Editorial

Recent advances and future prospects of metal organic frameworks (MOF)-based biosensors

Introduction

Metal-organic-frameworks (MOFs), constructed from a variety of organic ligands and metal nodes, are a type of ordered porous nanomaterial with outstanding properties like well-defined structures, high stability, and tunability, accordingly signifying enormous potential across various applications.¹ In terms of biosensors, sensitivity and stability are two fundamental components of an effective biosensor. However, these properties are often interrelated, as enhancing one frequently compromises the other.^2,3 Through careful structural design, MOFs serve as effective mediators in achieving an optimal balance between the two factors. In general, the extensive versatility of MOF nanostructures allows them to function as superior catalytic agents, nanoreactors, template frameworks, and stabilizing matrices, thereby substantially advancing the development of biosensors.

Structural engineering strategies of MOFs

The structural engineering of MOFs can be mainly categorized into three main approaches: heterostructure engineering, crystal engineering, and MOF derivative engineering, applicable to both two-dimensional (2D) and three-dimensional (3D) nanostructures. The integration of guest molecules, like doping or embedding to form bimetallic MOFs, can be termed as heterostructure engineering. Significantly, hybridizing lower-dimensional material components with MOFs or their derivatives via interfacial interactions, including electronic coupling and hydrogen bonding, represents a promising strategy for the development of synergistic nanocomposite materials.⁴ Crystal engineering typically entails the alteration of precursor materials, their stoichiometric ratios, and synthesis parameters to produce crystals with distinct morphologies and functional properties. These modifications leverage the functional versatility of organic linkers and metal nodes, as well as the easy adjustability of metal-linker ratios.⁵ In terms of derivative engineering, MOFs can function as sacrificial templates, enabling postsynthetic modifications or the fabrication of hollow structures, thereby the improvement of sensor function.⁶

Functional integration and guest material incorporation

Recent studies have concentrated on the integration of the aforementioned strategies to maximize sensing performance, emphasizing the intrinsic relationship between structure and function in the rational design of MOFs.⁷ Through crystal engineering, the aforesaid features of MOFs are optimized for improved topography and topology configurations through the utilization of the structural heterogeneity inherent in MOFs.⁸ For example, MOF structures by larger pore sizes can enhance sensor sensitivity by enabling increased diffusion rates of target molecules. Conversely, MOFs with smaller pore dimensions can improve selectivity through a size-exclusion mechanism that restricts the access of larger molecules.⁹ MOFs can possess exposed active sites as well as basic linker sites or Lewis acidic that facilitate enzyme-like catalytic functions. In particular, the presence of open metal coordination sites and Lewis acidic or basic linkers within MOFs serves as analyte-binding domains and catalytic centers, thereby enhancing the selectivity of enzyme-mimicking nanozymes.¹⁰ In addition to the rational design of the MOF structure, numerous sensors utilize MOFs as ideal host matrices for the integration of functional guest nanomaterials within heterostructure engineering approaches. Owing to their diverse synthetic approaches and ease of post-synthetic modification, MOFs exhibit considerable structural adaptability, rendering them highly suitable for applications in surface engineering, macromolecule encapsulation, and the integration of additional novel functionalities. MOF loading with guest molecules can be achieved through host-guest bindings like van der Waals forces, hydrogen bonding, and coordinative or covalent bonding.¹¹ For example, recent advancements in the specific determination of carcinoembryonic antigens (CEA) using MOF-based immunosensors demonstrate how MOFs can serve as robust matrices for antibody immobilization and signal amplification. Such non-enzymatic configurations leverage the structural stability and large surface area of MOFs to achieve highly selective detection of clinically relevant biomarkers, underscoring their promise for translational biosensing applications.¹²

The brilliance of MOFs lies not only in their design but also in their function as protective hosts that stabilize fragile biomolecules against chemical, thermal, and mechanical degradation. This property makes MOFs ideal scaffolds for enzyme immobilization, a fundamental component of many biosensing systems.¹³ Enzyme@MOF constructs, whether formed through post-synthetic infiltration or one-pot encapsulation, exemplify this synergy.¹⁴ In post-synthetic infiltration, the enzyme is incorporated after MOF synthesis, providing flexible control but limited pore accessibility. Conversely, in one-pot encapsulation, biomolecules direct MOF crystallization, resulting in strong protection but often at the expense of catalytic efficiency and structural diversity. Balancing these trade-offs remains an ongoing challenge and a promising opportunity for innovative materials design.

Challenges and limitations in MOF-based sensor design

Although MOF-based biosensors possess many desirable characteristics, they have not yet reached the performance standards required for a broad range of practical applications. Achieving the critical demands of stability, selectivity, and sensitivity concurrently remains a significant challenge. While MOFs generally afford a protective structure that enhances stability, they can also hinder analyte diffusion, leading to extended response times or reduced sensitivity. Recent developments in heterostructure engineering and crystal engineering have partially mitigated these challenges. Nevertheless, these structurally intricate MOFs frequently exhibit reduced stability, suboptimal and expensive synthetic methodologies, as well as irregular or unclear distribution of defects or guest species throughout the framework. Furthermore, the reproducibility and scalability of synthesis remain bottlenecks for device integration, while potential cytotoxicity and metal leaching pose biomedical safety concerns. These issues subsequently give rise to difficulties in performing material characterization and benchmarking, as well as result in low reproducibility during scale-up production. Furthermore, multifunctional MOFs can produce overlapping signals that are challenging to deconvolute, thereby complicating their real-world application.

Emerging trends and future outlook

To advance the development of next-generation MOF materials for sensing, it is essential to deepen our collective insight into the mechanistic structure-function relationships and to leverage this knowledge to precisely tailor MOF constructions. In the near future, the following developments are expected: i) Advancements aimed at optimizing existing MOF structures or creating new composite materials through the integration of supplementary guest molecules to enhance sensor functionality; ii) The utilization of newer MOFs in innovative sensing methods extends beyond conventional enzyme-derived biorecognition strategies, encompassing applications such as scintillating MOFs and MOF composites; iii) Comprehensive structural characterization techniques, computational modeling approaches, and ML-guided analyses could be employed to thoroughly elucidate the structures of MOF composites formed through various synthesis methods and crystallization pathways. Ongoing research continues to expand and deepen our currently limited understanding of complex MOF composites and their interfaces. For cancer detection, the future clinical translation of MOF-based biosensors holds tremendous promise besides fundamental research. On account of their promising properties and capability for immobilization of biorecognition element, MOFs could be applied to multiplexed and ultra-sensitive determination of cancer biomarkers. Integration of MOF-based sensing platforms with point-of-care (POC) or wearable diagnostic devices and microfluidic chips enable real-time cancer screening. Additionally, integration of ML-assisted data analysis or artificial intelligence (AI) could advance personalized cancer monitoring and early diagnosis, bridging materials innovation and clinical utility.

Despite these promising advances, numerous significant challenges must still be addressed before MOF-based nanobiosensors can reach extensive clinical application. Complex/non-scalable synthesis routes, metal ion leaching, limited long-term stability, and reproducibility are such significant issues. Furthermore, lack of standardized performance evaluation protocols, biocompatibility concerns, and signal interference hinder their consistent usage in clinical diagnostics. These restrictions could be addressed through biomedical validation, computational modeling, and materials engineering, to fully realize the translational potential of MOF-based biosensing platforms. It is anticipated that this progress will lead to the development of highly efficient MOF-based sensors, overcoming existing sensor limitations by leveraging the versatile and adaptable structural frameworks of MOFs.

Competing Interests

None to declare.

Data Availability Statement

Data sharing not applicable to this article.

Declaration of AI-assisted Tools in the Writing Procedure

The author declares that she has not used AI tools or technologies to prepare this paper.

Ethical Approval

Not applicable.

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