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  • Review Article
  • Published:

Microenvironmental regulation of biomacromolecular therapies

Nature Reviews Drug Discovery volume 6, pages 455–463 (2007)Cite this article

Key Points

  • Protein-based and nucleotide-based biomacromolecular therapies are being increasingly used in various clinical interventions, but the importance of the cellular microenvironment of the target cells has been not been carefully or broadly examined.

  • In vitro studies demonstrate that the cellular response to protein therapies (for example, growth factors and antibodies) is mediated by aspects of the cellular microenvironment that regulate adhesion and other cell functions, including the composition and structure of the extracellular matrix (ECM).

  • At least three strategies that modulate the cellular microenvironment in vivo may potentially be employed to enhance local protein therapies: regulating cell viability in the target tissue, controlling cell adhesion to the native ECM and providing an artificial microenvironment (for example, synthetic ECM) designed to amplify the desired response. These strategies have been used to create new tissues and to destroy diseased tissues.

  • Several in vitro studies demonstrate that the ability of a cell to take up and express nucleotides is mediated by variables of the cellular microenvironment, including the presentation of cell-adhesion molecules, the architecture and mechanical properties of the ECM, and external mechanical stimulation.

  • Potential strategies to regulate the effectiveness of nucleotide therapies in vivo include the delivery of supplemental signalling factors that modulate cell proliferation, regulation of integrin expression levels, and implantation of nucleotide-releasing engineered ECM. These strategies have been used to mediate tissue regeneration, gene-based vaccination and treatment of chronic and malignant diseases.

  • Careful translation of results from in vitro studies, together with exploitation of recently developed approaches to control nanoscale and microscale ECM signalling, could significantly enhance and broaden the utility of local biomacromolecular therapies.

Abstract

There is currently great interest in molecular therapies to treat various diseases, and this has prompted extensive efforts to achieve target-specific and controlled delivery of bioactive macromolecules (for example, proteins, antibodies, DNA and small interfering RNA) through the design of smart drug carriers. By contrast, the influence of the microenvironment in which the target cell resides and the effect it might have on the success of biomacromolecular therapies has been under-appreciated. The extracellular matrix (ECM) component of the cellular niche may be particularly important, as many diseases and injury disrupt the normal ECM architecture, the cell adhesion to ECM, and the subsequent cellular activities. This Review will discuss the importance of the ECM and the ECM–cell interactions on the cell response to bioactive macromolecules, and suggest how this information could lead to new criteria for the design of novel drug delivery systems.

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Figure 1: The cellular microenvironment varies with tissue injury and pathogenesis.
Figure 2: In vitro cell response to protein drugs is modulated by the microenvironment.
Figure 3: Potential strategies to engineer cell microenvironments in vivo to modulate the cellular response to protein drugs.
Figure 4: In vitro efficiency of gene transfer and subsequent level of expression are modulated by properties of the extracellular matrix (ECM).

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Acknowledgements

The authors thank the National Institutes of Health (R37 DE013033, R01 DE13349 and R01 HL069957) and the US Army Research Laboratories and Research Office (DAAD-19-03-1-0168) for financial support.

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Authors and Affiliations

  1. Division of Engineering and Applied Sciences, Harvard University, Cambridge, 02138, Massachusetts, USA

    Hyun Joon Kong & David J. Mooney

  2. Department of Chemical and Biomolecular Engineering, University of Illinois at Urbana-Champaign, Urbana, 48109, Illinois, USA

    Hyun Joon Kong

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Correspondence to David J. Mooney.

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Glossary

Biomacromolecule

A high molecular mass molecule formed from biological building blocks such as nucleic acids, amino acids and sugars.

Plasmid

A small circular piece of DNA that can replicate itself independently of chromosomal DNA; frequently used to introduce potentially therapeutic genes into cells.

Extracellular matrix

(ECM). A complex mixture of non-living material surrounding cells within tissues. The ECM provides space for tissue formation, mechanically supports the tissue and provides cues to regulate cell function.

Integrin

A specific type of cell-surface receptor that mediates adhesion to the extracellular matrix and subsequent signalling to the cell.

Silencing RNA

20–25 nucleotide-long double-stranded RNA molecules, referred to as small interfering RNA (siRNA), used to interfere with the expression of a specific gene. siRNA treatments are also termed interference therapies.

Aptamer

Short nucleic-acid- or amino-acid-based molecules that bind a specific target molecule. They are often used as macromolecular drugs.

Matrix metalloproteinase

(MMP). A specific type of enzyme that is capable of degrading extracellular-matrix proteins.

Antisense therapy

A treatment that uses a single strand of nucleic acid (antisense oligonucleotide) that is designed to bind a specific mRNA and inactivate its expression.

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Kong, H., Mooney, D. Microenvironmental regulation of biomacromolecular therapies. Nat Rev Drug Discov 6, 455–463 (2007). https://doi.org/10.1038/nrd2309

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