Review—Recent Advance in Multi-Metallic Metal Organic Frameworks (MM-MOFs) and Their Derivatives for Electrochemical Biosensor Application

One of the most common MM-MOF that has been explored is bimetallic MOF. ⁵⁷ As its name, bimetallic MOF consist of two different metal in one framework's architecture. Many strategies can be used to obtain this kind of MOF. Two different metals can directly mix in the synthesis solution or by adding the second metal to the prepared single metallic MOF through an ion-exchange mechanism. The transition metal with two valence states still becomes a favorable choice in this MOFs design due to its abundance on earth and cheaper compared to metals transition with higher valence states. In the bimetallic MOF preparation, one should give full attention to several aspects such as crystal structure, morphology, and electronic properties because the addition second metal node may cause a significant change in those aspects. In terms of crystal structure, the structure of bimetallic MOF strongly depends on the ratio of the two metals and the ligand itself. This dependency is caused by the different ability of the two metals to coordinate with the ligand and the difference of ionic radii that might limit the substitution of the second metal to the host metal. In addition, the different valence states of metals also strongly affect metal-ligand coordination. Mei et al. report the decrease in crystallinity of Ni-MOF based on BTC ligand after Co incorporation. ⁵⁸ Although the MOF structure is maintained even when 100% of Ni ions are replaced by Co ions, the weakening of diffraction peaks indicates the crystal distortion due to metal substitution. In the case of the zeolite imidazole framework, the isostructural of ZIF-8 and ZIF-67, and the slightly different ionic radii of Co²⁺ and Zn²⁺ make the ion exchange between them in the framework seems to be immune to the crystal distortion. ⁵⁹ The substitution of Zn ions with Co ion in the framework was observed to not disturb the crystal structure as well as its morphology, even when the Co ions completely replace the Zn ions. That case is different with the substitution of Zn²⁺ by Co²⁺ in the BDC framework or MOF-5 that was reported to be limited by 25% of Co²⁺ in maximum. ⁶⁰

Kim and Muthuarsu purposed bimetallic NiCu-MOF as non-enzymatic sensor materials. ⁵⁰ The as-synthesized bimetallic NiCu-MOF exhibit interconnected spherical structures at the optimum amount of BTC ligand. Interestingly, unlike Ni-MOF and Cu-MOF, the XRD pattern of bimetallic NiCu-MOF is mostly amorphous with no noticeable peaks. However, as predicted, the bimetallic NiCu-MOF has superior catalytic performance compared with Ni-MOF or Cu-MOF itself. Although the host crystal structure in several cases can be maintained, the second metal incorporation can affect the morphology and surface properties. For instance, the combination of Zn²⁺ and Ni²⁺ forming bimetallic hollow microsphere ZnNi-MOF has been reported by Tian et al. ²⁹ The morphology of this bimetallic MOF can be controlled by varying molar ratios of both Zn²⁺ and Ni²⁺. The increasing amount of Ni²⁺ changes the morphology of ZnNi-MOF from nanosheets to microspheres that are arranged by nanosheets (Fig. 1). Moreover, the addition of Ni²⁺ also significantly increases the sensitivity of ZnNi-MOF that is applied as a sensor material for adenosine detection. In a different report, incorporation of Zn²⁺ into Ni-MOF nanosheets can only increase the surface properties without changing its shape if the maximum ratio of Zn:Ni is 1:3. In that case, the surface area of ZnNi-MOF increases from 37.6 m² g⁻¹ to 40.1 m² g⁻¹. ⁶¹ It has been reported that in the same framework, different metals will possess different tendencies to grow. ⁵⁴ As reported by Song et al., single metallic Ni-MOF and Co-MOF have the shape of the olive-like icosahedron and flying saucer-like tetrakaidekahedron structure respectively, ⁵⁴ that indicating the anisotropic growth phenomenon. The combination of Ni and Co in the same framework resulted in the hexagonal prism structure with eighteen sides indicating isotropous growth.

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The presence of other metal centers in MOF not only impacted structural or morphological properties but also can change the electronic properties of MOFs. Commonly researchers investigate this phenomenon according to the XPS characterization which can comprehensively explain the difference of electronic states between single metal and multi-metal MOFs. ⁵⁷ As an example, compared to Co 2p spectrum of Co-MOF and Ni 2p spectrum of Ni-MOF, the XPS spectrum of both Co 2p and Ni 2p from bimetallic CoNi-MOF provides the combination valence states of Co²⁺/Co³⁺ and Ni^2+/Ni³⁺ that will provide the advantages of multivalent characteristics. Furthermore, as reported by Song et al. this comprises a mixed-valence state affects the enhancement of the electrochemical activity of the bimetallic CoNi-MOF, due to the presence of the more active sites for the attachment of the aptamer strand. ⁶² In another study Li et al. found that the state of Ni 2p has shifted to a lower energy region in bimetallic NiCo-MOF nanosheet compared to Ni-MOF nanosheet, exhibiting the presence of electron transfer from Co to N and Ni. ⁶³ As reported in several studies the strong coordination of the metal and nitrides species may increase the catalytic activity of the material. ⁶⁴ The NiCo-MOF displaying a wide peak of N 1 s from the metal nitrides content at 398.9 eV (Fig. 2). They explained that the presence of the N atom comes from the decomposition of DMF to dimethylamine. For biosensor applications, by using Ni²⁺ and Co²⁺ together with bipyridine dicarboxylic acid (dcbpy) ligand, Hu et al. designed novel bimetallic CoNi-MOF. ²⁷ Dcbpy ligand has several unique properties such as flexibility, stability, and multifunctionality that provide many options in MOF architectural design. The two contained carboxylic groups and two pyridyl N atoms in this organic ligand can act as bridging and chelating modes at the same time. The presence of two transition metal ions Ni²⁺/Co²⁺ possesses a high binding affinity toward biomolecules such as DNA, due to the rich metal-chelating groups on this double helix nucleic acid. Stable bimetallic CoNi-MOF also can be obtained from the combination of these transition metals with azolate based ligand. For example, Song et al. created bimetallic CoNi-MOF using Co²⁺ and Ni²⁺ as metal ions and tetrazol benzoic acid and tri pyridyl triazine as organic linkers. ⁵⁴ The bio affinity of this bimetallic MOF is reported stronger than the single metallic Co-MOF and Ni-MOF in the same treatment.

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Not limited to electrochemical biosensor material, bimetallic MOF was also recently studied as probe materials in luminescent biosensors. Several studies reported that bimetallic lanthanide MOF shows excellent and promising characteristics that are necessary for luminescent-based biosensor application. ^65,66 As an example, Othong et al. designed bimetallic MOF that was constructed from Europium and Terbium as metal nodes and phenylenediacetic as organic ligand via a simple solvothermal method and applied it for anthrax disease detection. ⁶⁷ Bimetallic lanthanide MOF provides several advantages such as sharp emission band, high color purity, and also tunable luminescent properties that can be used for dual emission through mixed Ln(III) centers to get rid of the fluctuate emission from the interferences. ^68,69 Furthermore, through the transfer energy mechanism Ln (III) ion can interact with the analyte target and resulting changeable emission which can be used as an interpretation sensor signal. Still related, using a simultaneous reaction of zinc and cobalt as metal ions and methyl-imidazole as organic linkers Amirzeni et al. designed bimetallic Cobalt-Zinc Zeolitic Imidazole Framework (CoZn-ZIF) as a selective colorimetric probe for sensing application. ⁷⁰ These two-metal centers are connected by the MIM ligan via its nitrogen atoms to construct the framework building. The sample with an equal Co and Zn ratio of 1:1 displays the highest catalytic properties. As they found in morphological characterization, the bimetallic MOF having rhombic dodecahedron shape with both Co and Zn atom dispersed well on the structure. Importantly as shown in Figs. 3A and 3B, they reported that the catalytic activity of the bimetallic CoZn-ZIF toward 3,3',5,5'-Tetramethylbenzidine-hydrogen peroxide(TMB-H₂O₂) was better than the horseradish peroxidase (HRP) enzyme.

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The incorporation of three different metals in the framework structure known as trimetallic MOF was published in several studies during the last decade. Commonly this material was used as an electrocatalyst for oxygen evolution reaction (OER) or hydrogen evolution reaction (HER). ^71–74 Despite still limited studies that explored trimetallic MOF in biosensors application, the resulting properties of this material are interesting to be studied. For example, Meshram and Sontakke investigate the comparison characteristics of monometallic Ni-MOF, Ce-MOF, Zr-MOF, and trimetallic Ni–Ce–Zr MOF. ²⁶ According to XRD characterization they reported that the single metallic Ni-MOF displayed strong diffraction at crystal planes of (100), (001), (101), and (210). Moreover, Ce-MOF shows major peaks at 2θ of 9.9, 14.5, 20, 22.3, 24.2, and 28.3. While the single metallic Zr-MOF has major peaks at crystal planes of (111), (200), (311), (222), and (531). Then, in the XRD pattern of trimetallic Ni-Ce-Zr MOF, all of these fundamental peaks are well presented and retained, however, the strongest peaks intensities were found to be different within each single metallic MOF form, which might be due to the change orientation of crystal growth direction after the addition of more metal ions in the framework structure. In addition, they found that the incorporation of metal ions also changes the surface morphology both in bimetallic and trimetallic MOF form, such as the possession of an enhanced porous network after the Ce metal was introduced into a single metallic Ni-MOF. Furthermore, the surface area of Ni–Ce–Zr MOFs was reported higher compared its monometallic and even its bimetallic (NiCe, CeZr, NiZr) MOF. As can be seen in Table I. this study showed that the MOF surface area linearly increase with the introduction of additional metal nodes in the frameworks. The MM-MOF also shows better thermal stability compared with single or monometallic MOF in the TGA analysis.

Designing trimetallic MOF in nanosheet structure will significantly enhance both conductivity and electrocatalytic properties of MOF. Using imidazole ligand Ding et al. successfully obtained 2D trimetallic NiFeCo-ZIF for OER catalyst. ⁷² The single pair electron in the N atom of the Imidazole ligand provides higher electron density and is easier for coordinating with the metal center than the carboxyl-based ligand. The integration of Co, Fe, and Ni center strongly regulates the electronic structure that impacted the catalytic performance of NiFeCo-ZIF. In this study, the Ni-ZIF was used as the core structure while the amount of Co and Fe was used as an additional metal for ion exchange. They explained that the addition of Fe increases the valence of Ni and forms Ni* (Ni with higher valence) which might enhance the Ni atom's ability for accepting electrons and accelerating the charge transfer process. Moreover, the addition of Fe together with Co further initiates the electron transfer of Ni by reducing the density of electron cloud, changing the electron environment, and providing mixed metal synergetic effect, which impacted the increasing conductivity as well as the catalytic activity of trimetallic NiFeCo-ZIF. They further explained that the addition of Fe and Co in Ni-ZIF also results in the increment of electric dipole which reduces the energy barrier of the electrocatalytic process due to the electron diffusing from Ni to Fe and Co, that provides advantages to the adsorption-desorption process in the materials and reactant interface.

The balanced composition of metal salt in trimetallic MOF was studied by Raja et al. by varying the amount of iron, cobalt, and nickel metal precursors and applying it as an efficient electrocatalyst. ⁵² In this study, nickel foam (NF) was used as conductive growth media of the desired trimetallic FeCoNi-MOF architecture. The use of in situ growth media is one effective way to enhance the stability of MOF in the electrocatalytic application without using any binder such as Nafion or chitosan that can decrease the available active site of MOF. ^75,76 The equimolar ratio of Fe:Co:Ni at 1:1:1 successfully resulted in the best performance samples with outstanding efficiency toward the oxygen evolution reaction. The binder-free FeCoNi–MOF/NF also displayed excellent stability even at the application of an extremely large current density of 1000 mA.cm⁻². The binder-free MM-MOFs electrode is attracted tremendous attention since it is predicted that the high electrocatalytic properties of MM-MOFs can be achieved. The problems caused by the binder including decrease conductivity, surface area active, charge transfer kinetics, ions diffusion, and mass transfer, can be diminished. ^77–80

In fact, designing trimetallic MOF or even tetra metallic MOF is more complicated than designing bimetallic MOF. The coordination of four different metals must be considered carefully before the synthesis process. As consequence to maintain the stability of tetra metallic MOF in electrocatalyst applications many studies reported the use of support materials such as Nickle Foam (NF) or carbon materials as growth media in the fabrication process. ^50,70 The in situ growth of MOF on NF provides many advantages such as reducing the internal impedance, reducing the energy barrier, and enhancing the electron transfer mobility. ^52,76,81 As an example, a combination of the Earth-abundant transition metal of FeCoMnNi-MOF74 on NF that synthesized through the hydrothermal method successfully resulted in a multilevel hollow nanostructure material that possesses excellent catalytic activity. ³⁰ They found that the addition of Mn ions increases the conductivity, and the active surface area that proved by a smaller diameter in the Nyquist plot (Rct) and higher double capacitance value (Cdl) compared with before the introduction of this metal ion. The obtained multi hollow nanostructure of as-synthesized FeCoMnNi-MOF74 could expose more metal active sites for more effective and efficient catalytic reaction. Furthermore, they also investigate the electronic states of each metal ion in the resulting FeCoMnNi-MOF-74 after the catalytic reaction. The 2p3/2 peak of Ni 2p shifted around 0.6 eV to lower energy binding, while the peak of Co 2p3/2 and Fe 2p3/2 shifted to the higher binding energy which might be due to the stem from lattice distortion and decomposition of metal-ligand binding coordination. The Mn 2p displayed multiple peaks that were more difficult to be explained, however, they said that the deconvolution of the Mn 2p3/2 spectra could be assigned to Mn²⁺, Mn³⁺, and Mn⁴⁺ species; thus, valence band 3d orbitals are occupied by unpaired electrons. They conclude that the Mn content provides the highest contribution to the excellent electrocatalytic activity of the FeCoMnNi-MOF-74.

Despite only a few publications that studied the use of four different metals in one frameworks structure we found that Blas et al. designed quaternary metallic MOF using Co, Mn, Ca, and Zn as cations and hfipbb (hexafluoroisopropylidene bis benzoic acid) as organic linkers. ⁵³ The effect of mixed metal ratio in the synthesis process of this tetra metallic MOF shows a kind of complex behavior. As they reported when the equimolar ratio (1:1:1:1) was used the incorporation of Ca in the resulting MOF is pretty low. Next, they increase the amount of Ca to 1:1:1:7, and the result shows that the incorporated Ca atom has increased, however, the increment of the Ca atom is not linear with the increment initial amount of Ca. Due to the Ca atoms will only be occupying the octahedral environment in SBU which is already occupied by manganese atoms. Interestingly, when they increase the amount of both Ca and Co (1:1:4:4) simultaneously, higher incorporation of Ca on the MM-MOF structure is obtained, resulting in the equivalent ratio of each metal in the final tetra metallic MOF product. Moreover, the structure of the resulting MOF dominantly shows the ZnPF-1 MOF structure consisting of helical shaped inorganic secondary building units (SBUs) from Zinc atoms in tetrahedral coordination (Fig. 4). The manganese, cobalt, and calcium with octahedral atoms were also introduced in SBUs and affected in the change of crystal symmetry but the original network topology is still maintained.

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As promising material, many studies have been explored to build MOF-on-MOF architectures. The integration of unique properties of two existing MOFs will provide many benefits to its application. The selecting of MOF-on-MOF combination is a very crucial factor. As examples in the analysis of synthesized Fe-MOF-on-Tb-MOF by Wang et al., according to XPS characterizations, they reported that Tb-MOF layer was fully covered by Fe-MOF and the Tb signal is completely not observed (Fig. 5). Interestingly when Tb-MOF on Fe-MOF architecture was used, a strong Tb 3d signal was clearly observed in XPS spectra as well as Fe 2p signal despite its intensity being lower. Thus, the Tb-MOF on Fe-MOF samples provides the advantageous properties of both parent MOF simultaneously. ⁸² In another study Zhou et al. found that the Zn 2p and Zr 3d signal was clearly observed in Zn-MOF-on-Zr-MOF architecture meanwhile the Zn 2p signal disappeared in Zr-MOF-on-Zn-MOF. ⁵⁵ Moreover, the presence of Zr 3d signal in this bimetallic MOF was similar to pure Zr-MOF which means the Zr-MOF-on-Zn-MOF have the same surface performance as the Zr-MOF parents. The observable Zn peaks in Zn-MOF-on-Zr-MOF indicate that Zr-MOF substrate can allow the penetration of Zn ions into the Zr-MOF nodes, on the other hand, the Zr ions with higher valence cannot easily penetrate into the Zn-MOF, thus the Zr-MOF only covered the Zn-MOF surface in Zr-MOF-on-Zn-MOF sample. They explained that this different growth approach will significantly contribute to the different biomolecule adsorption as well as sensing behaviors of Zn-MOF-on-Zr-MOF or Zr-MOF-on-Zn-MOF towards the analyte. The main advantageous aspect of the MOF-on-MOF design is that each MOF does not lose its unique properties even though it has formed a new structure. ^55,82 Inspiring by this Liu et al. fabricating bimetallic Fe-MOF@Ni-MOF as electrocatalyst for oxygen evolution reaction. ⁸³ The Ni-MOF with layered structure and the octahedral Fe-MOF was directly mixed under sonication treatment to form Fe-MOF@Ni-MOF. From morphology characterization, they reported that Ni-MOFs are uniformly wrapped on eight surfaces of Fe-MOF. As their analysis, these two materials have uniform assembly due to electrostatic interaction between positive charge from Fe-MOFs surface and the negative charge of Ni-MOFs surface. The Fe-MOF@Ni-MOF shows superior OER catalytic performance in many aspects compared with other control samples including Ni-MOF, Fe-MOF, Carbon paper, and commercial IrO₂.

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The unique structural configuration of multi metallic MOF opens new advances in the application of its derivative product including metal hybrids such as metal oxides, metal-carbon, metal sulfides, metal phosphate, metal nitrides, etc., and MM-MOF composites, in many fields. ^84–86 Especially in sensing application, the adjustable pores, morphologies, and electronic structures of MM-MOF provide many benefits on its derived product such as enhanced electrical conductivity, stability, bio affinity, as well as catalytic activity. ⁸⁶ To obtain MM-MOF derived product in metal hybrids form, usually, the parent MM-MOF was used as a sacrificial template through heating treatment under certain temperature and gas conditions or through solution-based treatment. ^87,88 One of the most common derived MM-MOF products that have already been explored is metal oxide compounds that can be obtained from sacrificial MOF templating strategy. ^89,90 The metal oxide compounds derived from MM-MOF have superior conductivity and excellent electrocatalytic performance compared with the parent MOF. ^50,91 In fact, since the presence of the abundant organic component in MOF, the conductivity of this material is relatively low. Thus, many strategies have been used to solve this problem including the combination of MOF with conductive material or using MOF just as a sacrificial template. Furthermore, calcination is the easiest method to remove organic ligands from the structure of MOF for obtaining metal oxide compounds. For example, the cobalt-based zeolite imidazole framework (ZIF-67) was used as a template to obtain bimetallic CuCo oxide with a leaf-like structure. In the typical strategy, the carbon Cloth (CC) is used for the growth media of ZIF-67. Then the ion exchange of Cu metal salts in ethanol solution with the ZIF-64 performing bimetallic Cu-ZIF-67. After that, through the calcination process, Cu-ZIF-67/CC will be sacrificed to form the final product of CuCo/CC. ³² In another study Wu et al. reported the synthesize of Nickle Cobalt oxide nanocages as derived material from Co-based MOF. ⁹² Nickle in various forms like oxide, hydroxide, or sulfide having some weakness such as low structural stability and low electrical conductivity. ^93,94 Thus, it is common if nickel oxide was combined with hetero metal such as cobalt to enhance their electrochemical behavior. The combination of Ni and Co MOFs was obtained through the ion exchange of Co-MOF with nickel-metal salt in an alcoholic solution. With the benefit of tuneable MOF structures, the formation of NiCo oxide can be formed in any desired structure which is purposed to create more defects as the active catalytic sites and promote the kinetics reaction as well as shorten the diffusion pathways.

Using MOF on MOF architecture Gu et al. synthesized bimetallic cobalt-nickel ZIF (CoNi-ZIF) that was grown on bimetallic Cobalt Iron Prussian Blue Analogue (CoFe-PBA) and applied it as a template to obtain NiFeCo-Oxides. ³¹ They study the effect of different pyrolysis temperatures towards the resulting nickel/ferric oxides and nickel-cobalt spinel composite. As shown in Fig. 6, At 300 °C the chore shell structure with low crystallinity of CoNiZIF@CoFePBA was still maintained. When the temperature increases to 600 °C a large amount of nanoparticles NiO, Fe₂O₃, and NiCo₂O₄ was observed. And at 900 °C the NiO and Fe₂O₃ formed aggregation nanoparticles that coexisted with NiCo₂O₄ phase.

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Not limited to metal oxides product the derivatization of MM-MOF also can be obtained in metal-carbon form or even metal oxide-carbon form. In this case by using bimetallic NiCo-MOF as a template Jia and co-workers successfully synthesized NiCo₂O₄/CoO@CNT through the pyrolysis process under nitrogen atmosphere and applied it as HIV sensors material (Fig. 7). ³⁵ They investigated the effect of the different atmospheres (N₂ and H₂) that applied during the calcination process towards the obtained derived MM-MOF product. As result, the NiCo-MOF that calcined at 700 °C under nitrogen atmosphere resulting NiCo₂O₄/CoO@CNTs composite meanwhile the NiCo-MOF that calcined using hydrogen atmosphere at the same temperature, only resulting NiCo₂O₄/CoO with the absence of CNTs which possibly due to the organic ligand were almost decomposed in H₂ atmosphere. The presence of CNTs on the N₂ calcined samples was proved by Raman and IR spectroscopy due to the observation of strong peaks in the carbon region besides metal-oxides binding peaks. The synergetic effect of temperature calcination, ligand, and Ni ions provides a favorable environment for the surface growth of CNT. Moreover, they explained that according to XPS characterization, the C 1s spectrum of NiCO-MOF sample that calcined under H₂ atmosphere displayed C–C, C–O, and COO groups. While, in NiCo-MOF sample that calcined under N₂ atmosphere displayed additional peaks of C=O a π–π* which specifically attributed to the CNT from NiCo₂O_4/CoO@CNT. ⁹⁵

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In another study, MM-MOF-derived metal and nitrogen co-dopped carbon (M, N–C) was prepared by Shang et al. using ZnCo-ZIF as a template and mesoporous silica (mSiO₂) as a protected shield during calcination to obtain Co,N co-doped carbon nano framework (Co,N-CNF). ⁹⁶ Interestingly the Zn content disappears from ZnCo-ZIF coated mSiO₂ in the final obtained product. They explained that the loss of Zn content was caused by the volatilization of Zn during the heating step or the dissolution of Zn during the acid etching step in the removing mSiO₂ process. The obtained Co,N-CNF was in the dodecahedral structure of ZIF-8(Zn) and also their crystal structure. Thus, despite the Zn content being removed, the final derived product of ZnCo-ZIF still brings the advantages properties from its parents MM-MOF. In another case bimetallic FeCo-phosphides/carbon composite derived from carbonization of bimetallic FeCo-ZIF was successfully prepared by Zhang et al. ³³ The as-synthesized FeCo-ZIF was passed heating treatment at 800 °C under Ar atmosphere to obtain FeCo-carbon followed by P-doping reaction at 300 °C to obtain the final FeCo-phosphides/carbon composite. They reported that the surface area of FeCo-P/C product was smaller than its parent FeCo-C which might be due to composition evolution during the preparation step. While the SEM images of this final derived product looked similar to the rhombic dodecahedron shape of the parents FeCo-ZIF. In the high magnification of TEM images, they found the presence of many graphite carbons with high crystallinity was induced into the material after the carbonization process which is beneficial for improving conductivity and stabilizing the resulting nanoparticles. Importantly they claimed that the all of FeCo-P/C samples had better catalytic activity compared to without P-doping.

In another case, Young et al. reported that the carbonization of bimetallic NiCo-MOF74 at 800 °C under nitrogen atmosphere (NC-800) successfully produces graphitic carbon-metal composites material, while when the same sample was treated at 350 °C in the air (NC-350) the metal/metal oxides composites were obtained. ⁹⁷ As they explain the unobserved graphitic carbon in NC-350 sample because the low of used temperature that not enough for graphitization. Despite both samples having high specific capacitance, the NC-800 sample displayed slightly better performance due to the synergetic effect of graphitic carbon and mixed metal which enhance the conductivity of the materials that combine with the large surface area and mesoporous structure of the parent MOF which provide an abundance of active sites for chemical reaction.

In practical MM-MOF is also commonly composited with another material to produce derived MM-MOF composite that has excellent properties in electrocatalytic and biosensing application. One of the most interesting ideas is the growth of 2D MM-MOF on 1D carbon nanofiber. The kind of this material was successfully synthesized by Guo and co-workers. ⁹⁸ In detail they designed CoMn-ZIF nanosheet that vertically grows on carbon nanofiber (CNF). As they reported, according to morphologies characterization CoMn-ZIF nanosheet was continuously growing and tightly tacked around CNF surface (Fig. 8). The combination of 1D CNF exhibits high charge transfer efficiency with a short distance, together with a 2D nanosheet of bimetallic CoMn-ZIF that provides many active stive for the catalytic reaction. Making these different dimension composites beneficial for promoting the electrochemical sensing performance.

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One-pot synthesis is a facile synthesize process to obtain the desired MM-MOF through directly mixing all of the metal precursor and organic ligand in one synthesis solution and the nucleation of the desired MM-MOF generally occurs through the solvothermal heating process. Not only the ratio of each metal, the synthesis parameter including solution pH, solubility, and the addition of additive agents also significantly impacted the final MM-MOFs product. Despite direct mixing being the easiest process to synthesis MM-MOF, only mixing two, three, or even four different metals is not guaranteeing the MM-MOF can be formed due to the varying MOF nucleation kinetics of each metal ion. However, a variety of MM-MOF has been successfully synthesized by using this method. As the example's three different metal precursors, FeCl₂, CoCl_2, and MnCl_2, were dissolved in DMF together with Nickel Foam as growth media and ethanol solution containing H₄DOT as an organic ligand to obtain tetra metallic FeCoMnNi-MOF74 through solvothermal heating at 100 °C for 24 h. The nickel-metal ion was obtained from NF without using any additional Ni metal salts in the synthesis process. However, the Ni atom was dominating the metal content of the final MOF structure. As they reported the chemical interaction between NF and organic ligand initiates the production of Ni²⁺ ions. Moreover, since there are O₂ and H₂O₂ molecules in the synthesis solution, the Fe²⁺ and Mn²⁺ oxidized to Fe³⁺ and Mn³⁺ and then stick to NF to produce more Ni²⁺ ions. The synthesized FeCoMnNi-MOF74 displayed excellent catalytic properties when the optimum amount of metal salts ratio was used. As reported, the XRD characterization proved that these materials have a specific pattern of MOF-74. Inductively coupled plasma atomic emission spectroscopy ICP-AES also confirmed that all metals presented well in the final product. ³⁰

As reported by Tian et al. The mixed metal ratio significantly contributes to the final structure of MM-MOF. The molar ratio of Zn²⁺ and Ni²⁺ was varied in the synthesis of ZnNi-MOF. ²⁹ In the synthesis process, zinc metal salt, and H₂BDC were directly dissolved in a mixture of N-dimethylacetamide (DMAC) and ethanol solution, continue with the addition of nickel-metal salt precursors within the ratio of 1:1, 1:2, and 1:3 respectively. Shortly, via 150 °C and 4 h solvothermal heating process, ZnNi-MOF series with different molar ratios were obtained. Interestingly As the increased ratio of Ni content the resulting ZnNi-MOF morphological structure changes from irregular nanosheets to the microsphere sphere assembled from its nanosheets. Meshram, et al. used the one-pot synthesis method to obtain trimetallic Ni–Ce–Zr MOFs. ²⁶ The equimolar ratio of Nickel nitrate, Cerium nitrate, and Zirconium nitrate, and H₂BDC was mixed in DMF solution before solvothermal heating process at 150 °C for 48 h. After the washing and drying step the trimetallic Ni–Ce–Zr MOF powder was successfully collected. The obtained Ni–Ce–Zr MOF displayed a large surface area and excellent thermal stability. Still using the one-pot synthesis approach, Hu et al. firstly dissolve bipyridine dicarboxylic acid ligand in the mixed solution of DMF, ethanol, chlorobenzene and continue with adding cobalt nitrate and nickel nitrate to synthesized bimetallic CoNi MOF. ²⁷ As a favorable method that results in high yield MOF nucleation, solvothermal heating is also used in this process. Furthermore, the Co:Ni ratio was varied of 1:3, 3:1, and 1:1 to obtain the best sample properties. From the morphology characterization, these three samples displayed relatively similar spherical shapes. However, as they reported according to EIS characterization the CoNi-MOF 1:1 sample showed the lowest ΔRct compared with other samples which indicate that CoNi-MOF 1:1 has excellent conductivity. After bioreceptors immobilization steps the CoNi-MOF 1:1 showing highest ΔRct that revealing the excellent immobilization capability of CoNi-MOF 1:1 compared with the other samples.

In post-synthesis modification, the freshly prepared MOF was treated with another metal or ligand precursors or another existing MOF to form MM-MOF materials. In general MM-MOF composites, MOF-on-MOF materials, or unique MM-MOF properties from ion-exchange generally cannot be obtained through direct mixing synthesis. For example in the preparation of Tb-MOF-on-Fe-MOF, Wang et al. synthesis Fe-MOF first and use it as core and the Tb-MOF was used as a sell. That's why MOF-on-MOF materials are also well known as core-shell bimetallic MOF. Shortly the fresh synthesized Fe-MOF suspension was mixed with the dissolved solution of TbCl and followed with the addition of benzene tricarboxylic acid ligand and sodium acetate. The solvothermal heating process at 80 C for 24 h of these mixture solutions successfully produces the high crystalline Tb-Fe-MOF without losing the unique properties of both Tb-MOF and Fe-MOF. ⁸² Another MOF-on-MOF material obtained from post-synthesis modification has been reported by Liu et al. ⁸³ They designed a layered Ni-MOF on octahedral Fe-MOF architecture through the sonication process (Fig. 9). prior, the layered Ni-MOF was obtained from direct mixing of Ni metal salt and terephthalic acid with the hydrothermal method. The formation layered structure of Ni-MOF is caused by the acceleration of deprotonation ligand since the use of potassium hydroxide in the synthesis solution. on the other hand, the octahedral Fe-MOFs were also obtained from mixed Fe metal salt and terephthalic acid ligand in DMF solution.

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Ionic exchange mechanism also can be used as a post-synthesis modification strategy to produce MM-MOF. Metal ions with higher coordination numbers can undergo the cation exchange. The reaction time is a crucial factor in the exchange of metal ions in MOF. As reported by Das et al. 98% of Cadmium ion in Cd-MOF was changed to Palladium ions when the synthesized Cd-MOF was immersed in Palladium nitrate solution for 2 h and all of the Cadmium ions completely changed to Palladium ions after 2 d. Interestingly the palladium ion on its MOF be able to change to cadmium again when the Pd-MOF was immersed in Cadmium nitrate solution. However, the process takes a long time and only 50% of Palladium ions that change to Cadmium ions after 1 d of immersion. This study displayed that the ion exchange in MOF was a reversible process. ¹⁰¹

Fei et al. introduce Mn as catalytic active transition metal into highly robust ZIF-71 to obtain bimetallic Mn-ZIF-71(Zn) with excellent stability and high catalytic properties through metal ion exchange strategy. ¹⁰² In detail, to initiate the ion exchange process the dissolved manganese metal in methanol solution was added to the prepared ZIF-71 and continued with the incubation process at 55 °C for 24 h (Fig. 10). Through this method, according to XRF analysis, they reported that the almost 12% Zn ions in the ZIF-71 change to Mn ions. As reported EDX mapping further confirmed the formation of bimetallic Mn-ZIF-71(Zn) since the exhibited signal of both Mn and Zn within atomic ratio Mn:Zn of 0.126:1. Same as above work by treating Mn-ZIF-71(Zn) with 3 eq molar of Zn solution the presence of Mn ions change back to Zn ions and the atomic ratio of Zn:Mn become 99:1. It further confirmed the reversible process of ionic exchange in the synthesis of MM-MOF.

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Tan et al. prepared trimetallic Zn–Co–Ni MOF via post-synthesis modification through a facile hydrothermal synthesis process. ¹⁰⁰ At first Zn–Co MOF was synthesized by mixing zinc nitrate cobalt nitrate and 2-methyl imidazole ligand in an aqueous solution. shortly through the washing and drying process the obtained Zn–Co MOF was further mixed with nickel nitrate in ethanol solution to obtain Zn–Co–Ni MOF. In this reported work they also combined the synthesized MOF with carbon nanotubes (CNTs) to enhance the sensing performance. The Zn–Co MOF carbon composite has leaf-like particles and this structure is still maintained after the addition of Ni. To enhance the sensing performance of single metallic MOF in glucose sensor application, Kim and Muthuarsu prepared bimetallic CuNi-MOF via post-synthesis modification. ⁵⁰ Shortly, they dissolve Ni metal salts and benzene tricarboxylic acid ligand in a different container, and then these solutions are mixed to obtain Ni-MOF through solvothermal heating at 150 °C for 3 h. In the post-synthesis modification process, the obtained Ni-MOF in DMF suspension was introduced with cooper nitrate as second metal nodes precursors. Another solvothermal heating process at 150 °C for 1 h was used to obtain bimetallic CuNi-MOF. As they reported this synthesized material has a microsphere structure within the interconnected spherical structure in the presence of the optimum amount of BTC ligand. Furthermore, according to elemental mapping analysis, they reported that the stichometry composition ratio of Ni:Cu is around 1:0.4 in the bimetallic CuNi-MOF.

Metal oxide compounds obtained from sacrificial templated MM-MOF attract tremendous attention in recent decades. The synthesis process of this derived MM-MOF is usually designed through two main steps, first synthesizing the parent MOF and then losing the presence of organic linkers using a high-temperature calcination process. Thus, only the mixed metal nodes in the framework building that still present. One of the beneficial aspects of this strategy is the stichometry of each component in the final product can easily be controlled from MOF preparation steps. For example, the CuCo bimetallic oxide has successfully synthesized using ZIF 67 as a template. ³² The Cobalt nitrate was mixed with methyl imidazole in an aqueous solution and carbon clothes (2 × 2 cm) were dipped as growth media of ZIF-67. To obtain bimetallic CuCo-MOF, the carbon cloth with ZIF-67 on its surface soaked to the cooper nitrate in an ethanol solution, continue with 1 h solvothermal heating at 120 °C. The calcination at 450 °C for 2 h burning the imidazole linker and resulted in the desired CuCo oxide carbon cloth composite.

Liu et al. designed carbon-doped bimetallic oxide ZnO/Co₃O₄ from derivatization of bimetallic ZnCo-ZIF. ¹⁰³ The hollow dodecahedra structure in the final product was obtained from the annealing of the parent MOF (Fig. 11). As they reported in the typical synthesis process of ZnCo-ZIF, the Zn and Co were used as metal precursors and methyl imidazole and methyl alcohol were used as organic ligand and as solvent respectively. The nucleation process of this MOF can occur through the aging process at room temperature for one day. The transformation of the ZnCo-MOF to its oxide phase is obtained from the calcination process at 400 °C. In this study the also synthesized the derived single metal oxide of Zn-ZIF and Co-ZIF to compare each property. Calcination temperature plays an important role in the sacrificial MM-OF templated synthesis. Wang et al. synthesized CeO₂/FeOx mesoporous carbon using sacrificial bimetallic CeFe MOF at different calcination temperatures of 500 °C, 700 °C, and 900 °C. ³⁷ When the calcination process was set at 500 °C the well-distributed of CeO₂ and FeOx nanoparticles with highly graphitized carbon matrix was obtained. However, when the higher temperature of 700 °C and 900 °C were used the obtained nanoparticle was agglomerated and formed a larger crystal.

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In another study, Li et al. synthesized vertically standing two-dimensional bimetallic NiCo-MOF on the surface of nanoporous gold via the solvothermal method. ⁶³ The vertical alignment of the resulting NiCo-MOF provides a more accessible site and facilitates fast mast and charge transfer that enhances electrocatalytic reactions. In the preparation process the nickel-metal salt, cobalt metal salt, and amino terephthalic acid ligand were dissolved in the mixed solution of DMF and water. As a template for nucleation growth, the nanoporous gold was immersed in the mixed metal-ligand solution and continued with solvothermal heating at 120 °C for 4 h to obtain the desired material. Moreover, in their experiment, they also used other substrates such as carbon paper, carbon foam, and nickel foam as growth media. However, the obtained CoNi-MOF using these substrates were stacked together in a lying down feature. The pyrolysis process of MM-MOF also can be combined with another shielding template to protect the final derived product from fusion, aggregation, and structural collapse during the heating process at high temperatures. For example Shang et al. coating the ZnCo-ZIF using mesoporous silica to prepare Co,N-CNF material. ⁹⁶ In detail the freshly prepared ZnCo-ZIF was coated using mSiO₂, continue with pyrolysis at 900 °C under N₂ atmosphere, and followed by removing mSiO2 through chemical etching. They claimed that this strategy effectively prevents the irreversible fusion and aggregation of the resulting Co,N-CNF. Moreover, the Co,N-CNF obtained from mSiO2 shell coated displayed superior electrocatalytic activity compared to the samples that pyrolyzed without mSiO₂.

Another strategy was proposed by Tian et al. to prepare bimetallic oxyhydroxide nanosheets using the electric field-assisted hydrolysis method. ¹⁰⁴ Fe-Co MOF was firstly prepared by solvothermal method and bulky MOFs were observed as a product. The electric field-assisted hydrolysis was carried out by cycling the MOF at the potential of 1.2 to 1.8 V for ten times in the alkaline media, in this case, 1 M of KOH. The conversion of Fe–Co MOF to Fe–Co oxyhydroxide was supported by the weak binding of Co–O hence the Co is easily attacked by hydroxide ion in the basic condition. The same procedure was applied to Fe-MOF and the morphology conversion did not observe indicating the important role of Co. Moreover, the electric field helps to destroy the bulk of MOFs into the arranged nanostructures. The prepared Fe–Co oxyhydroxide was reported to have excellent electrocatalytic activity.

Furthermore, metal-sulfide-based material also can be obtained from the derivatization of MM-MOF. As an example, metal-sulfide CdZn-S was applied by Mu et al. as photocatalyst material due to its suitable conduction band potential of <−0.55 eV. ³⁴ In this study the mesoporous CdZn-S polyhedrons were obtained from bimetallic CdZn-ZIF as a template through in situ sulfidation reaction. They reported that compared with the parent bimetallic MOF, the edges of the polyhedron become rough after 0.5 h of the sulfidation process, which indicates the sulfidation reaction started from the edge of the polyhedron. The mesoporous polyhedron structure completely formed after 2 h of the sulfidation process. They further explained that the formation of mesoporous CdZn-S polyhedrons was through anisotropic chemical etching which is similar to the Kirkendall effect. At the initial step of sulfidation via exchange reaction of Zn²⁺ and Cd²⁺ ions, the S²⁻ ions partially etch the edges of polyhedrons resulting in the rough edge surface. The larger ionic radius of S²⁻ than the ionic radius of metal ions, making unbalance diffusion between metal ions and S²⁻ ions which produce voids. This reaction will continue to the side surface until the whole of the polyhedron CdZn-S forms a mesoporous structure.

Triggered by unhealthy human lifestyles, diabetes disease become a serious health problem in recent decades. Not only indicated by high concertation level of glucose in the blood, but the diabetes disease also related with the pancreas dysfunction that failed to produce insulin hormone. ¹⁰⁹ Moreover despite many studies has been reported non-enzymatic glucose sensors using various detection strategies. Until now more than 85% of commercial glucose sensors are based on enzymatic reactions. ¹¹ This indicates that the non-enzymatic glucose sensor is still under development and researchers still trying to find the best sensing material with excellent selectivity and sensitivity to replace the use of natural enzymes. Due to its superior selectivity and efficient catalytic activity, Wang et al. designed an enzymatic glucose sensor based on bimetallic FeNi-MOF immobilized glucose oxidase enzyme (GOx). ¹² Despite this strategy using GOx as a natural enzyme, the FeNi-MOF that is used as a matrix also has mimetic enzyme characteristics, thus the advantages from the combination of the simulated enzyme and natural enzyme can be obtained (Fig. 12). They reported the use of bimetallic FeNi-MOF was better than the use of single metallic Fe-MOF or Ni-MOF. The GOx FeNi-MOF can detect glucose within the range of 0.3–35 mM this is enough for clinical diagnosis the diabetes patient with a glucose concentration above 8 mM. The application of GOx enzyme also potentially to be substituted with another enzyme for different analyte detection.

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Metal oxide compound derived from MM-MOF has attracted much attention, especially in nonenzymatic glucose sensors application due to its excellent electrocatalytic activity and good electrical conductivity that can directly generate the oxidation of Glucose. As an example, Gu et al. designed an electrochemical aptasensor based NiO/Fe₂O₃/NiCo₂O₄ derived from CoNi-ZIF on CoFe-PBA architecture as biosensing platform for insulin detection. ³¹ Since the presence of mixed metal ions with different valence, also a porous structure obtained from the parent MOF, the aptamer strand not only can immobilize over the material surface but also can penetrate to the interior of the framework structure. The formation of G quadruplex from the interaction between aptamer and insulin can lead to the change of aptamer strand that impacted the increasing impedance response of the sensors. This developed impedimetric sensor displayed wide linear range detection of insulin from 0.01 pg ml⁻¹ to 100 ng ml⁻¹ and ultra-low LOD of 9.1 fg ml⁻¹. In another work, Long et al. fabricated a non-enzymatic electrochemical glucose sensor-based CuCo oxide array from derivatization of bimetallic CuCo-MOF that grew on a carbon cloth substrate. ³² The synergetic effect from the carbon cloth and CuCo oxide can promote the conductivity and catalytic activity of the sensors. The purposed sensors successfully achieved ultrahigh sensitivity of 41.02 AM⁻¹ cm⁻² and a low detection limit of 26 nM towards glucose molecules. Xiao et al. fabricated an electrochemical glucose sensor using metal/metal oxide carbon composite that obtained from direct carbonization of bimetallic CuNi-MOF. ¹¹⁰ The synergetic effect from CuO, NiO, and porous carbon showing wide linear range detection of glucose from 0.1 μM to 2.2 mM within 0.06 μM of detection limit, excellent stability, and selectivity toward possible interference substrate. The comparative performance of the MM-MOF-glucose sensor with the other reported work and the commercially available product was presented in Table IV.

Cancer is a very terrible disease due to its difficulty to cure and potentially becoming malignant. Many biological substances such as adenosine, carbohydrate antigen, microRNA, HER 2, protein tyrosine kinase, and etc., were related to several cancer malignancies. As an example, Adenosine, a purine nucleoside, has an important contribution to human pharmacological function such as angiogenesis process, immunological response, and inflammatory reaction. ¹¹³ However abnormal levels of this substance are related to some cancer malignancies. ^29,114 Tian et al. purposed bimetallic ZnNi-MOF for early detection of adenosine. ²⁹ The presence of Ni metal nodes was used to immobilize aptamer as bio receptor due to the strong interaction between Ni metal ions and amino groups of the aptamer strands. The synergetic effect of the Zn and Ni in the frameworks not only provides an abundant active site for aptamer immobilization but also performs an excellent electrochemical activity. This purposed aptasensor shows a wide linear range of adenosine detection from 0.1 pg ml⁻¹ to 100 ng ml⁻¹ within a limit of detection of 20.32 fg ml⁻¹. importantly this MM-MOFs based sensor also shows excellent selectivity according to the neglectable response toward the possible interference in real systems such as uridine, guanosine, cytidine, and mucin 1.

Still related to cancer marker, Carbohydrate antigen 125 (CA 125), is largely found in humans with ovarian cancer. ¹¹⁵ In normal humans, the concentration level of CA 125 is under 35 U ml⁻¹ but, in human with ovarian cancer, this concentration was increased. ¹¹⁶ Detection of CA 125 is very important for early diagnoses and monitoring treatment of ovarian cancer patients. Therefore, Wang et al. purposed an aptamer biosensor-based Tb-MOF-on-Fe-MOF for CA 125 detection (Fig. 13). ⁸² Fe MOF has good stability and excellent catalytic activity, while Tb-MOF has a unique luminescent property and provides a fit pore for G quadruplex formation. Thus, the combination of both Tb-MOF and Fe-MOF provides a promising novel sensing material for CA 125 detection. The fabricated aptasensor successfully achieved a low detection limit of 58 μU ml⁻¹ and a wide linear range of detection from 100 μU ml⁻¹ to 200 μU ml⁻¹ toward CA 125. After 15 d storage, this sensor still showed good stability.

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A novel electrochemical biosensor-based bimetallic CoNi-MOF immobilized complementary DNA probe (cDNA) for mirRNA-126 detection has successfully fabricated by Hu et al. ²⁷ miRNA-126 is an important biomarker of Lung cancers that is necessary to be detected for diagnosis and monitoring of this disease. ¹¹⁷ Compared with isostructural Co-MOF and Ni-MOF, bimetallic CoNI MOF provides superior electrochemical properties. As an example, they reported the impedance (ΔRct) of the modified electrode after Co-MOF and Ni-MOF deposition was 402.6 and 238.1 ohm respectively, meanwhile, the CoNi-MOF having lower ΔRct of 193.3 ohm which indicates the good conductivity of bimetallic CoNi-MOF. Moreover, the large amount of cDNA not only can be immobilized on CoNi-MOF surface via π−π interaction but also can penetrate the structure of the framework, initiate the full occupation of the active sites of CoNi-MOF. As the result, a low detection limit of 0.14 fM and wide linear range detection from 1 fM to 10 nM towards miRNA-126 has been achieved. Moreover, this developed sensor also displayed good reproducibility within 1.01% of relative standard deviation in five different electrodes.

Another cancer marker, protein tyrosine kinase-7 (PTK7), is very important to be detected in the early stage of leukemia disease. ¹¹⁸ Based on this problem Zhou et al. fabricated PTK7 biosensor using bimetallic ZnZr-MOF that synthesized through MOF-on-MOF strategy. ⁵⁵ Zr-MOF is used to strongly immobilize aptamer strand and the Zn MOF is used to enhance the stability of the complex interaction between the aptamer strands and PTK-7. Moreover, they also compared the electrochemical performance between Zn-MOF on Zr-MOF and Zr-MOF on Zn-MOF materials. As result, the Zn-MOF on Zr-MOF modified sensor has a lower LOD of 0.66 pg ml⁻¹ compared with Zr-MOF on Zn-MOF with LOD of 0.84 pg ml⁻¹. This result confirmed that the arrangement strategy in MOF-on-MOF architectures significantly impacted the sensing performance of the obtained material.

In the case of breast cancer, the highest cancer case in women can be detected based on Human epidermal growth factor receptor 2 (HER 2) levels in human bodies. ^119,120 According to this fact, Gu et al. purposed bimetallic ZrHF-MOF dopped carbon dots as a sensing platform for ultrasensitive HER 2 detection. ⁵⁶ Zirconium-based MOF (Zr-MOF) has high biocompatibility and strong bio affinity toward any bioreceptors including DNA strands, aptamers, or antibodies. ¹²¹ However, the low electrocatalytic activity of zirconium causes a restriction in the electrochemical biosensor application. Therefore, combining Zr with another metal such as Hf and dopped of carbon dots significantly enhance the electrochemical performance of this material. The fabricated CDS@ZrHf-MOF based sensor has a low limit of detection toward HER2 of 19 fg ml⁻¹ in concentration ranges of 0.001–10 ng ml⁻¹ as well as good selectivity, stability, and reproducibility. As a comparison Zhou et al. fabricated aptamer-based biosensors for HER 2 detection using bimetallic MnFe-PBA dopped gold nanoparticles. ¹²² This composite has strong binding interaction toward the aptamer strands due to the application of AuNPs. the small size within the homogenous distribution of MnFe-PBA@AuNPs also shows long stability and excellent electrochemical sensing performance. However, without using MOF architecture in the synthesis process this purposed sensor displayed a higher limit of detection compared to the above work. The obtained LOD of HER 2 detection was 0.247 pg ml⁻¹.

In another study of MOFs derivative for cancer detection, Wang et al. purposed CeO2/FeOx embedded mesoporous carbon obtained from the calcination of CeFe-based MOF as a sensing platform for the detection of carbohydrate antigen 19–9 (CA 19–9). ³⁷ Several studies reported that the increasing level of CA 19–9 is possibly indicating various tumor malignancies such as gastric cancer, pancreatic cancer, and liver cancer. ¹²³ Thus, the sensitive detection of CA-19-9 is very needed. The integration of diverse valence Ce and Fe in the framework structure of CeO2/FeOx metal oxide compound shows excellent electrocatalytic activity and high bio affinity toward the specific antibody CA19-9. The immobilization of the antibody occurred via the chemisorption by the ester-like bridging between CeO₂ and the carboxyl group of the antibody. meanwhile, Fe₂O3 is purposed to enhance the electrochemical activity of the electrode. This fabricated sensor provides a wide linear range of CA-19-9 detection from 0.1 mU ml⁻¹ to 10 U ml⁻¹ and a low detection limit of 10 μU ml⁻¹.

HIV infection can lead to acquired immunodeficiency syndrome (AIDS) that has been recognized as a critical threat to human life. In 2017 estimated 36.9 million people living with HIV and almost 940.000 of them ends with the dead. ¹²⁴ So, the detection of HIV is very important to prevent and control the transmission of this virus. In this case of HIV infection detection, reports on the use of MM-MOF cannot be found anywhere. However, for MOFs derivative, Jia et al. purposed an ultrasensitive biosensor-based NiCo₂O₄/CoO@CNTs spinel derived from bimetallic NiCo-MOF for human immune deficiency virus-1 (HIV-1) gene detection. ³⁵ Compared with NiCo-MOF and NiCo₂O₄/CoO, the NiCo₂O₄/CoO@CNTs show superiority in many aspects including high bio affinity toward the probe DNA. Thus, by using NiCo2O4/CoO@CNTs materials this purposed sensor achieved wide linear range detection of HIV-1 DNA from 0.1 pM to 20 nM and a detection limit of 16.7 fM. According to real samples analysis in diluted human serum samples, this fabricated sensor also showed satisfying results with a 101.85%–111.94% range of recoveries for the detection of HIV-1 DNA.

Simultaneous biomarkers detection using one device in once time measurement gives a lot of advantages, especially for the detection of related human metabolic system biomarkers such as Ascorbic Acid (AA), Uric Acid (UA), and Dopamine (DA). ¹²⁵ In detail, ascorbic acid, one of the vital components in the human diet, is very important for cancer prevention, maintaining immunity, and as an antioxidant. ¹²⁶ While, uric acid, a product of purine metabolism, will cause several diseases on its abnormal level including gout, hyperuricemia, and hyperuricemia Lesch-Nyandisease. ¹²⁷ On the other hand, an unbalanced concentration level of dopamine indicates neurodegenerative related disorders such as Parkinson and Schizophrenia. ¹²⁸ Thus, accurate and rapid detection of these analytes is necessary. Inspiring by this, Hu et al. fabricated bimetallic porous Co Fe loaded g-CN nanocomposite for simultaneous non-enzymatic detection of ascorbic acid, uric acid, and dopamine. ¹²⁹ Prior, bimetallic CoFe was obtained through the pyrolysis of bimetallic CoFe-MOF. The combination of effective catalytic activity of Co and Fe as transition metal combined with the presence of mesoporous carbon structure endowed this prepared nanocomposite with tremendous electrocatalytic activity and high adsorption ability toward selective and simultaneous detection of AA, UA, and DA. Furthermore, the LOD of the fabricated sensors towards AA, UA, DA is reported to be 12.55 μM, 0.18 μM, and 0.21 μM respectively. In another study α-synuclein oligomers, a kind of intraneuronal protein aggregates is largely found in many patients with pathogenic species of Parkinson's. ¹³⁰ The detection of α-Syn oligomers is necessary for monitoring the treatment of this disease. Due to this problem, Guo et al. purposed an electrochemical aptamer biosensor for α-Syn oligomers detection based on bimetallic CoMn-ZIF on carbon nanofibers. ⁹⁸ The CoMn-ZIF was vertically grown on carbon nanofibers obtained from the calcination of polyacrylonitrile at 800 °C. This strategy resulted in the more accessible active site for electrochemical reaction and in optimum condition, the purposed sensor displayed excellent recognition ability toward α-synuclein oligomers with calculated LOD of 0.87 fg ml⁻¹ and a wide linear range from 1 fg ml⁻¹ to 0.2 ng ml⁻¹.

The health problem in human life is not only limited to degenerative diseases, cancer diseases, or even infectious diseases. Hazard pollutant that contaminates food, cattle product, or water can also cause serious health problem if ignored. ¹³¹ Despite has the purpose of toxic pollutant detection, in this section, the designed sensor majority involve the use of antibodies or aptamer as bioreceptors. Generally, most of the recent reports on hazardous pollutant detection focused on the use of MOFs derivatives. However, Wen et al. designed two-dimensional bimetallic NiZn-MOF for another environment pollutant detection, phenol. ⁶¹ Phenol is widely used as a chemical reagent in various industries such as pharmaceutical, petrochemical, plastics, pesticides, etc. Unfortunately, phenol is remarkable as a dangerous substance in nature or living organisms, even a large amount of phenol can cause dizziness, muscular retardation, and also liver and kidney damage. ¹³² Again, facile and accurate detection of phenol is really important for society. In this study, they used tyrosinase enzyme to oxidize phenol to quinone species, an electroactive product that can generate the electrochemical signal response. The synergetic effect from Ni MOF that has high catalytic activity and stability also the strong bio affinity toward the amino group in enzyme combined with nontoxic high stability and excellent biocompatibility of Zn displaying the excellent performance of the NiZn-MOF. In the optimum of Zn was used the electrochemical sensing performance of NiZn-MOF significantly increase. Thus this purposed sensor displayed wide linear range detection of phenol from 0.08 μM to 58.2 μM within LOD of 6.5 nM.

In the case of MOFs derivative, an electrochemical immunosensors for monensin detection was successfully fabricated by Hu ad co-workers using Zn-NI bimetallic MOF combined with graphene and AuNPS. ¹³³ The ZnNi-MOF is used as a sacrificial template for obtaining Zn/Ni-ZiF-8 via pyrolysis under a nitrogen atmosphere at 800 °C. The graphene materials were used to increase the electrical conductivity and Au NPS was used to capture the antigen molecules. The synergetic effect of AuNPs, Zn/Ni bimetallic oxide, and graphene composite on the purpose displayed a low LOD of 0.11 ng ml⁻¹ of monensin with a linear range from 0.25 to 100 ng ml⁻¹. As information monensin is a kind of anti-biotics that is commonly used for treating infection and enhancing growth in cattle. ¹³³ This substance can improve the milk production of cows significantly. However, the accumulation of monensin has been reported can cause several disorders such as severe skeletal, muscle rhabdomyolysis, and necrosis. ¹³⁴ Thus, the amount of monensin level is a big concern in food safety management. One of the dangerous toxic pollutants is 4-nitrophenol (4-NP). Nitrophenol is generally used in pharmaceutical production, leather product, and dyes. However, on the above permissible standard level,4-NP can significantly damage human health. ¹³⁵ Based on this problem Wan et al. purposed bimetallic Fe/Ti-oxides composed mesoporous carbon from the pyrolysis of Fe/Ti-MOF-NH₂. ¹³⁶ The excellent functionality of iron oxides combined with high catalytic activity and stability of titanium oxide, as well as the large surface area of carbon porous material, promoting the charge transfer ability electrocatalytic activity of the as-synthesized FeOx/TiO₂@mC toward 4-NP detection. The fabricated sensor displayed wide linear detection of 4-NP from 5–310 μM within LOD of 0.183 μM.

Tobramycin (TOB), one kind of antibiotic, is commonly used as a veterinary drug for medical treatment, due to its low price TOB is also widely used in animal husbandry. ¹³⁷ However, the residues of tobramycin become pollutants in the environment and resulting in a serious threat to human health. Wang et al. design novel bimetallic cerium copper oxide embedded mesoporous carbon from derivatization CeCu-MOF as label-free tobramycin detection. ⁵¹ The CeCu oxide mesoporous carbon obtained from 900 °C calcination temperature exhibit the highest detection sensitivity compared with other prepared samples. This purposed sensor exhibits an ultra-low detection limit of TOB of 2 fg ml⁻¹ with a linear range from 0.01 pg ml⁻¹ to 10 ng ml⁻¹. This excellent result is due to the synergetic effect of each component in CeO2/CuOx@mC including large surface area, variegated chemical functionality, excellent electrical properties, and also strong bio affinity toward the aptamer strand as bioreceptors.

Toxic pollutant such as antibiotic waste is very dangerous when contaminating water or organism in the environment. Thus, examining pollutant concentration and ensuring it's below the standard is necessary. Enrofloxacin (ENR), commonly used as fluoroquinone antibiotic potentially causing bacteria drug resistance the can affect a serious problem on human health. ¹³⁸ Considering this fact Song et al. fabricated a label-free enrofloxacin electrochemical aptasensor based bimetallic CoNi-MOF. ⁶² The desired CoNi-MOF was synthesized using hexaaminotriphenylene (HITP) as the organic linker. the bimetallic CoNi-HITP shows a two-dimensional structure within high biocompatibility and stability in the water solution. Compared with single metallic Co-HITP and Ni -HITP based MOF, the bimetallic CoNi exhibit more defects in its structure due to the presence of the synergetic effect of the diverse metal valence Co²⁺/Co³⁺/Ni²⁺/Ni³⁺. Therefore, the CoNi-HITP can more promote redox reaction and owing superior sensing performance compared with other prepared single metallic samples. The low detection limit of 0.2fg ml⁻¹ toward ENR was achieved by this aptasensor including excellent selectivity, reproducibility, stability, and applicability.

Aside from linear range and limit of detection, materials stability is also a very important aspect in biosensors application. In many studies, materials stability often to be evaluated based on the signal response consistency in every cyclic measurement also known as regenerability or in the different times of storage. ^139,140 If the material were stable, the electrochemical signal response would display relatively similar data in one line curve. After certain cycles or storage time, the electrochemical response of the electrode-modified material will decrease due to the loss of material from the electrode surface or due to the deformation of the material chemically or physically. Table V displays the summary of electrochemical sensing performance including sensitivity, selectivity, and stability parameters of MM-MOF and their derivatives. Table VI lists the performance comparison between MM-MOFs and mono-metallic MOFs as a biosensor.

Table V. Electrochemical sensing performance of multi metallic MOF in electrochemical biosensor application.

Materials	Analyte	Method	Linear range	LOD	Selectivity	Stability	References
CuCo/CC	Glucose	Amperometric	0.05 μM–1 mM	26 nM	Cl−, AA, UA, DA, sucrose, fructose, galactose, maltose and sorbitol	99.12% in 14 d	32
CuNi/C	Glucose	Amperometric	0.1 μM–2.2 mM	0.06 μM	Cl−, AA, UA, DA, sucrose, and lactose	99.7% in 30 d	110
FeNi-MOF/GOx	Glucose	Colorimetric	0.3 mM–35 mM	1.3 μM	K+, Ca2+, sucrose, lactose, and maltose	95% in 7 d	12
NiO/Fe2O3/NiCo2O4	Insulin	EIS	0.01 pg ml−1–100 ng ml−1	9.1 fg ml−1	BSA, CEA, IgG, PSA, AFP, EGFR,	100% in 15 d. Slightly change response in 10 cycles	31
ZnNi-MOF	Adenosine	EIS	0.1 pg ml−1–100 ng ml−1	20.32 fg ml−1	CYT, URI, GUA, VEGF, EGFR, MUC1, CEA, BSA	100% in 15 d. Insignificant change response after 5 cycles	29
TbMOF-FeMOF	CA-125	EIS	100 μU ml−1–200 U ml−1	58 μU ml−1	CA19–9, AFP, IgG, PSA, CEA, and mixture of these interferents with CA125	101.4% in 15 d	82
ZnMOF-ZrMOF	PTK-7	EIS	1.0 pg ml−1–1.0 ng ml−1	0.66 pg ml−1	lysozyme, mouse IgG, PSA, VEGF, HEGF receptor-2, and their mixed solution,	100% in 15 d. Good regenerability in 4 cycles	55
CeO2FeOx@mC	CA-19-9	EIS	0.1 mU ml−1 − 10 U ml−1	10 μU ml−1	VEGF, IgG, CEA, MUC1, EGFR, PSA, AFP and CA125	3.72% of RSD after 14 d	37
CDs@ZrHf-MOF	HER2	EIS	0.001–10 ng ml−1	19 fg ml−1	VEGF, EGFR, PSA, IgG, PTK7, CEA, MUC1 and their mixed solution	108.5% in 15 d. Consistent response in 15 cycles	56
MnFePBA@AuNPs	HER2	EIS	0.001–1.0 ng ml−1	0.247 pg ml−1	Mucin 1, PSA, EGFR, PTK7, IgG	107% in 15 d and stable response in 8 cycles	122
CoNi-MOF	miRNA-126	EIS	1 fM–10 pM	0.14 fM	MM1, MM2, miRNA-141, miRNA-155, and miRNA-21	consistent response in15 d and 14 cycles measurement	27
NiCo2O4	HIV-1 gene	EIS	0.1 pM–20 nM	16.7 fM	Non-complementary DNA, Two-base mismatch DNA	consistent response in 15 d and 15 cycles measurement	35
CoMn-ZIF	α-Syn	EIS	1 fg ml−1–0.2 ng ml−1	0.87 fg ml	Several proteins in human serum, PD-related biomarkers, and several cancer markers	consistent response in 15 d and 10 cycles measurement	98
FeOxTiO2@mC	4-nitrophenol	Amperometric	5 μM–310 μM	0.183 μM	Glucose, NaNO3, MgCl2, KCl, and CaCl2	Stable response in 1000 s amperometry measurement	136
AuNPs/ZnNi-ZIF@graphene	Monensin	DPV	0.25–100 ng ml−1	0.11 ng ml−1	Maduramicin, dinitolmide, nicarbazin, sulfadiazine, sulfamethoxazole, sulfathiazole, olaquindox, tetracycline and clenbuterol	Reduce 7.1% after 50 cycles. Remains 97.4%, 93.3%, and 87.7% after 5, 10, and 20 d	133
CeO/CuO	Tobramycin	EIS	0.01 pg ml− 1 –10 ng ml−1	2.0 fg ml−1	Ca2+, Mg2+, Cl−, ${{\rm{CO}}}_{3}^{2-},$ glucose, L-Alanine, DL-PHE, Doxy, OTC, KANA, ST	106% in 14 d and 1.6% RSD after 10 cycles	51
CoNi-(HITP)MOFs	Enrofloaxcin	EIS	0.001−1 pg ml−1	0.2 fg ml−1	Several antibiotics, small biomolecules, and harmful ions	0.95% of RSD after 15 d	62
NiZn-MOF	Phenol	Amperometric	0.08–58.2 μM	6.5 nM	Mg2+, K+, Ca2+, Zn2+, Fe2+, ${{\rm{SO}}}_{4}^{2-},$ ${{\rm{PO}}}_{4}^{3-},$ ${{\rm{CO}}}_{3}^{2-},$ ${{\rm{NO}}}_{3}^{-},$ AA, UA, Glucose	93% in 5 weeks	61

AA = Ascorbic Acid; UA = Uric Acid; DA = Dopamine; VEGF = Vascular endothelial growth factor; IgG = immunoglobulin G; CEA = carcino embryonic antigen; MUC1 = mucin 1; EGFR = epidermal growth factor receptor; PSA = prostate specific antigen; AFP = alpha-feto protein; CA 125 = carbohydrate antigen 125; EGFR = epidermal growth factor receptor; CYT = cytidine; URI = uridine; GUA = guanosine;PTK7 = protein tyrosine kinase-7; OTC = Goxytetracycline; Doxy = doxycycline; KANA = kanamycin, and ST = streptomycin sulphate.