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Folding and Characterization of a Bio-responsive Robot from DNA Origami
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Multivalent insulin receptor activation using insulin-DNA origami nanostructures.

Joel Spratt1, José M Dias1,2, Christina Kolonelou1

  • 1Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.

Nature Nanotechnology
|October 9, 2023
PubMed
Summary

Researchers engineered insulin nanostructures to control receptor activation, improving diabetes treatment. This novel approach enhances insulin receptor (IR) signaling and glucose reduction in vivo.

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Area of Science:

  • Biochemistry
  • Nanotechnology
  • Molecular Biology

Background:

  • Insulin receptor (IR) signaling is crucial for metabolic processes.
  • Dysfunctional IR signaling is linked to diseases like diabetes, cancer, and neurodegenerative disorders.
  • IRs can form nanoclusters on cell membranes, suggesting a role for spatial organization.

Purpose of the Study:

  • To investigate how nanoscale spatial organization and multivalency of insulin affect IR activation.
  • To develop novel insulin delivery systems with controlled nanoscale properties.
  • To explore the therapeutic potential of precisely organized insulin for diabetes treatment.

Main Methods:

  • Development of rod-like insulin-DNA origami nanostructures with varying insulin numbers and spacings.
  • Assessment of insulin-DNA nanostructure residence time and IR activation levels in adipocytes.
  • Evaluation of insulin-mediated transcriptional responses.
  • Testing the efficacy of monovalent and multivalent insulin nanostructures in a zebrafish diabetes model.

Main Results:

  • Increasing insulin valency on nanostructures significantly prolonged their residence time at IRs.
  • Both insulin valency and spacing on nanostructures modulated IR activation levels in adipocytes.
  • Multivalent insulin nanostructures demonstrated enhanced insulin-mediated transcriptional responses compared to monovalent ones.
  • In vivo, multivalent insulin nanostructures effectively reduced glucose levels in a zebrafish diabetes model.

Conclusions:

  • Precise control over insulin multivalency and nanoscale organization can modulate IR responses independently of concentration.
  • Insulin nanoscale organization is a promising design parameter for developing advanced insulin therapies.
  • This approach offers a new strategy for treating diseases associated with impaired IR signaling.