Multivalent insulin receptor activation using insulin-DNA origami nanostructures.
Autor: | Spratt J; Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden., Dias JM; Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.; Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden., Kolonelou C; Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden., Kiriako G; Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden., Engström E; Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden., Petrova E; Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden., Karampelias C; Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden., Cervenka I; Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden., Papanicolaou N; Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden., Lentini A; Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden., Reinius B; Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden., Andersson O; Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden., Ambrosetti E; Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.; Center for Life Nano- and Neuro-Science, Istituto Italiano di Tecnologia, Rome, Italy., Ruas JL; Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden., Teixeira AI; Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden. Ana.Teixeira@ki.se.; Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden. Ana.Teixeira@ki.se. |
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Jazyk: | angličtina |
Zdroj: | Nature nanotechnology [Nat Nanotechnol] 2024 Feb; Vol. 19 (2), pp. 237-245. Date of Electronic Publication: 2023 Oct 09. |
DOI: | 10.1038/s41565-023-01507-y |
Abstrakt: | Insulin binds the insulin receptor (IR) and regulates anabolic processes in target tissues. Impaired IR signalling is associated with multiple diseases, including diabetes, cancer and neurodegenerative disorders. IRs have been reported to form nanoclusters at the cell membrane in several cell types, even in the absence of insulin binding. Here we exploit the nanoscale spatial organization of the IR to achieve controlled multivalent receptor activation. To control insulin nanoscale spatial organization and valency, we developed rod-like insulin-DNA origami nanostructures carrying different numbers of insulin molecules with defined spacings. Increasing the insulin valency per nanostructure markedly extended the residence time of insulin-DNA origami nanostructures at the receptors. Both insulin valency and spacing affected the levels of IR activation in adipocytes. Moreover, the multivalent insulin design associated with the highest levels of IR activation also induced insulin-mediated transcriptional responses more effectively than the corresponding monovalent insulin nanostructures. In an in vivo zebrafish model of diabetes, treatment with multivalent-but not monovalent-insulin nanostructures elicited a reduction in glucose levels. Our results show that the control of insulin multivalency and spatial organization with nanoscale precision modulates the IR responses, independent of the insulin concentration. Therefore, we propose insulin nanoscale organization as a design parameter in developing new insulin therapies. (© 2023. The Author(s).) |
Databáze: | MEDLINE |
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