Inducing Cancer Cell Killing Using DNA Nanostructure-Mediated Superclustering of Death Receptors
Nano Letters, vol. 25, pp. 6310–6317
Abstract
Clustering of type-II tumor necrosis factor receptors (TNFRs) is required to induce intracellular signaling. Current methods for receptor clustering lack precise control over ligand valency and spatial organization, potentially limiting optimal TNFR activation, biological insight, and therapeutic efficacy. DNA nanostructures provide nanometer-precise control over molecular arrangement, allowing control of both ligand spacing and valency. Here, we produce a DNA nanostructure decorated with controlled numbers of engineered single-chain TNF-related apoptosis-inducing ligand (sc-TRAIL) trimers, which bind death receptor 5 (DR5) with native affinity and geometry and enable investigation of the geometric parameters influencing apoptotic pathway activation. We show that cell killing is affected by receptor valency and separation and enhanced by superclustering sc-TRAIL trimers, which can induce cell killing in human primary pancreatic and colorectal cancer organoids. Together, our data show that control of receptor superclustering enhances our understanding of receptor activation mechanisms and informs the development of more effective cancer therapies.
Authors 9
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Göktuğ Aba Aachen
Leiden University Medical Center
Affiliation as printed
Department of Cell and Chemical Biology
Leiden University Medical Center
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Subinuer Abudukelimu Aachen
Leiden University Medical Center
Affiliation as printed
Department of Gastroenterology and Hepatology
Leiden University Medical Center
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Gabriella Collu Aachen
Leiden University Medical Center
Affiliation as printed
Department of Cell and Chemical Biology
Leiden University Medical Center
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Erik Bos Aachen
Leiden University Medical Center
Affiliation as printed
Department of Cell and Chemical Biology
Leiden University Medical Center
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Sebastiaan M. W. R. Hamers Aachen
Leiden University Medical Center
Affiliation as printed
Department of Cell and Chemical Biology
Leiden University Medical Center
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Lukas J.A.C. Hawinkels Aachen
Leiden University Medical Center
Affiliation as printed
Department of Gastroenterology and Hepatology
Leiden University Medical Center
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Nadine van Montfoort Aachen
Leiden University Medical Center
Affiliation as printed
Department of Gastroenterology and Hepatology
Leiden University Medical Center
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Leiden University Medical Center
Affiliation as printed
Department of Dermatology
Leiden University Medical Center
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Leiden University Medical Center · University of Bristol
Affiliation as printed
Department of Cell and Chemical Biology
Leiden University Medical Center
School of Biochemistry
University of Bristol
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