and MOF-545(Fe), a metal-organic framework endowed with peroxidase-like characteristics. This framework, MOF-545(Fe), functions dually as an immobilization matrix for the enzymes and as a catalyst in a synergistic cascade reaction alongside natural enzymes [70]. The GOx@MOF-545(Fe) composites prepared by surface adsorption are schematically shown in Fig. S5a (Supporting information). The GOx@MOF-545(Fe)-based biosensor offers a sensitive and specific platform for glucose detection, with the enzyme immobilized, demonstrating enhanced reusability and stability under various conditions due to the protective effect of MOF-545(Fe). The integration of mimetic MOF with natural enzymes in tandem catalysis presents a novel strategy for creating efficient, stable, and functionalized chemo-enzymatic catalysts, with significant potential for biosensing, biotherapeutics, and industrial applications.

  2.2.2   MOF nano-enzymatic multi-enzyme catalytic system

  MOFs, as multi-enzyme mimics, feature highly ordered porosity for dispersed catalytic sites, tunable chemistry for tailored catalytic properties, and robust thermal and chemical stability for harsh environments. Their inherent multifunctionality enables the replication of diverse enzymatic activities, positioning MOFs as superior materials for enzyme-mimicking catalysis.

  In 2022, Wang et al. harnessed a solvothermal synthesis involving trimeric uronic acid and Cu²⁺ to replicate the active sites of enzymes [71]. They successfully synthesized an innovative amorphous MOF nanozyme, designated CA-Cu, which demonstrated enhanced laccase and catecholase-like activities surpassing those of laccase and the previously reported MOF818. Furthermore, they delineated a potential catalytic pathway for the Cu(Ⅱ) and Cu(Ⅰ) present in the CA-Cu nanozyme. Solomon et al. conducted an in-depth study of the catalytic mechanisms of natural polyphenol oxidases. They elucidated that the binuclear Cu II active site of these oxidases initially engages and oxidizes bisphenol substrates to form quinones. Subsequently, Cu(Ⅱ) is reduced to Cu(Ⅰ), establishing a binuclear Cu(Ⅰ) site. The oxygen molecule then attaches to this binuclear Cu(Ⅰ) site, resulting in a Cu(Ⅰ) site bonded with an oxygen ligand. The sequence culminates in the reduction of oxygen to water and the oxidation of Cu(Ⅰ) back to Cu(Ⅱ), thus completing the enzymatic catalytic cycle. Guided by the catalytic mechanism of the natural polyphenol oxidase, a conceivable catalytic mechanism for Cu(Ⅱ) in the CA-Cu nanozyme was hypothesized. To simplify and clarify the schematic representation of this mechanism, the catalytic active site of the CA-Cu nanozyme was depicted in a streamlined manner as shown in Figs. S5b and c (Supporting information). The complexation between cyanuric acid and copper was condensed into an N-Cu coordination model to emulate the dinuclear copper active center found in natural polyphenol oxidases.

  Leveraging the modifiable nature of MOF materials through the incorporation of functional groups, in 2023, Hu et al. synthesized NO₂-MIL-53(Cu) via a straightforward hydrothermal process [72]. The Cu-centered regular complex framework endowed this material with the capacity to emulate a spectrum of enzymatic functions, such as peroxidase, oxidase, and laccase activities. To delineate the impact of the functional group, the synthesis of MIL-53(Cu) as a comparative sample was executed, and a comparative analysis of the enzymatic activities between NO₂-MIL-53(Cu) and its counterpart was conducted. Subsequently, the influence of various reaction conditions on the mimetic enzymatic activities was investigated. Capitalizing on the superior peroxidase-like activity of NO₂-MIL53(Cu) at neutral pH values, a colorimetric detection platform for H₂O₂ and glucose in physiological conditions was developed, thereby highlighting the beneficial role of the nitroxide group in MOF materials.

  3. Prospects of MOF-based nanozymes for brain chemistry applications

  In the realm of nanozymes, those derived from MOFs distinguish themselves with their distinctive architectural attributes and customizable catalytic behaviors. These characteristics pave the way for innovative avenues in the field of biomedical applications [73-76]. In the diverse landscape of nanozyme, MOF-based catalysts are particularly prominent. Their distinctive structural characteristics and the ability to fine-tune their catalytic activities introduce unprecedented opportunities within the biomedical sector. In the field of brain chemistry, MOF nanozymes have even shown great potential and application value [77,78]. Brain chemistry is the science of how chemicals in the brain affect neurotransmission, synaptic function and neurobehavior. In the treatment of brain diseases, regulating the chemical environment of the brain, inhibiting inflammation and removing harmful molecules are the keys to treatment, and MOF nanozymes, with their high catalytic activity and stability, show unique advantages in the application of brain chemistry.

  Firstly, MOF nanozymes, with their enzyme-mimicking properties, selectively target and regulate neurochemicals like neurotransmitters and metabolites, thereby enhancing neurotransmission efficiency and neuronal function. This precision offers novel therapeutic strategies for neurodegenerative diseases and depression, highlighting the potential of MOF nanozymes in advancing neurobiological treatments [79].

  Secondly, the application of MOF nanozymes in brain chemistry also includes the removal of harmful molecules in the brain, such as reactive oxygen species and inflammatory factors [80-82]. In the context of brain disorders, these detrimental molecules are pivotal in both the initiation and progression of the conditions. The MOF nanozyme demonstrates an efficacious capacity to eliminate such noxious agents, mitigating inflammatory reactions and safeguarding neuronal integrity. This capability offers innovative perspectives for therapeutic interventions in inflammatory brain disorders and cerebral trauma.

  In addition, MOF nanozyme have good biocompatibility and targeting properties [83-85], which can realize the precise treatment of the brain. By modifying the surface of MOF nanozymes, they can be made to have specific targeting properties, which can precisely reach the brain lesions and reduce the damage to normal brain tissues. This feature makes MOF nanozymes have higher safety and effectiveness in the treatment of brain diseases. In summary, the application of MOF-based nanozymes in brain chemistry has great potential and prospects.

  3.1 Diagnosis of brain diseases

  As a novel class of enzyme mimics, MOF-based nanozymes have emerged as a promising diagnostic tool for brain disorders, attributed to their remarkable catalytic efficiency, inherent stability, and adjustable structural properties. Utilized in clinical assays, these nanozymes benefit from their substantial specific surface area coupled with porosity, uniform distribution of catalytic sites, potent catalytic capabilities, and enduring stability. Their capacity to identify biomarkers indicative of brain disorders, including nucleic acids, proteins, and molecular fragments, within affected brain regions, holds the potential for the early identification of localized brain conditions [86]. The surveillance of neurochemical biomarkers plays a pivotal role in understanding their role in both the normal functioning and pathological processes of the brain, as well as in the diagnosis of a spectrum of neurological conditions. We summarize examples of MOF-based nanozymes for the detection of neurochemicals in Table S1 (Supporting information). Consequently, the development of real-time in vivo detection systems that employ electrochemical or optical methods has become a focal point of contemporary research. Drawing on the mimetic activities of oxidase and peroxidase, nanozymes have been investigated for their ability to track individual or multiple neurochemicals within the brain.

  3.1.1   Acetylcholine (ACh)

  ACh, a pivotal neurotransmitter, is intricately linked to the processes of neuronal signaling and modulation [87]. Medications that foster typical cerebral maturation are advantageous for mitigating memory deterioration and cognitive impairments associated with aging. Imbalances in the levels of choline (Ch) and ACh have been implicated in a spectrum of neurological conditions, such as Down syndrome, Parkinson's disease, Alzheimer's disease, and schizophrenia. Consequently, the precise measurement of Ch and ACh is crucial for diagnosing these brain-related illnesses. Choline, a precursor to ACh, serves a dual role as both a vital nutrient and a neuroprotective agent [88].

  In 2020, Zhao et al. crafted a sophisticated [89], label-free fluorescent biosensor endowed with dual capabilities: peroxidase-mimetic activity and fluorescent signal emission, designed for the quantitative analysis of choline and ACh. This innovative sensor leverages the catalytic properties of the MIL-101(Fe) nanozyme. The operational mechanism of the biosensor is depicted in Fig. 6 and involves a sequence of enzymatic reactions. Initially, acetylcholinesterase (AChE) facilitates the hydrolysis of ACh into choline. Subsequently, choline oxidase (ChOx) acts on choline, converting it to H₂O₂. The MIL-101(Fe) nanozyme then catalyzes the breakdown of H₂O₂, generating highly reactive hydroxyl radicals. These radicals, in turn, convert the non-fluorescent compound terephthalic acid into the intensely fluorescent product, 2-hydroxyterephthalic acid. This orchestrated enzymatic cascade allows for the label-free and sensitive detection of choline and ACh, with respective detection thresholds of 20.0 nmol/L and 8.9 nmol/L. Additionally, the practical utility of the MIL-101(Fe)-based dual-function sensing approach was confirmed through its application in detecting choline in milk samples and ACh in human plasma, demonstrating its effectiveness [90,91].

  Figure 6

  

  Figure 6.  Principle for detection of choline and ACh by the bifunctional MIL-101(Fe) nanozyme based fluorescence biosensor. Reproduced with permission [89]. Copyright 2020, Elsevier B.V.

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  3.1.2   Dopamine (DA)

  In the realm of neurochemistry, DA emerges as a crucial neurotransmitter, exerting a pivotal influence on the modulation of mood, cognition, and motor coordination within the brain [92,93]. Irregularities in dopamine levels have been implicated in the onset of several neurodegenerative conditions, including Parkinson's disease and schizophrenia [94-96]. Therefore, the development of highly sensitive and selective dopamine assays is important for understanding brain function and diagnosing related diseases [97].

  For instance, in 2021, Ren et al. introduced an innovative synthetic nanozyme [98]. This nanozyme is anchored in heme-doped HKUST-1, a face-centered cubic MOF that contains nano-channels, and is utilized as a redox agent for the quantification of DA. The schematic of the preparation of heme-doped HKUST-1, as well as the step-by-step assembly process of the DA sensor and the principle of electrocatalytic detection are shown in Fig. 7. The synthesis of heme-infused HKUST-1 was accomplished efficiently via a single-step hydrothermal process. Subsequently, the sensor, designated as heme-doped HKUST-1/rGO/GCE, was fabricated by integrating the heme-enriched HKUST-1 with reduced graphene oxide (rGO) on a glassy carbon electrode (GCE) surface. This nanozyme composite demonstrated superior electrocatalytic performance for the oxidation of DA, ascribed to the heightened activity of the heme group within the MOF structure, as well as the collaborative interaction between the heme-doped HKUST-1 and rGO components within the nanozyme. The developed sensor showcased remarkable sensitivity, recording a value of 1.224 mA L mol⁻¹, and it achieved a minimal detectable concentration of 3.27 × 10⁻⁸ mol/L for DA. It also provided a linear detection range spanning from 0.03 mmol/L to 10 mmol/L. The sensor's reliability was underpinned by the stabilizing influence of the MOFs on the heme component. Furthermore, this sensor demonstrated its practical utility by effectively quantifying DA in serum samples.

  Figure 7

  

  Figure 7.  Schematic illustration for the preparation of Hemin-doped-HKUST-1 and the stepwise assembly procedure and electro-catalysis detection principle of the DA sensor. Reproduced with permission [98]. Copyright 2021, Royal Society of Chemistry.

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  3.1.3   Uric Acid (UA)

  UA is a waste product produced by the body when it metabolizes purines, which are usually eliminated from the body through the kidneys [99,100]. In brain chemistry studies, the monitoring of uric acid levels is important for the diagnosis and understanding of certain diseases such as stroke, neurodegenerative diseases and metabolic syndrome [101-103]. Uric acid serves as a natural antioxidant within the human body, neutralizing free radicals and shielding cells against oxidative stress-induced harm. Nonetheless, deviations in uric acid concentrations, either excessively high or low, can be indicative of various diseases. Consequently, precise measurement of uric acid is essential for clinical diagnostics and therapeutic management.

  In 2021, Lin et al. developed a strategy for adjusting the structural defects in MOFs to fine-tune the catalytic properties of an artificial nanozyme [104]. They synthesized a series of zeolite imidazolate frameworks, designated as ZIF-L-Co, which featured a progressively relaxed structure. Utilizing ZIF-L-Co-10 mg cysteine (Cys), the assay system was capable of tracking UA concentrations in the striatal region of a mouse brain following ischemia-reperfusion injury. The synthesis and characterization of ZIF-L-Co-10 mg Cys, as well as the online measurement of UA, are depicted in Fig. 8. Cysteine was chosen for its strong binding capacity to Zn²⁺ as a modifier to introduce structural defects into the MOF. By incorporating cysteine into a solution containing Co²⁺ and 2-methylimidazole, a controlled introduction of structural defects was achieved, which, as the cysteine concentration increased, led to an expansion of the specific surface area and a greater exposure of catalytic sites. This enhancement was attributed to the induction of structural defects through the doping process. The resulting ZIF-L-Co could emulate a range of natural enzymatic functions, such as those of ascorbate oxidase, glutathione oxidase, and laccase. The effectiveness of these mimetic activities was notably augmented by the presence of cysteine and was proportional to the extent of doping.

  Figure 8

  

  Figure 8.  Schematic illustration of synthesis and properties of ZIF-L-Co-10 mg Cys and online measurements of UA. Reproduced with permission [104]. Copyright 2021, American Chemical Society.

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  In particular, the ZIF-L-Co nanozyme, fortified with 10 mg of cysteine, exhibited a significant enhancement in its ascorbate oxidase-like and laccase-like activities, with increases of over 5 times and 3 times, respectively, when compared to the unmodified ZIF-L-Co. The introduction of defects was likely responsible for altering the cobalt-nitrogen coordination within the 2-methylimidazole, which in turn led to a distortion of the crystal lattice. This change enhanced the affinity of the framework for oxygen and its characteristics of adsorptive oxidase-like activity.

  3.2 Treatment of brain diseases

  3.2.1   Ischemic stroke (IS)

  Stroke, identified by the abrupt onset of neurological deficits, is a vascular condition affecting the brain. It represents a significant threat to worldwide public health, given its high incidence, potential to cause long-term impairments, and mortality rates [105]. IS accounts for roughly 87% of all stroke incidents, predominantly affecting developing nations [106]. The complex pathophysiology of IS encompasses a range of mechanisms, including excitotoxicity, impaired mitochondrial function, autophagy dysregulation, oxidative stress, and neuroinflammation. Post-ischemic stroke, inflammation plays a pivotal role in both the initial brain injury and subsequent neuronal damage [107]. A critical component of the pathophysiological process is the escalated production of reactive oxygen species (ROS), which is intricately linked to both oxidative stress and inflammatory reactions.

  Accordingly, the reduction of ROS is essential in the therapeutic approach to ischemic stroke. ROS are inherently generated through the metabolism of oxygen and are vital for cellular communication and the preservation of oxidative equilibrium within the body. A disruption in the equilibrium between ROS generation and clearance, which may arise from either a lack of antioxidants or an excessive production of ROS, results in oxidative stress. This can lead to a variety of diseases such as aging [108], diabetes [109], cardiovascular and inflammatory diseases [110], neurological disorders including Parkinson's disease and Alzheimer's disease [111-113], and cancer [114].

  In 2022, Tian et al. developed the Fe₂NC@Selenium (Se) antioxidant nanozyme with multi-enzymatic activities, including SOD and CAT mimicry, synthesized via a wet-chemical strategy with "precursor pre-selection" for cerebral ischemia-reperfusion injury (CIRI) treatment. This nanozyme represents a potential therapeutic advancement in addressing oxidative stress in ischemic stroke [115]. The synthetic route of Fe₂NC@Se with multi-enzyme mimetic activity and its therapeutic use for ischemic stroke reperfusion injury is schematically shown in Fig. 9.

  Figure 9

  

  Figure 9.  Schematic illustration of the synthetic route of Fe₂NC@Se with multi-enzyme mimicking activities and its therapeutic use for reperfusion injury in ischemic stroke. Reproduced with permission [115]. Copyright 2022, Wiley.

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  Selected metal precursors were strategically utilized to form stabilized binuclear iron (Fe₂) centers within nitrogen-enriched carbon frameworks, originating from ZIF-8. This approach yielded the Fe₂NC nanozyme, which demonstrated enhanced activities resembling those of SOD, CAT, and OXD, outperforming the monoatomic iron nanozyme (Fe₁NC). In vitro studies revealed that the Fe₂NC@Se antioxidant nanozyme effectively neutralized excessive ROS, mitigated oxidative stress-induced cellular damage, and suppressed apoptosis. Utilizing a middle cerebral artery occlusion model in Sprague-Dawley rats, the therapeutic efficacy of the nanozyme on CIRI was assessed, uncovering its potential to modulate the ASK1/JNK signaling pathway. The Fe₂NC@Se nanozyme offered significant neuroprotection, characterized by its antioxidant properties, inhibition of oxidative stress-induced apoptosis, reduction in infarct size, and improvement in neurological outcomes. Collectively, the nanocomposite's multifaceted antioxidant enzyme-mimetic activities emulate the body's natural antioxidant defenses, positioning it as a promising agent for ischemic stroke treatment.

  In 2023, Jiang et al. demonstrated that by engineering a Ru MOF-based nanozyme encapsulated within endoplasmic reticulum-targeted liposomes, they devised an innovative strategy for penetrating cellular barriers. This method effectively harnesses the catalytic prowess of a SOD/CAT mimetic system to selectively neutralize mitochondrial reactive oxygen and nitrogen species, offering a hopeful avenue for cellular protection [116]. The customization of ER liposome-encapsulated MOF and its therapeutic mechanism based on oxidative stress modulation of central post-stroke pain (CPSP) is shown in Fig. S6 (Supporting information).

  Additionally, this approach presents a potent therapeutic avenue for managing pain disorders centered around the retina following stroke, by neutralizing free radicals and alleviating pain associated with stroke. Moreover, p-DBSN, functioning as an endoplasmic reticulum-targeting moiety, facilitates the penetration of MOF-based nanozymes across the blood-brain barrier (BBB) and their subsequent accumulation in the neuronal endoplasmic reticulum. Notably, these nanozymes have displayed commendable antioxidant properties and neuroprotection in models of CPSP, affording relief from behavioral disorders and pathological symptoms. These discoveries introduce innovative concepts in the precision targeting of drug delivery and catalytic therapies for CPSP and a spectrum of neurodegenerative conditions. In summary, MOF nanozymes emerge as a hopeful therapeutic option for stroke, adept at reducing oxidative stress and inflammatory reactions while ensuring precise targeting to brain regions of interest. By eliminating ROS/ reactive nitrogen species, sequestering excessive Zn²⁺, and traversing the BBB, these nanozymes present a comprehensive therapeutic strategy for ischemic stroke. Their innovative design and multifunctional capabilities hold significant promise in tackling the intricate pathophysiological aspects of stroke [117].

  3.2.2   Brain tumor

  Glioblastoma multiforme (GBM) is an aggressively invasive brain cancer, characterized by rapid disease progression and a poor prognosis [118]. The immunosuppressive tumor microenvironment of this disease poses challenges to conventional cancer therapies. To overcome these challenges, scientists have constructed a copper-based nanoplatform termed BSO-CAT@MOF-199@DDM (BCMD), designed to promote the immunotherapy of GBM by mediating cuproposis, a form of copper-dependent cell death [119].

  Within the BCMD nanoplatform, MOFs play a crucial role as efficient drug carriers, capable of encapsulating and protecting pharmaceutical molecules such as buthionine sulfoximine (BSO) and CAT. The porous structure of MOFs not only provides a stable microenvironment for the pharmaceutical molecules but also facilitates controlled drug release, ensuring precise delivery within the tumor microenvironment. Furthermore, the environmental responsiveness of MOFs allows for the release of Cu²⁺ in the acidic tumor microenvironment. These Cu²⁺ ions, under the regulation of high levels of ferredoxin 1 within tumor cells, are further reduced to toxic Cu⁺, inducing cuproposis. Additionally, the enhanced targeting and multifunctional integration capabilities of MOFs improve the bioavailability of drugs and enhance immunogenic cell death, activating the immune system and thereby improving therapeutic efficacy. These features enable MOFs within the BCMD nanoplatform to not only increase the stability and bioavailability of drugs but also to enhance therapeutic outcomes, offering a novel strategy for the treatment of cancers such as GBM.

  3.3 Neurodegenerative diseases

  3.3.1   Parkinson's disease (PD)

  PD, the second most prevalent neurodegenerative condition, is marked by a spectrum of motor impairments, including tremors, slow movements (bradykinesia), muscular rigidity, impaired gait, and balance issues (postural instability). Additionally, it encompasses a variety of non-motor manifestations, such as cognitive impairments, psychiatric disturbances, sleep disorders, and sensory deficits [120]. PD impacts various neuronal populations across a few brain regions, with the dopaminergic (DA) neurons of the substantia nigra pars compacta (SNc) being particularly pivotal. Alpha-synuclein (α-syn), a key protein found in Lewy bodies within these DA neurons, is prone to misfolding and aggregation. When α-syn becomes misfolded and accumulates, it can exert toxic effects, contributing to the gradual degeneration of the dopaminergic neurons, which underlies the functional impairments observed in PD [121,122].

  MOF-based nanozyme have emerged as promising tools for alleviating oxidative stress in brain diseases by promoting ROS scavenging. By catalyzing the breakdown of ROS molecules, MOF nanozyme help maintain redox homeostasis and protect neurons from oxidative damage. In addition, the tunable properties of MOF nanozyme allow tuning their catalytic activity and surface chemistry to facilitate targeted ROS scavenging in specific brain regions or cell types. Li et al. developed a MOF@Man liposomal nanozyme system, which involves encapsulating the nanozyme in mannitol liposomes [81]. Fig. S7 (Supporting information) illustrates the schematic representation of the fabrication procedure for the MOF@Man liposomal nanozyme and outlines its mechanism in mitigating oxidative stress and neuroinflammation. This is achieved by preventing the formation of NLRP3 inflammatory bodies and curbing the release of inflammatory cytokines, which is instrumental in the therapeutic approach to PD. The system has demonstrated the capability to effectively traverse the blood-brain barrier, thereby suppressing the genesis and aggregation of pro-inflammatory elements. Additionally, it has been shown to diminish the reactivity of glial cells and the neuroinflammatory reactions, culminating in the efficacious regulation of the pathophysiological processes inherent to PD.

  3.3.2   Alzheimer's disease (AD)

  AD is a neurodegenerative disorder that predominantly affects the elderly population, characterized by the presence of β-amyloid (Aβ) plaques, neurofibrillary tangles, microglial proliferation, dystrophic neuritis, and the loss of neurons and synapses. Despite some advancements in monoclonal antibody therapies targeting Aβ, the therapeutic effects have been limited, necessitating the development of novel treatment strategies.

  To address this challenge, an innovative nanoparticle delivery system known as nanozyme-boosted MOF-CRISPR platform (CMOPKP) has been successfully developed [123]. This system is ingeniously designed to penetrate the BBB and specifically target the microenvironment associated with AD, thereby modulating redox balance. The core mechanism of CMOPKP lies in its modified targeting peptide KLVFFAED (K8), which interacts with advanced glycation end products (RAGE) to actively target regions of AD pathology, effectively overcoming the BBB penetration issue associated with clustered regularly interspaced short palindromic repeats (CRISPR) applications in the brain. Furthermore, an intelligent element built into CMOPKP responds to redox imbalances by triggering the expression of a plasmid-encoded CRISPR a system guided by Nrf2-sgRNA; this promotes the activation of Nrf2 and the subsequent expression of downstream redox genes, restoring redox homeostasis. Additionally, cerium dioxide (CeO₂), as an antioxidant nanozyme integrated into MIL-100, works in concert with the CRISPR a system to effectively eliminate ROS, further enhancing the intervention against oxidative stress in AD pathology. This design not only improves therapeutic efficacy but also reduces potential side effects.

  Moreover, through biomimetic engineering, a neutrophil membrane-coated MOF nanozyme, Neu-MOF/Fla, has been developed [124]. This system can recognize pathological inflammatory signals in AD and deliver anti-inflammatory CO triggered by light, as well as MOF hydrolytic nanozyme, to the brain's lesion areas in an autonomous manner. The cell membrane coating strategy of Neu-MOF/Fla enhances the targeting and BBB penetration capabilities of the drug delivery, allowing it to reach the brain's pathological regions spontaneously. In an Alzheimer's mouse model, Neu-MOF/Fla has shown significant therapeutic effects, capable of suppressing neuroinflammation, reducing the burden of Aβ, modulating the phenotype of microglia, and improving cognitive function.

  These research outcomes not only demonstrate the potential of nanoparticle platforms in regulating the pathological network of AD but also provide strong evidence for the development of new multifunctional nano therapeutic drugs, offering new strategies and broad application prospects for the treatment of AD.

  4. Conclusions and perspectives

  Nanozymes based on MOFs show promise in managing brain chemical disorders by neutralizing ROS and offering precise drug delivery and disease monitoring. Advances in MOF-based nanozymes could enhance catalytic activity and substrate specificity, addressing therapeutic challenges in brain disorders. However, clinical translation requires deeper understanding of nanozyme mechanisms, improved biocompatibility, and cost-effective production. Interdisciplinary collaboration is key to overcoming these challenges and realizing the potential of nanozymes in improving brain disease treatment and human health.

  Future research will focus on several key directions:

  (1) Enhancing catalytic specificity in nanozyme design: Gaining an in-depth understanding of the interactions between the active sites of nanozymes and substrates, with guidance from computational chemistry and structural biology in the design process.

  (2) Optimizing in vivo real-time monitoring sensors: Improving the stability, sensitivity, and biocompatibility of sensors to ensure long-term stable operation and accurate measurements.

  (3) Assessing in vivo metabolism and safety of nanozymes: Investigating the biodistribution, metabolic pathways, and potential toxicity of nanozymes to ensure their feasibility for clinical applications.

  (4) Designing MOF nanozymes capable of penetrating the BBB: Developing nanozymes that maintain stability and activity while overcoming the main obstacle in drug delivery.

  (5) Developing multifunctional integrated MOF nanozymes: Integrating multiple functions, such as antioxidant and anti-inflammatory activities, to provide new strategies for the treatment of complex diseases.

  These research directions will guide future work towards the widespread clinical application of MOF-based nanozymes.

  Declaration of competing interest

  The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

  CRediT authorship contribution statement

  Changmin Liu: Conceptualization, Methodology, Writing – original draft, Visualization, Investigation. Ying Wang: Investigation. Yongqi Bao: Investigation. Yuqing Lin: Supervision, Conceptualization, Writing – review & editing.

  Acknowledgments

  This work was financially supported by the National Natural Science Foundation, China (Nos. 22074095 & 22374103 (Y. Lin)) and Beijing Natural Science Foundation (No. 2222005 (Y. Lin))

  Supplementary materials

  Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.cclet.2024.110652.

  
  
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  Scheme1  Types of MOF-based mimics of natural enzymes and their relevant applications in the field of brain chemistry.

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  Figure 1  A brief development timeline for MOF-based simulation of POD. All figures are reproduced with permission. SEM of Fe-MIL-88NH₂. Reproduced with permission [23]. Copyright 2013, The Royal Society of Chemistry. SEM of MIL-53(Fe). Reproduced with permission [24]. Copyright 2013, Wiley. SEM of HKUST-1. Reproduced with permission [25]. Copyright 2014, Elsevier B.V. SEM of Fe-MIL-88A. Reproduced with permission [26]. Copyright 2016, Elsevier B.V. SEM of 2D Co-TCPP(Fe) nanosheets. Reproduced with permission [27]. Copyright 2016, Wiley. SEM of Cu-MOFs. Reproduced with permission [28]. Copyright 2017, Elsevier B.V. SEM of Ni-MOF. Reproduced with permission [29]. Copyright 2018, Elsevier B.V. SEM of 2D Fe-BTC. Reproduced with permission [30]. Copyright 2020, The Royal Society of Chemistry. SEM of Fe₃Ni-MOF. Reproduced with permission [31]. Copyright 2022, American Chemical Society. SEM of MIL-101(Fe/Co). Reproduced with permission [32]. Copyright 2022, The Royal Society of Chemistry. SEM of FeCo-MOF-H₂. Reproduced with permission [33]. Copyright 2023, The Royal Society of Chemistry and Chinese Chemical Society. SEM of Fe Co-MOF. Reproduced with permission [34]. Copyright 2024, American Chemical Society.

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  Figure 2  A brief development timeline for MOF-based simulation of OXD. All figures are reproduced with permission. SEM of MVCM. Reproduced with permission [38]. Copyright 2015, The Royal Society of Chemistry. SEM of Ce-MOF. Reproduced with permission [39]. Copyright 2017, The Royal Society of Chemistry. HRTEM of Co-Mn NS. Reproduced with permission [40]. Copyright 2019, Springer. SEM of Cu-MOF. Reproduced with permission [41]. Copyright 2022, The Royal Society of Chemistry. TEM images of the Mg/NC. Reproduced with permission [42]. Copyright 2022, Elsevier B.V. FESEM of MVCM. Reproduced with permission [43]. Copyright 2022, Elsevier B.V. TEM of MVCM@β-CD. Reproduced with permission [44]. Copyright 2023, Elsevier B.V.

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  Figure 3  A brief development timeline for MOF-based simulation of laccase. All figures are reproduced with permission. SEM of Cu/GMP. Reproduced with permission [47]. Copyright 2017, American Chemical Society. SEM of Cu/H₃BTC MOF. Reproduced with permission [48]. Copyright 2019, The Royal Society of Chemistry. SEM of UiO-67-Cu²⁺. Reproduced with permission [49]. Copyright 2021, Springer. SEM of Ce-MOFs. Reproduced with permission [50]. Copyright 2022, Elsevier B.V. SEM of Cu-SM-MOF. Reproduced with permission [51]. Copyright 2023, The Royal Society of Chemistry. SEM of Cu-Mn-MOF. Reproduced with permission [52]. Copyright 2024, Elsevier B.V. SEM of Cu-MOF. Reproduced with permission [53]. Copyright 2024, Elsevier B.V.

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  Figure 4  A brief development timeline for MOF-based simulation of SOD. All figures are reproduced with permission. SEM of MOF-818. Reproduced with permission [56]. Copyright 2022, American Chemical Society. TEM of Ce(Ⅲ)- and Ce(Ⅳ)-MOFs. Reproduced with permission [57]. Copyright 2022, American Chemical Society. TEM of Sn-PCN. Reproduced with permission [58]. Copyright 2022, American Chemical Society. SEM of Mn/Cu−C−N₂. Reproduced with permission [59]. Copyright 2023, American Chemical Society. SEM of Cu-MOF. Reproduced with permission [60]. Copyright 2023, The Royal Society of Chemistry.

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  Figure 5  A brief development timeline for MOF-based simulation of CAT. All figures are reproduced with permission. TEM of MnTCPP–Hf–FA. Reproduced with permission [62]. Copyright 2019, American Chemical Society. SEM of MOF Eu-pydc. Reproduced with permission [63]. Copyright 2020, Elsevier B.V. TEM of Ce-MOF. Reproduced with permission [64]. Copyright 2021, Elsevier B.V. TEM of Ce-MOF. Reproduced with permission [65]. Copyright 2023, American Chemical Society. SEM of Co-MOF. Reproduced with permission [66]. Copyright 2024, Elsevier B.V.

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  Figure 6  Principle for detection of choline and ACh by the bifunctional MIL-101(Fe) nanozyme based fluorescence biosensor. Reproduced with permission [89]. Copyright 2020, Elsevier B.V.

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  Figure 7  Schematic illustration for the preparation of Hemin-doped-HKUST-1 and the stepwise assembly procedure and electro-catalysis detection principle of the DA sensor. Reproduced with permission [98]. Copyright 2021, Royal Society of Chemistry.

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  Figure 8  Schematic illustration of synthesis and properties of ZIF-L-Co-10 mg Cys and online measurements of UA. Reproduced with permission [104]. Copyright 2021, American Chemical Society.

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  Figure 9  Schematic illustration of the synthetic route of Fe₂NC@Se with multi-enzyme mimicking activities and its therapeutic use for reperfusion injury in ischemic stroke. Reproduced with permission [115]. Copyright 2022, Wiley.

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