Abstract
The nanoscale spatial organization of transmembrane tumor necrosis factor (TNF) receptors has been implicated in the regulation of cellular fate. Accordingly, molecular tools that can induce specific arrangements of these receptors on cell surfaces would give us an opportunity to study these effects in detail. To achieve this, we introduce DNA origami nanostructures that precisely scaffold the patterning of TNF-related apoptosis-inducing ligand-mimicking peptides at nanoscale level. Stimulating human breast cancer cells with these patterns, we find that around 5 nm is the critical interligand distance of hexagonally patterned peptides to induce death receptor clustering and a resulting apoptosis. We thus offer a strategy to reverse the non-efficacy of current ligand- and antibody-based methods for TNF superfamily activation.
Highlights
Because the tumor necrosis factor (TNF) receptor superfamily (TNFRSF) plays important roles in cell proliferation, cell death, immune regulation, and morphogenesis, it has been extensively targeted for disease treatment.[1−5] structural information on TNFRSF, corresponding ligands, and even the receptor−ligand complexes have been quite thoroughly characterized,[6,7] molecular tools and drugs that can effectively trigger TNFRSF signaling are still missing.[3,5] Currently available agonists usually fail to work as expected.[8]
We produced a collection of structures displaying protruding 5′ single-stranded DNA handles for subsequent hybridization of ssDNA−ligand conjugates
We demonstrated an effective strategy of using a DNA origami method to regulate death receptor clustering and following cell apoptosis
Summary
Because the tumor necrosis factor (TNF) receptor superfamily (TNFRSF) plays important roles in cell proliferation, cell death, immune regulation, and morphogenesis, it has been extensively targeted for disease treatment.[1−5] structural information on TNFRSF, corresponding ligands, and even the receptor−ligand complexes have been quite thoroughly characterized,[6,7] molecular tools and drugs that can effectively trigger TNFRSF signaling are still missing.[3,5] Currently available agonists usually fail to work as expected.[8]. AntiTRAIL antibodies, which can cross-link TRAIL, were used together with TRAIL to promote the formation of DR5 clusters.[15,16] This strategy improved the apoptosis of cancer cells Another strategy was to covalently multimerize TRAIL or TRAIL-mimicking peptide on peptide-, dextran-, or graphenebased scaffolds,[17−20] which was demonstrated to be efficient. By conjugating ligands onto surfaces with prepatterned nanodot arrays, other groups have achieved a nanoscale arrangement of TNF with spacings between 58 and 290 nm.[21] Cell culture on those surfaces showed a dependence on interligand distances, revealing the importance of interligand distance control for efficient death receptor activation. Clinical translations of surface patterning methods are typically limited as the path from patterning large planar surfaces to patterning biocompatible nanoparticles is not straightforward
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