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Inducing Cancer Cell Killing Using DNA Nanostructure-Mediated Superclustering of Death Receptors
Göktuğ Aba1, Subinuer Abudukelimu2, Margot de Winter1
1Department of Cell and Chemical Biology, Leiden University Medical Center, 2333 ZG Leiden, The Netherlands.
Nano Letters
|April 8, 2025
Summary
Precise control over tumor necrosis factor receptor (TNFR) clustering using DNA nanostructures enhances cancer cell killing. This approach improves understanding of receptor activation and informs new cancer therapies.
Area of Science:
- Biochemistry and Molecular Biology
- Nanotechnology in Medicine
- Cancer Therapeutics
Background:
- Type-II tumor necrosis factor receptors (TNFRs) require clustering for intracellular signaling.
- Existing methods for TNFR clustering offer limited control over ligand valency and spatial arrangement.
- Suboptimal TNFR activation can hinder biological insights and therapeutic efficacy.
Purpose of the Study:
- To develop a method for precise control over TNFR clustering using DNA nanostructures.
- To investigate the impact of ligand valency and spatial organization on apoptotic pathway activation.
- To explore the potential of engineered ligands for enhanced cancer therapy.
Main Methods:
- Fabrication of DNA nanostructures functionalized with engineered single-chain TNF-related apoptosis-inducing ligand (sc-TRAIL) trimers.
- Utilizing sc-TRAIL trimers that bind death receptor 5 (DR5) with native affinity and geometry.
- Assessing cell killing in cancer organoids based on varying receptor valency and separation.
Main Results:
- Cell killing is significantly influenced by receptor valency and inter-receptor separation.
- Superclustering of sc-TRAIL trimers on DNA nanostructures enhances cell death.
- Demonstrated efficacy of superclustered sc-TRAIL trimers in inducing cell killing in human primary pancreatic and colorectal cancer organoids.
Conclusions:
- Precise control over receptor superclustering via DNA nanostructures is crucial for understanding TNFR activation mechanisms.
- This engineered approach offers a promising strategy for developing more effective cancer therapies.
- The findings provide a foundation for designing targeted therapies that optimize apoptotic signaling.
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