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Metal–organic frameworks for biological applications

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Abstract

Metal–organic frameworks (MOFs) have emerged as exciting potential new candidates for application across nanomedicine, with the first example now in a phase II human clinical trial. MOFs have a range of desirable properties that make them suitable for various applications, including drug delivery, imaging and new treatment modalities, often in concert. In this Primer, we present an overview of the application of MOFs in biomedicine, focusing on drug delivery and imaging, but highlighting the chemical and structural versatility that is enabling their implementation in emerging treatment modalities and new biological applications. We discuss best practices in synthesis, characterization and application, including ongoing issues with reproducibility and limitations of applications, ending with an outlook of the field.

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Fig. 1: Schematic overview of the biomedical applications of metal–organic frameworks based on their composition.
Fig. 2: An overview of practical and synthetic considerations when selecting a metal–organic framework for a particular biological application.
Fig. 3: The loading and release of cargo from nanoparticulate metal–organic frameworks.
Fig. 4: Recommended workflow for physicochemical characterization of nanoparticulate metal–organic frameworks for biological applications.
Fig. 5: Overview of analytical methodologies that can be used to assess the biological behaviour of nanoparticulate metal–organic frameworks in a research laboratory context, with example data.
Fig. 6: Exemplar studies of nanoparticulate metal–organic frameworks in biomedical applications.
Fig. 7: Emerging frontier biomedical applications of metal–organic frameworks.

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Acknowledgements

A.E., D.F.-J. and R.S.F. thank the EPSRC for funding (EP/S009000/1). R.G. acknowledges funding from ANR-20-CE19-0020. I.A.L. and M.G.-M. thank financial support from LCF/BQ/PR23/11980041 and MCIN/AEI/10.13039/501100011033 (TED2021-132729A-I00), respectively. T.L. and W.L. thank the National Cancer Institute for funding (1R01CA253655).

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Authors and Affiliations

  1. Institute of Molecular Science (ICMol), University of Valencia, Valencia, Spain

    Isabel Abánades Lázaro & Mónica Giménez-Marqués

  2. The Adsorption & Advanced Materials Laboratory (A2ML), Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge, UK

    Xu Chen & David Fairen-Jimenez

  3. Institut des Sciences Moléculaires d’Orsay, UMR 8216 CNRS, Paris Saclay University, Paris, France

    Mengli Ding & Ruxandra Gref

  4. School of Chemistry, University of Glasgow, Glasgow, UK

    Arvin Eskandari & Ross S. Forgan

  5. Department of Chemistry, University of Chicago, Chicago, IL, USA

    Wenbin Lin & Taokun Luo

Authors
  1. Isabel Abánades Lázaro
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  2. Xu Chen
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  3. Mengli Ding
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  4. Arvin Eskandari
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  5. David Fairen-Jimenez
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  6. Mónica Giménez-Marqués
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  7. Ruxandra Gref
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  8. Wenbin Lin
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  9. Taokun Luo
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  10. Ross S. Forgan
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Contributions

Introduction (R.S.F.); Experimentation (I.A.L., M.G.-M., M.D., R.G. and A.E.); Results (R.G., M.D., I.A.L., M.G.-M., A.E., X.C. and D.F.-J.); Applications (W.L., T.L., R.G. and M.D.); Reproducibility and data deposition (R.S.F.); Limitations and optimizations (R.S.F., W.L. and T.L.); Outlook (R.S.F., W.L. and T.L.); Overview of the Primer (R.S.F. and A.E.).

Corresponding author

Correspondence to Ross S. Forgan.

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Glossary

Activation

The process of removing unreacted reagents and/or solvents from the pores of a synthesized metal–organic framework to maximize the available porosity and molecular storage capacity.

Burst release

Rapid release of cargo from a drug delivery system.

Coordinative functionalization

Postsynthetic modification involving formation of a coordinative bond between the metal–organic framework and the functionality, typically occurring at the inorganic secondary building unit.

Covalent conjugation

Postsynthetic modification involving formation of a covalent bond between the metal–organic framework and the functionality, typically occurring at the organic linker.

Defect loading

The process of loading a drug within a metal–organic framework by deliberately incorporating it as a charge-balancing defect during synthesis. This requires the drug to have a coordinating unit to allow it to replace a linker at the secondary building unit during metal–organic framework synthesis.

Drug delivery systems

Also known as drug delivery devices and drug delivery vectors. A formulation or device that enhances the uptake and efficacy of a specific drug within the body.

Drug loading

A measure of the loading capacity of a drug delivery system that is defined as the mass of the drug divided by the mass of the carrier and converted to a percentage. Note that this measure can result in >100% drug loading values and is distinct from the alternative wt% loading measure.

Encapsulation efficiency

A measure of the uptake efficiency of a drug delivery system for a specific analyte, which is calculated as the percentage of drug encapsulated from the total amount of drug contacted with the drug delivery system in a loading experiment.

Hard inorganic systems

A classification of drug delivery systems that includes inorganic systems such as noble metal nanoparticles, mesoporous silica, layered double hydroxides and metal–organic frameworks that are characterized by high drug loading values but often poorer biocompatibility and clearance.

Modulated self-assembly

Synthetic protocols for metal–organic frameworks in which additives are used to control pH and coordinative equilibria during self-assembly and so influence phase formation and/or metal–organic framework physical properties such as size, porosity and defectivity.

Organic linkers

Multitopic organic ligands used to construct metal–organic frameworks, typically carboxylates, phosphonates or N-donor heterocycles.

Pearson’s hard and soft acids and bases principle

Qualitatively, hard Lewis acids will be more stabilized by hard Lewis bases, and similarly soft Lewis acids will be more stabilized by soft Lewis bases, which can explain stability (and selectivity) of metal coordination chemistry.

Secondary building unit

(SBU). Inorganic metal ions or clusters that connect the organic linkers into the metal–organic framework structure.

Soft organic systems

A classification of drug delivery systems that includes organic, often polymer-based systems, such as liposomes or lipid nanoparticles, that are characterized by excellent biocompatibility and clearance but often low drug loading values.

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Abánades Lázaro, I., Chen, X., Ding, M. et al. Metal–organic frameworks for biological applications. Nat Rev Methods Primers 4, 42 (2024). https://doi.org/10.1038/s43586-024-00320-8

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