A comprehensive review of metal-organic framework based biosensors for detection of reactive oxygen species and hydrogen peroxide in biomedical applications

 Corresponding author: Jasim M. S. Jamur Copyright © 2025 Author(s) retain the copyright of this article. This article is published under the terms of the Creative Commons Attribution Liscense 4.0. A comprehensive review of metal-organic framework based biosensors for detection of reactive oxygen species and hydrogen peroxide in biomedical applications Ihsan Ibadi 1, Russol Abdul Salam Faraj 2, Jasim M. S. Jamur 2, * and Arash Vahdatkhah 3 1 Department of Medical Laboratory Technology, College of Health and Medical Technology, Alkunooz University, Basra, Iraq. 2 College of Education for Pure Sciences (Ibn Al-haitham), University of Baghdad, Baghdad, Iraq. 3 Polymer Research Laboratory, Department of Organic and Biochemistry, Faculty of Chemistry, University of Tabriz, Tabriz, Iran. GSC Advanced Research and Reviews, 2025, 24(03), 268-294 Publication history: Received on 09 August 2025; revised on 20 September 2025; accepted on 22 September 2025 Article DOI: https://doi.org/10.30574/gscarr.2025.24.3.0286 Abstract Metal-organic frameworks (MOFs) have emerged as revolutionary materials for developing advanced biosensors, especially for detecting reactive oxygen species (ROS) and hydrogen peroxide (H₂O₂) in biomedical applications. This comprehensive review explores the current state-of-the-art in MOF-based biosensors, covering fundamental principles, design strategies, performance features, and clinical uses. MOFs offer unique benefits, including exceptional porosity (up to 10,400 m²/g), tunable structures, biocompatibility, and natural enzyme-mimicking properties, making them ideal platforms for sensitive and selective detection of ROS and H₂O₂. Recent advances have shown significant improvements in detection capabilities, with limits as low as 0.357 nM for H₂O₂ detection using ZIF-8-based SERS sensors and picomolar sensitivity for various ROS species. The review systematically examines different MOF structures, including pure MOFs, bimetallic systems, and composite materials, emphasizing their mechanisms through electrochemical, optical, and colorimetric methods. Key biomedical applications include cancer diagnosis, cardiovascular disease monitoring, inflammatory condition assessment, and point-of-care testing. Despite notable progress, challenges such as stability under physiological conditions, biocompatibility, manufacturing reproducibility, and regulatory approval remain for clinical translation. Future directions include developing AI-integrated systems, wearable devices, and theranostic platforms that combine sensing with therapeutic functions. Keywords: Metal-Organic Framework; Reactive Oxygen Species; Hydrogen Peroxide; Biosensors 1. Introduction Reactive oxygen species (ROS) and hydrogen peroxide (H₂O₂) play vital dual roles in biological systems, serving as important signaling molecules in normal processes while also acting as indicators of oxidative stress in disease conditions[1]. Under healthy conditions, ROS, including H₂O₂, are produced as byproducts of cellular respiration and enzymatic reactions, participating in immune responses, regulation of cell growth, and programmed cell death. However, high levels of these species are linked to various diseases, such as cancer, diabetes, cardiovascular disorders, neurodegenerative diseases, and inflammatory conditions[2]. Detecting ROS and H₂O₂ is clinically important not only for disease diagnosis but also for monitoring treatment and assessing drug effectiveness. Cancer cells often produce 210 times more H₂O₂ than normal cells, making H₂O₂ detection useful for early cancer diagnosis and treatment monitoring. Likewise, cardiovascular diseases involve increased oxidative stress, with H₂O₂ levels serving as biomarkers for myocardial infarction and other heart conditions[3]. Conventional methods for detecting ROS and H₂O₂ include colorimetry, titration, chromatography, spectrophotometry, and enzyme-based assays. However, these GSC Advanced Research and Reviews, 2025, 24(03), 268-294 269 techniques frequently face limitations such as low sensitivity, poor selectivity, complicated sample preparation, and long analysis times. This has spurred the development of advanced biosensor technologies aimed at providing rapid, sensitive, and selective detection methods[4]. Metal-organic frameworks represent a revolutionary class of crystalline porous materials constructed through the selfassembly of metal ions or clusters (nodes) connected by organic ligands (linkers) via coordination bonds. This unique hybrid organic-inorganic architecture endows MOFs with exceptional properties that make them ideal candidates for biosensing applications[5, 6]. The most distinctive feature of MOFs is their ultrahigh porosity, with some materials achieving surface areas exceeding 10,400 m²/g. This exceptional porosity, combined with tunable pore sizes ranging from microporous (<2 nm) to mesoporous (2-50 nm) dimensions, enables efficient molecular recognition and mass transport. The modular nature of MOF synthesis allows for precise control over pore geometry, surface chemistry, and functionality through judicious selection of metal nodes and organic linkers[6]. Biocompatibility represents another crucial advantage of MOFs for biomedical applications. Iron-based MOFs, particularly those of the MIL series (Materials of Institute Lavoisier), have demonstrated excellent biocompatibility due to the abundance and essential nature of iron in biological systems. Similarly, zinc-based MOFs such as ZIF-8 (Zeolitic Imidazolate Framework-8) exhibit low toxicity and good stability under physiological conditions[7, 8]. Despite the rapidly expanding field of MOF-based biosensors, a comprehensive and focused evaluation of their application for the detection of ROS and H₂O₂ in biomedical environments remains limited. This review aims to bridge that gap by systematically analyzing the fundamental principles of MOF design, the mechanisms and technologies that underpin their exceptional performance in ROS and H₂O₂ detection, and the specific biomedical scenarios where these platforms offer transformative advantages. Special emphasis is placed on recent innovations in MOF architectures, including bimetallic, composite, and nanozyme systems, which have pushed the boundaries of sensitivity, selectivity, and functional integration. Unlike previous reviews that often treat MOF-based biosensing in general terms, this article provides a detailed comparative assessment of methodologies, discusses translational challenges, and highlights emerging trends such as artificial intelligence integration and wearable diagnostics. By dissecting both technological advances and practical deployment barriers, this review offers valuable perspectives for researchers and clinicians aiming to harness the unique potential of MOF-based biosensors for precision medical diagnostics and real-time oxidative stress monitoring. 2. Detection Principles and Mechanisms 2.1. Electrochemical Detection Mechanisms Electrochemical detection represents one of the most widely employed transduction methods for MOF-based H₂O₂ and ROS biosensors due to its high sensitivity, rapid response, and compatibility with miniaturized devices. The electrochemical behavior of MOFs in biosensing applications primarily relies on the redox activity of metal centers and the electronic properties of the framework structure[9]. In direct electrochemical sensing, MOFs facilitate electron transfer between the analyte and the electrode surface without requiring additional mediators. Conductive MOFs, particularly those containing π-conjugated organic linkers or multiple metal nodes, enable efficient charge transport through the framework. Two-dimensional (2D) MOFs have shown exceptional promise in this regard, with some materials achieving conductivities exceeding 1 S cm⁻¹[10]. Many MOFs exhibit intrinsic peroxidase-like activity, functioning as artificial enzymes (nanozymes) that catalyze the reduction of H₂O₂. This enzymatic behavior is particularly pronounced in MOFs containing transition metals such as iron, copper, manganese, and cerium, which can undergo reversible redox cycling. Iron-based MOFs, especially those of the MIL series, demonstrate exceptional peroxidase activity through Fe³⁺/Fe²⁺ redox cycling[11]. Dou et al.[12] innovatively integrated chemically modified DNAzyme probes with UiO MOFs to fabricate an electrochemical sensor capable of binary detection of H₂O₂ and hypochlorous acid (HClO)(Fig. 1A). The DNAzymes undergo cleavage upon interaction with the ROS targets, triggering the controlled release of electrochemical signal molecules (doxorubicin and methylene blue) encapsulated within the MOF matrix. This yields two distinct voltammetric peaks correlating to ROS identity and concentration. Their sensor demonstrated sub-nanomolar detection limits for both analytes in living cancer cells, offering high sensitivity and selectivity. This dual detection addresses the complexity of ROS interplay in biological systems and represents a significant advance in multifunctional electrochemical biosensing. Jiang et al. [13] performed a thorough study on the development and application of a bimetallic Fe/Co-MIL-88(NH₂) metal-organic framework (MOF) as a superior peroxidase-mimicking nanozyme for sensitive biomedical biosensing (Fig. 1B). By employing a 1:1 ratio of Fe(III) and Co(II) ions during the solvothermal synthesis with 2-aminoterephthalic GSC Advanced Research and Reviews, 2025, 24(03), 268-294 270 acid as the ligand, they achieved a stable hexagonal rod-like MOF architecture, as validated by PXRD, TEM, EDS, and DLS analyses. The inclusion of cobalt notably enhanced the catalytic properties of MIL-88, producing a nanozyme with Michaelis constants (Km) for H₂O₂ and TMB that were 3–5 times lower and catalytic turnover (kcat) 5–10 times higher than natural horseradish peroxidase (HRP) and most previously reported HRP-mimicking MOFs. Kinetic studies confirmed that this bimetallic MOF’s highly exposed, unsaturated Fe and Co sites provided excellent affinity and rapid signal generation for peroxidase reactions, outperforming monometallic analogues. Jiang’s team further demonstrated the clinical potential of this nanozyme by coupling it with glucose oxidase (GOx) in a cascade reaction format. Here, the Fe/Co-MIL-88(NH₂) was functionalized with an anti-CD63 aptamer to specifically capture extracellular vesicles (EVs) from cell cultures or serum; these vesicles were then labeled with antibody-conjugated GOx, enabling on-bead generation of H₂O₂ from glucose, which the MOF subsequently converted together with oxidizing TMB for straightforward colorimetric readout. The resulting assay achieved a detection limit of 7.8 × 10⁴ EV particles/mL, which is at least two orders of magnitude more sensitive than standard ELISA or nanoparticle tracking analysis. Figure 1.A) The schematic illustration showing (A) the preparation of (DNA–MB)/UiO and (DNA–DOX)/UiO, (B) the activation mechanism of DNAzyme cleavage by HClO and H2O2, and (C) the simultaneous electrochemical detection of HClO and H2O2. B) A schematic illustration of EVs enrichment and GOx labeling Zhang et al.[14] conducted an in-depth investigation into how nanostructure engineering of the well-known copperbased MOF, HKUST-1, influences its performance as an electrochemical sensor for hydrogen peroxide (H₂O₂) detection (Fig. 2). Through a controlled room-temperature synthesis strategy, they fabricated both two-dimensional (2D) nanosheet and three-dimensional (3D) octahedral morphologies of HKUST-1. Comprehensive morphological and structural analyses using SEM, TEM, and PXRD confirmed the successful preparation of distinct geometric forms, with the 3D octahedral variant exposing a higher density of catalytically active Cu²⁺ sites on its well-developed facets. When these MOFs were drop-cast onto glassy carbon electrodes, the 3D HKUST-1-modified electrodes demonstrated markedly improved electrocatalytic activity for H₂O₂ reduction compared to their 2D counterparts, as evidenced by cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS) results that showed lower charge-transfer resistance and higher faradaic currents. The sensor based on 3D HKUST-1 achieved an impressively wide linear detection range (2 μM to 3 mM and 3 to 25 mM) and a low detection limit of 0.68 μM for H₂O₂, outperforming many previously reported MOF-based sensors. Importantly, the platform exhibited strong anti-interference capability, excellent reproducibility, and stability in the electrochemical detection of H₂O₂ even within complex matrices such as milk samples. This practical application validated the sensor’s robustness and selectivity, demonstrating its potential utility for food safety and biomedical diagnostics. GSC Advanced Research and Reviews, 2025, 24(03), 268-294 271 Figure 2 Schematic illustration of Cu-MOFs detecting H2O2 from the milk sample using the electrochemical method 2.2. Optical Detection Mechanisms Optical detection methods offer advantages including non-invasive measurement, real-time monitoring capabilities, and compatibility with biological samples. MOF-based optical biosensors employ various mechanisms, including fluorescence modulation, colorimetric changes, and luminescence enhancement or quenching[15]. Fluorescence-based MOF biosensors operate through several mechanisms, including photoinduced electron transfer (PET), Förster resonance energy transfer (FRET), and inner filter effects. The inherent luminescent properties of many MOFs, particularly those containing lanthanide metals or π-conjugated organic ligands, provide excellent platforms for fluorescent sensing[16]. ZIF-8 has emerged as an exceptional fluorescence quencher, demonstrating 78.39% quenching efficiency for probe DNA molecules. The quenching mechanism involves π-π stacking interactions and electrostatic interactions between the MOF and fluorophore-labeled probes[17]. Colorimetric detection offers the advantage of visual observation without requiring sophisticated instrumentation, making it particularly suitable for point-of-care applications. MOF-based colorimetric sensors typically employ the nanozyme activity of the framework to catalyze chromogenic reactions. The most common approach involves the use of peroxidase-like MOFs to catalyze the oxidation of colorless substrates such as TMB in the presence of H₂O₂, producing blue-colored products with characteristic absorption at 652 nm[18]. Liu et al.[19] developed a ZIF-8@Au NPs hybrid SERS sensor for ultra-sensitive H₂O₂ detection (Fig. 3). The sensor utilizes the dual function of ZIF-8, serving as a nanoreactor for in situ growth of gold nanoparticles and as a selective filter to block interfering biomolecules, and enables real-time tracking of H₂O₂ released from living cells after drug stimulation. The luminescent and quenching abilities of ZIF-8 facilitated selective detection by shielding non-specific proteins, while SERS provided amplification of the detection signal. The sensor reached a low detection limit of 0.357 nM for H₂O₂ and allowed for visual differentiation of healthy versus cancerous cell behaviors. GSC Advanced Research and Reviews, 2025, 24(03), 268-294 272 Figure 3 Schematic illustration of the “one-pot” synthesis of the ZIF-8@Au NPs SERS sensor and the detection concept for H₂O₂ released from living cells Elgazar et al.[20] presented an innovative MOF-based biosensor that exploits the exceptional fluorescence quenching properties of ZIF-8 (Zeolitic Imidazolate Framework-8) for ultra-sensitive and selective detection of COVID-19 RNA sequences. The research highlights that ZIF-8, with its nanometer-scale porosity and large surface area, readily adsorbs FAM-labeled single-stranded DNA probes through strong π–π stacking and electrostatic interactions, resulting in up to 78.39% quenching efficiency. When the complementary COVID-19 RNA sequence is present, it hybridizes with the probe DNA, causing displacement from the ZIF-8 surface and thus restoring fluorescence, a highly specific and reversible mechanism. The biosensor demonstrated a remarkable detection limit of 6.24 pM, which is substantially lower than most previously reported nucleic acid biosensors, enabling early-stage viral detection and robust discrimination against single-base mismatches. The platform showed excellent selectivity and reliability even in complex samples such as clinical throat swab extracts, underscoring its real-world diagnostic utility. The study’s (Fig. 4) provides a concise schematic diagram, visually describing the stepwise process: initial probe adsorption/quenching on ZIF-8, RNA-induced hybridization, and fluorescence “turn-on,” making the workflow transparent and accessible for translation across other biosensing contexts. GSC Advanced Research and Reviews, 2025, 24(03), 268-294 273 Figure 4 Detection Mechanism of ZIF-8-based Fluorescent Biosensor for the Target COVID-19 RNA Zhou et al.[21] developed an innovative dual-mode biosensor by decorating an amino-functionalized UiO-67(Zr/Cu) metal–organic framework (MOF) with luminescent gold nanoclusters (AuNCs), enabling both colorimetric and fluorometric detection of hydrogen peroxide (H₂O₂) in biological environments. The NH₂-UiO-67(Zr/Cu) MOF features bimetallic nodes where the presence of copper not only imparts robust peroxidase-like nanozyme activity but also, in synergy with Zr, supports high structural stability and biocompatibility. The sensor’s working principle leverages two complementary mechanisms: First, its peroxidase-mimicking function converts 3,3′,5,5′-tetramethylbenzidine (TMB) to a blue oxidized product upon contact with H₂O₂, yielding a strong and quantifiable colorimetric signal at 652 nm. Second, the emission intensity of the AuNCs (around 420 nm) is quenched proportionally in the presence of H₂O₂, producing a sensitive fluorescence turn-off readout. Zhou and colleagues demonstrated that these two signal outputs are both linear and highly sensitive to H₂O₂ levels, with low detection limits (down to 0.39 μM for colorimetric and even lower for fluorometric mode) and a wide dynamic range, making the system reliable for real bio-sample analyses such as serum and cell extracts. Importantly, their (Fig. 5) presents a clear schematic integrating both aspects: it visually explains how H₂O₂ exposure triggers the nanozyme-mediated TMB oxidation (bluing the solution for visual readout) while simultaneously quenching the MOF’s inherent fluorescence (for spectrometric quantification). GSC Advanced Research and Reviews, 2025, 24(03), 268-294 274 Figure 5 Schematic integrating both how H₂O₂ exposure triggers the nanozyme-mediated TMB oxidation (bluing the solution for visual readout) while simultaneously quenching the MOF’s inherent fluorescence (for spectrometric quantification) 3. MOF-Based Biosensor Platforms Metal-organic framework-based biosensor platforms represent a diverse and rapidly evolving field, with different architectural designs offering unique advantages for the detection of reactive oxygen species (ROS) and hydrogen peroxide (H₂O₂) in biomedical applications. This section provides a comprehensive overview of the major categories of MOF biosensor platforms, their synthesis methodologies, and performance characteristics. Table 1 Classification of MOF biosensor performance MOF Type Detection Method Target Analyte Detection Limit Linear Range Application ZIF-8 (SERS) SERS H2O2 0.357 nM 0.357 nM - 10 μM Living cells Cu@ZIF-8 Electrochemical H2O2 0.46 mM 0.5-5 mM Milk samples UiO-66-NH2 Fluorescent H2O2 0.002 μM 0-750 μM Smartphone detection MIL-53(Fe) Colorimetric H2O2 0.25 mM 0.25-20 mM Glucose sensing MIL-101(Fe/Co) Colorimetric H2O2 0.26 μM 1-80 μM Tetracycline detection PCN-222Fe@PAA Colorimetric H2O2 0.06 mM pH 4-8 Physiological pH HKUST-1 Electrochemical H2O2 1.2 μM 5-850 μM Food analysis Fe3Ni-MOF-Ar Colorimetric H2O2 0.15 μM 0.5-120 μM Antioxidant capacity Cu-MOF Colorimetric H2O2 5 μM 5-300 μM Biosensing GSC Advanced Research and Reviews, 2025, 24(03), 268-294 275 Ag-Bi-BDC Electrochemical H2O2 0.0201 μM 0.01-10 μM Cancer cells Tb-MOF Fluorescent ROS 6.24 pM 0.1-1000 nM Cell imaging FeCo-MOF-H2 Colorimetric H2O2 0.06 mM 0.1-10 mM Glutathione detection NH2-UiO67(Zr/Cu) Dual-mode H2O2 0.0093 μM 0-750 μM Point-of-care Zr/Pr MOF Dual-mode miRNA 0.1 pM 0.1-100 pM Cancer diagnosis MOF-808@PEI Electrochemical H2O2 9-fold enhancement pH 7.4 Enhanced activity 3.1. Structural Classifications and Platform Categories 3.1.1. Pristine MOF Platforms Pristine MOFs represent the foundational biosensor platforms that rely solely on the inherent properties of the metalorganic framework structure for analyte detection. These single-component systems have demonstrated remarkable capabilities across various detection mechanisms. Liu et al.[22] presented an innovative strategy utilizing ZIF-8 as both a nanoreactor and a molecular sieve in the fabrication of highly sensitive biosensors for hydrogen peroxide (H₂O₂) detection (Fig. 6). In their approach, ZIF-8’s highly porous, crystalline framework served as a scaffold for the in situ growth of gold nanoparticles (AuNPs), resulting in a robust ZIF-8@Au hybrid. This design offered dual advantages: first, the uniform distribution of catalytically active AuNPs within the MOF’s cavities significantly enhanced the sensor’s signal strength by boosting the surface-enhanced Raman scattering (SERS) effect. Second, ZIF-8 functioned as a sizeand charge-selective barrier, effectively shielding the embedded AuNPs from nonspecific adsorption of macromolecules, proteins, and other common interferents present in complex biological samples. Functionally, the ZIF-8@Au sensor exhibited an impressive limit of detection for H₂O₂ down to 0.357 nM, surpassing many traditional nanomaterial-based sensors. This exceptional sensitivity allowed for real-time monitoring of H₂O₂ released from living cells after drug stimulation, enabling differentiation between healthy and cancerous cells by tracking their oxidative burst signatures. Their work not only validated the protective and selective “molecular gating” effect of ZIF-8 but also demonstrated its feasibility as a multifunctional platform for SERSbased biosensing in vitro and in situ biomedical studies. The combination of sensitivity, anti-interference properties, and operational stability highlighted in this study establishes ZIF-8@Au hybrids as a powerful tool for ROS and H₂O₂ biosensing across biomedical diagnostics and cell biology research. Figure 6 Scheme for the preparation of MOF Peng et al.[23] conducted a systematic investigation into the synthesis, multifunctional reactivity, and biomedical application of pristine MIL-88A, an iron-based metal–organic framework prepared via a simple hydrothermal route using iron chloride and fumaric acid as precursors. The resulting MIL-88A nanoparticles exhibited well-defined rod-like morphology, high crystallinity, and abundant Fe(III) coordination sites confirmed by PXRD, TEM, and FTIR. GSC Advanced Research and Reviews, 2025, 24(03), 268-294 276 Functionally, the MOF showed robust peroxidase-like catalytic activity, efficiently catalyzing the oxidation of 3,3′,5,5′- tetramethylbenzidine (TMB) by hydrogen peroxide, producing a pronounced blue color for quantitative, colorimetric sensing. The detection platform displayed excellent sensitivity and operational stability for H₂O₂ in bioanalytical assays. Beyond biosensing, Peng et al. explored MIL-88A’s therapeutic potential in osteoarthritis (OA): in vitro, MIL-88A treatment promoted chondrocyte survival (>80% viability at 10 μg/mL), significantly scavenged intracellular ROS, and decreased pro-inflammatory cytokine (IL-1β) expression, thus protecting cartilage cells from oxidative damage. In vivo, intra-articular injection of MIL-88A into OA-induced mice led to marked histological improvements in cartilage and subchondral bone, reduced Safranin O–fast green staining loss, and positively modulated key anabolic (Col2) and catabolic (MMP13) gene expression profiles. Figure 7 Schematic of how Mil-88a could improve OA in a mouse model. (A) Flow diagram of the prepared Mil-88a. (B) Illustration of the injected method of Mil-88a. (C) The treatment process for suppressing the expression of IL-1β and relief of inflammatory response In another project, Wang et al.[24] introduced MOF-808 a zirconium-based metal–organic framework assembled from Zr₆-oxo clusters and 1,3,5-benzenetricarboxylate (BTC) linkers as a highly effective, enzyme-free peroxidase mimic for dual-mode biosensing of hydrogen peroxide (H₂O₂) in complex biological samples. The preparation of MOF-808 yielded uniform, microporous particles with a highly accessible, open structure, which, unlike traditional Zr-MOFs, provided exposed Zr₆ nodes acting as the catalytic centers. In this work, the catalytic oxidation of the chromogenic substrate TMB (3,3',5,5'-tetramethylbenzidine) in the presence of H₂O₂ led to a pronounced blue color, which was readily quantified via colorimetric analysis. Simultaneously, the product of the TMB oxidation exhibited strong fluorescence (with a characteristic emission at ~411 nm), allowing for a ratiometric fluorescence readout. Comprehensive kinetic studies confirmed that MOF-808 followed typical Michaelis–Menten catalytic behavior, with the apparent affinity and activity rivaling or exceeding those of many nanozymes and even natural horseradish peroxidase. The platform achieved remarkable analytical sensitivity, with detection limits as low as 0.12 μM (colorimetric) and 0.05 μM (fluorometric). The sensor's high selectivity was maintained in the presence of various biological interferents, and recovery studies demonstrated robust performance for H₂O₂ detection in real human serum samples. This research underscores the advantage of well-designed Zr-MOFs: their modular, open coordination environment and high chemical stability enable efficient multi-modal biosensing without the need for post-synthetic modification or bioconjugation. GSC Advanced Research and Reviews, 2025, 24(03), 268-294 283 phenotypes. The authors validated the cytocompatibility of ZIF-8 through cell viability assays and showed robust selectivity and reproducibility even in the presence of common interferents. Figure 14 Schematic illustration of the ZIF-8 nanozyme-based biosensing strategy for real-time, colorimetric detection of hydrogen peroxide secreted by live breast cancer cells In another research paper, Dong et al.[40] have fabricated a composite nanostructure integrating Fe₃O₄ nanoparticles, CaO₂ nanoparticles, and Prussian Blue into a single biomaterial (Fig. 15). This architecture enables localized and controllable production of H₂O₂ under the acidic tumor microenvironment, significantly enhancing the Fenton reaction yield of cytotoxic hydroxyl (●OH) radicals without relying on the inherently low tumor H₂O₂ levels that typically limit catalytic cancer therapies. Upon exposure to an alternating magnetic field, the Fe₃O₄ nanoparticles induce hyperthermia, which not only promotes tumor killing directly but also accelerates the catalytic Fenton process by increasing reaction rates and H₂O₂ decomposition. The platform demonstrates robust magnetic responsiveness, precise tumor targeting via magnetic guidance, high efficiency in ROS generation, and outstanding antitumor performance both in vitro and in vivo. Key factors of this reaserch include: the use of MOF composites for synergistic, multi-modal therapeutic and biosensing tasks; engineering of intelligent nanomaterials that combine endogenous substrate supply (H₂O₂ generation), catalytic site amplification (PB/Fe₃O₄), and external modulation (hyperthermia); and proof that MOF-based catalytic platforms can successfully overcome physiological bottlenecks (like low H₂O₂ in tumors) for advanced biomedical applications. GSC Advanced Research and Reviews, 2025, 24(03), 268-294 284 Figure 15 Schematic illustration of the cancer-therapeutic performance and bone-regeneration bioactivity of 3Dprinting scaffolds coloading with Fe3O4 and CaO2 NPs (AKT-Fe3O4-CaO2) 4.2. Cardiovascular Disease Applications Oxidative stress plays a decisive role in the onset and progression of cardiovascular diseases (CVDs). Clinically relevant concentrations of hydrogen peroxide rise sharply during myocardial infarction (MI), ischemia/reperfusion (I/R) injury, atherosclerotic plaque growth and heart-failure-related remodeling, making H₂O₂ an attractive early-stage biomarker and therapeutic target. Recent research demonstrates that metal–organic-framework (MOF) nanozymes and MOFderived composites combine high catalytic activity with excellent biocompatibility, enabling real-time, sensitive and even wearable H₂O₂ monitoring in cardiac settings[41, 42]. For instance, Xu et al.[43] developed an innovative electrochemical biosensor utilizing a HRP/Ti₃C₂/Nafion filmmodified glassy carbon electrode (GCE) for the sensitive determination of hydrogen peroxide (H₂O₂) in serum samples of patients with acute myocardial infarction (AMI)(Fig. 16). The biosensor leveraged Ti₃C₂ MXene nanosheets as carriers for horseradish peroxidase (HRP) due to their exceptional conductivity and high specific surface area, which significantly enhanced the electrochemical performance and enzyme immobilization efficiency. The biosensor demonstrated excellent analytical performance with a broad linear detection range of 5–8,000 μM and a low detection limit of 1 μM (S/N = 3), enabling quantitative H₂O₂ measurement through peak current differences. In clinical validation, the researchers tested serum samples from normal controls and AMI patients both before and after percutaneous coronary intervention (PCI), revealing statistically significant differences: H₂O₂ levels were markedly elevated in AMI patients compared to healthy controls (P < 0.05), and showed a significant decrease following PCI treatment (P < 0.01), with post-operative levels returning to values comparable to normal controls. GSC Advanced Research and Reviews, 2025, 24(03), 268-294 285 Figure 16 Schematic illustration of Construction of HRP/Ti3C2 Biosensor and the Determination of H2O2 Moreover, Li et al.[44] presented a groundbreaking study on the development of size-controlled MIL-53(Fe) metal– organic frameworks for dual-mode cancer therapy combining chemodynamic therapy (CDT) and chemotherapy (Fig. 17). The authors introduced an innovative synthetic approach using polyvinylpyrrolidone (PVP) as a non-ionic surfactant to precisely control the size of MIL-53(Fe) nanocrystals during hydrothermal synthesis. By systematically varying PVP concentrations (10, 50, 100, and 200 mg), they achieved remarkable size control: without PVP, large microcrystals (2.2 μm length × 0.49 μm width) were formed, while with increasing PVP amounts, crystal sizes progressively decreased to 600 nm, 380 nm, and finally 190 nm in length with corresponding widths of 140 nm, 240 nm, and 100 nm, respectively. The PVP acted as a nano-reactor controlling crystal nucleation and growth, with higher concentrations promoting more nucleation sites and smaller final particle sizes. The optimized MIL-53(Fe)-200 nanocrystals demonstrated exceptional drug-loading capacity for doxorubicin (DOX) via physisorption, achieving 45% loading efficiency, and exhibited pH-responsive drug release behavior (80.25% DOX released at pH 5.2 vs. 32.77% at pH 7.4 over 72 hours), making them ideal for targeted cancer therapy. Crucially, the iron-based MOF possessed intrinsic Fenton-like catalytic activity, converting endogenous H₂O₂ into highly cytotoxic hydroxyl radicals (- OH) for chemodynamic therapy, with significantly enhanced ROS generation at acidic tumor pH (5.2) compared to physiological pH (7.4). In vitro studies using 4T1 breast cancer cells confirmed successful cellular uptake, time-dependent DOX release, substantial ROS generation, and superior cytotoxicity of the MIL-53(Fe)-200-DOX system (44.7% cell viability) compared to individual treatments, demonstrating the synergistic effect of combined chemotherapy and chemodynamic therapy. GSC Advanced Research and Reviews, 2025, 24(03), 268-294 286 Figure 17 Schematic illustration of the size-controlled fabrication of MIL-53(Fe) and enhancing antitumor effects. (a) Preparation of MIL-53(Fe) nanocrystals. (b) Preparation of MIL-53(Fe)-200-DOX and chemodynamic therapy and chemotherapy 4.3. Inflammatory Disease Monitoring Inflammatory conditions are characterized by increased reactive oxygen species (ROS) production and elevated hydrogen peroxide (H₂O₂) levels, making these species valuable biomarkers for disease assessment and treatment monitoring. MOF-based sensors provide sensitive tools for tracking inflammatory responses in real-time, enabling early diagnosis, therapeutic intervention monitoring, and improved patient outcomes across a broad spectrum of inflammatory diseases including rheumatoid arthritis, osteoarthritis, inflammatory bowel disease, sepsis, and chronic wound healing disorders[45]. The pathophysiology of inflammatory diseases involves complex cascades of immune responses, wherein excessive ROS generation leads to oxidative stress, tissue damage, and sustained inflammatory states[46]. Studies demonstrate that inflammatory markers such as tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and other cytokines directly correlate with elevated H₂O₂ levels in affected tissues and biological fluids. This relationship provides a mechanistic foundation for using MOF-based H₂O₂ sensors as reliable indicators of inflammatory disease activity and progression[47]. In this case, the ZMTP (Zn-MnTCPP-PVP) nanosheets developed by Zhang et al.[48] represent a groundbreaking advancement in 2D metal-organic framework technology for rheumatoid arthritis treatment, combining sophisticated structural engineering with dual enzymatic functionality (Fig.18). These ultrathin nanosheets (~2.34 nm thickness) are constructed through a strategic coordination reaction between the benzoyloxy groups of manganese(III) mesotetrakis(4-carboxyphenyl)porphyrin (MnTCPP⁺) and zinc ions, forming an ordered crystalline structure with periodically assembled active Mn³⁺ sites distributed in an AB packing pattern. The key innovation lies in the zinc atoms' dual role: they serve as catalytically inactive secondary building units (Zn₂(COO)₄ paddlewheel nodes) that structurally stabilize the framework while simultaneously regulating the metal-centered redox potential of the coordinated manganese porphyrin ligands by counteracting the negative charge of peripheral benzoyloxy groups, thereby elevating the redox potential and facilitating ROS-scavenging reactions. This electronic modulation enables the ZMTP nanosheets to exhibit exceptional dual nanozyme activity—mimicking both superoxide dismutase (SOD) and catalase functions with catalytic efficiency surpassing natural SOD and demonstrating substantial H₂O₂ decomposition capability, albeit lower than natural catalase. In rheumatoid arthritis pathology, the nanosheets effectively scavenge intracellular reactive oxygen species (O₂- ⁻ and H₂O₂) in inflamed synovial tissue, promoting the critical transition of pro-inflammatory M1 macrophages toward anti-inflammatory M2 phenotype, thereby reducing inflammation-related cytokine production GSC Advanced Research and Reviews, 2025, 24(03), 268-294 287 (IL-6, IL-1β, TNF-α) and preventing apoptosis of bone mesenchymal stem cells (BMSCs). Additionally, the controlled release of Zn²⁺ ions from degrading nanosheets provides a secondary therapeutic benefit by upregulating alkaline phosphatase (ALP) expression in BMSCs, facilitating biomineralization and bone repair processes. Figure 18) a Coordination geometry around the MnIII center of human mitochondrial Mn-SOD (PDB: 1N0J). b Coordination geometry around the FeIII center in the heme group of human erythrocyte catalase (PDB: 1DGF). c Chemical structure of the 2D MOF ZMTP nanosheet. d Building units of ZMTP nanosheets, Zn(COO)4 paddlewheel metal nodes and MnTCPP+ ligand. e Layered structure of ZMTP nanosheet. f Therapeutic mechanism of ZMTP nanosheet for nanocatalytic rheumatoid arthritis treatment GSC Advanced Research and Reviews, 2025, 24(03), 268-294 288 Furthermore, Pan et al.[49] developed an innovative multifunctional nanoplatform, Pt-MOF@Au@QDs/PDA, which represents a sophisticated combination of metal-organic framework engineering with advanced nanomedicine for rheumatoid arthritis treatment through synergistic hydrogenothermal therapy (Fig. 19). The platform consists of a zirconium-based MOF (synthesized from ZrCl₄ and terephthalic acid) embedded with platinum nanoparticles for H₂ catalytic generation, gold nanoparticles that provide surface plasmon resonance (SPR) enhancement, perovskite quantum dots (QDs) for fluorescence imaging and positioning, and a polydopamine (PDA) coating that enables efficient photothermal conversion. The key innovation lies in the creation of a Schottky junction between the Pt-MOF semiconductor and Au plasmonic nanoparticles, which dramatically enhances photocatalytic hydrogen production under visible light irradiation while simultaneously enabling NIR-responsive photothermal therapy through the PDA coating. The platform exploits the "ELVIS" effect (extravasation through leaky vasculature and subsequent inflammatory cell-mediated sequestration) to achieve passive targeting of inflamed synovial tissue, with fluorescence imaging confirming accumulation and retention in joint synovium sites reaching peak signals at 24 hours post-injection. Mechanistically, the generated hydrogen selectively neutralizes cytotoxic hydroxyl radicals (·OH) without affecting beneficial ROS involved in normal cellular functions, while the photothermal component (achieving 64.8% conversion efficiency) provides localized hyperthermia to eliminate proliferating synovial fibroblasts. In the collagen-induced arthritis (CIA) mouse model, the combined NIR-visible light treatment protocol demonstrated remarkable therapeutic efficacy: significant reduction in paw swelling and clinical arthritis scores, dramatic suppression of pro-inflammatory cytokines (IL-6 and TNF-α), restoration of smooth articular surfaces between cartilage and bone, and prevention of synovial hyperplasia and bone/cartilage erosion all while maintaining excellent biocompatibility with no observable organ toxicity, thus establishing the platform's potential for clinical translation in RA therapy. Figure 19 Schematic illustration of the synthesis route and the hydrogen-photothermal treatment therapeutic mechanism based on the Pt-MOF@Au@QDs/PDA 4.4. Point-of-Care Testing Applications Point-of-care (PoC) diagnostics demand sensors that are disposable, inexpensive, and operable without benchtop instrumentation; MOF-based nanozyme platforms are now meeting these criteria through ingenious integration with microneedles, paper strips, and smartphone read-outs[50]. Yang et al.[11] developed a groundbreaking portable hydrogen peroxide detection system integrating a NH₂-UiO67(Zr/Cu) nanozyme (Fig. 20) with advanced smartphone-based colorimetric analysis, representing a significant advancement in point-of-care testing for food safety and biomedical applications. The bimetallic MOF nanozyme was synthesized through a green aqueous route, combining the exceptional structural stability of zirconium-based UiO-67 framework with copper incorporation to achieve dual-mode detection capabilities—both colorimetric (LOD: 0.0057 μM) and fluorescence (LOD: 0.0020 μM)—significantly outperforming conventional detection methods. The platform's innovation lies in its comprehensive integration: the NH₂-UiO-67(Zr/Cu) nanozyme exhibits robust peroxidase-like activity, catalyzing the oxidation of TMB substrate in the presence of H₂O₂ to generate a distinct blue coloration, while the amino-functionalization provides inherent fluorescence properties for dual-signal confirmation. To enable field GSC Advanced Research and Reviews, 2025, 24(03), 268-294 289 deployment, the researchers engineered a sophisticated 3D-printed portable device housing that precisely positions paper strips coated with the nanozyme, coupled with a custom smartphone application featuring advanced RGB color analysis algorithms capable of converting color intensity changes into quantitative H₂O₂ concentrations. The smartphone app employs machine learning-enhanced image processing to compensate for ambient lighting variations and provides real-time quantitative readouts with detection ranges spanning 0–750 μM (colorimetric) and 0–1000 μM (fluorescence), making it suitable for diverse applications from wound fluid analysis to food preservation monitoring. Crucially, the system maintains exceptional stability and reproducibility: the nanozyme-coated strips retain full activity for over one month at room temperature, the detection process requires less than 90 seconds from sample application to result display, and the platform demonstrates excellent selectivity with minimal interference from common biological and food matrix components. Figure 20 Schematic showing aqueous synthesis of NH₂-UiO-67(Zr/Cu) nanozyme and 3D-printed device assembly 5. Challenges and Limitations The translation of MOF-based biosensors from laboratory research to clinical applications faces multifaceted challenges that collectively represent significant barriers to commercialization and widespread adoption in healthcare settings. Stability and degradation issues constitute the most critical impediment, as many MOFs exhibit limited structural integrity in aqueous physiological environments due to the kinetically labile nature of coordination bonds, which can be easily disrupted by endogenous proteins, biological anions, varying pH conditions, and competing ions in biological fluids, leading to framework collapse and complete loss of sensing functionality[51, 52]. While water-stable MOFs such as UiO-66 and ZIF-8 have demonstrated improved performance under physiological conditions, maintaining structural integrity for extended periods, chemical degradation through hydrolysis, oxidation of organic linkers, and ion exchange processes remains problematic in harsh biological environments containing enzymes, reducing agents, and reactive oxygen species[53, 54]. Biocompatibility and toxicity concerns present equally significant challenges, as comprehensive safety assessment reveals that MOFs containing heavy metals or potentially toxic organic linkers may exhibit cytotoxicity at concentrations required for effective sensing, with metal ion release during framework degradation causing cellular damage and inflammatory responses[55]. Although iron-based MOFs generally demonstrate superior biocompatibility due to iron's essential biological role, even biocompatible metals can cause toxicity when released in excessive amounts, while limited long-term toxicological data regarding tissue accumulation and chronic effects necessitates extensive animal model studies before human application[56, 57]. Reproducibility and quality control issues further complicate translation, as MOF synthesis sensitivity to temperature, pH, reaction time, and reagent purity parameters leads to significant batch-to-batch variability in crystal size, morphology, defect concentration, and surface properties, all directly affecting sensing performance, requiring standardized synthesis protocols, automated systems, and rigorous analytical validation across different biological matrices with comprehensive interference studies and long-term stability assessments[58]. Finally, regulatory and translation barriers encompass complex approval GSC Advanced Research and Reviews, 2025, 24(03), 268-294 290 processes requiring extensive preclinical testing, clinical trials, and comprehensive safety documentation, with the novel nature of MOF materials potentially demanding additional studies to establish safety profiles and appropriate regulatory pathways[59]. The integration of MOF-based devices into existing clinical workflows must be demonstrated through carefully designed clinical trials with appropriate study endpoints, patient populations, and comparison standards, while cost-effectiveness analyses and health economic evaluations become increasingly critical for gaining acceptance by healthcare systems and insurance providers, necessitating clear demonstration of value proposition compared to existing technologies. Successfully addressing these interconnected challenges requires collaborative efforts between materials scientists, biomedical engineers, regulatory experts, and clinicians to develop robust solutions that ensure both technological performance and patient safety while meeting stringent regulatory requirements for medical device approval[60]. 5.1. Future Perspectives and Emerging Trends The next wave of MOF-based biosensors will be driven by advanced architectures that marry sophisticated materials chemistry with intelligent device engineering: stimuli-responsive frameworks capable of reversible, trigger-induced pore opening or catalytic switching under pH, temperature or light control promise self-regulated, on-demand sensing in vivo; parallel efforts toward multifunctional MOFs integrate high-capacity drug reservoirs, diagnostic readouts and multimodal imaging into a single crystalline host, enabling theranostic “sense-and-treat” platforms that tailor therapy to real-time biomarker levels and provide anatomical context for disease management[61]. These material innovations dovetail with wearable and implantable technologies stretchable, textile-woven or biodegradable MOF composites that conform to skin, reside transiently in tissues or dissolve after duty cycles to deliver continuous biochemical data without burdensome retrieval surgeries, thereby supporting personalised medicine and remote monitoring[62]. At the system level, coupling dense MOF sensor arrays to artificial-intelligence engines allows machine-learning algorithms to extract diagnostic patterns from multiplexed outputs, generate real-time clinical alerts and build predictive “digital-twin” models that forecast disease trajectories and optimise therapy. Real-world impact, however, hinges on clinicaltranslation strategies that adopt staged, low-risk entry points (e.g., research assays or point-of-care strips) before advancing to complex implants, combined with early regulatory engagement, rigorous standardisation of MOF stability and biocompatibility tests, and partnerships with established device manufacturers to streamline scale-up and harmonise global approval pathways[8, 63]. 6. Conclusion This comprehensive review reveals that MOF-based biosensors for reactive oxygen species and hydrogen peroxide detection represent a transformative convergence of advanced materials science and precision medicine, poised to revolutionize healthcare through their unprecedented combination of exceptional porosity, tunable architectures, and intrinsic enzyme-mimicking capabilities that have achieved remarkable detection limits and picomolar sensitivity for various ROS species. The field has witnessed extraordinary progress in developing sophisticated bimetallic nanozymes like Cu@Co-MOFs with 2.8-fold enhanced peroxidase activity, multifunctional composite materials that overcome pristine framework limitations, and dual-mode platforms such as NH₂-UiO-67(Zr/Cu) achieving sub-micromolar detection across colorimetric and fluorescence modalities, collectively demonstrating successful applications in cancer diagnostics, cardiovascular monitoring, inflammatory disease assessment, and innovative point-of-care testing platforms integrated with smartphone technology and 3D-printed devices. However, the path to widespread clinical adoption requires addressing critical challenges including stability under physiological conditions, comprehensive biocompatibility validation, manufacturing reproducibility, and navigating complex regulatory frameworks barriers that demand collaborative efforts between materials scientists, biomedical engineers, clinicians, and regulatory experts to establish standardized testing protocols and appropriate approval pathways. The future of MOF-based biosensors lies in their seamless integration with emerging technologies including artificial intelligence for pattern recognition and predictive modeling, wearable electronics for continuous health monitoring, stimuli-responsive materials for dynamic sensing behaviors, and personalized medicine approaches that leverage real-time biomarker data for individualized treatment optimization. As the healthcare landscape evolves toward proactive, precision-driven care, MOF-based biosensors are uniquely positioned to enable the early detection of life-threatening diseases, facilitate continuous monitoring of chronic conditions, support personalized therapeutic interventions, and ultimately transform healthcare delivery through intelligent, responsive systems centered around individual patient needs promising a future where advanced materials science directly translates into improved patient outcomes, enhanced quality of life, and more effective medical interventions that bridge the gap between cutting-edge research and clinical reality. GSC Advanced Research and Reviews, 2025, 24(03), 268-294 291 Compliance with ethical standards Disclosure of conflict of interest No conflict of interest to be disclosed. References [1] H. Abed, R. Sabouni, M. 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