Nucleic acid constructs for the interrogation of multivalent protein interactions

Yeldell, Sean B.; Seitz, Oliver

doi:10.1039/d0cs00518e

Cited by 48 publications

(36 citation statements)

References 55 publications

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“…[ 5 ] Until now, various strategies have been developed for multivalent assembly of proteins. [ 6 ] However, there are rarely reports on the precise formation of oriented protein assemblies with controlled valency for tumor targeting.…”

Section: Introductionmentioning

confidence: 99%

Modular Assembly of Tumor‐Penetrating and Oligomeric Nanozyme Based on Intrinsically Self‐Assembling Protein Nanocages

et al. 2021

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Biomimetic design of nanomaterials with enzyme‐like characteristics has emerged as a promising method for the generation of novel therapeutics. However, synthesis of nanomaterials while maintaining a high degree of control over both geometry and valency poses a prominent challenge. Herein, the authors introduce a nanomaterial‐based synthetic biology strategy for accurate and quantitative tailoring of high‐ordered nanostructures that uses a “bottom‐up” hierarchical incorporation of protein building blocks. The assembled nano‐oligomers possessed tunable protein motifs and multivalent binding domains, which facilitated prolonged blood circulation time, accumulation within tumor cells through direct targeting of cell receptors, and deep tumor tissue penetration via a transcytosis mechanism. Using these protein/protein nano‐oligomers as scaffolds, the authors created a new series of artificial nano‐scaled metalloenzymes (nanozymes) by the in situ incorporation of metal nanoclusters within the cavity of the protein nanocages. Nanozymes were capable of mimicking peroxidase‐like activity and generated cytotoxic free radicals. Compared to nanozyme alone, the systemic delivery of oligomeric nanozymes demonstrated significantly enhanced therapeutic and anti‐tumor benefits. This study shows a new insight into nanotechnology by taking advantage of synthetic biotechnology.

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Section: Introductionmentioning

confidence: 99%

Modular Assembly of Tumor‐Penetrating and Oligomeric Nanozyme Based on Intrinsically Self‐Assembling Protein Nanocages

et al. 2021

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“…25 PNA is a bio-stable oligonucleotide analogue acting as a unique barcode for the target protein, which can be addressed with complementary DNA, offering the application of DNA nanotechnology beyond typical fluorescence imaging. [26][27][28][29] In this study, we introduce the simultaneous and orthogonal labelling of two membrane receptors: epidermal growth factor receptor (EGFR) and epidermal growth factor receptor 2 (ErbB2) on living Chinese Hamster Ovary (CHO) cells. We show that interfacing live cell protein labelling with DNA technology provides a direct read-out of EGFR/ErbB2 internalisation.…”

Section: Introductionmentioning

confidence: 99%

Orthogonal coiled coils enable rapid covalent labelling of two distinct membrane proteins with peptide nucleic acid barcodes

et al. 2021

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“…34 Some of the initial challenges for the use of DNA nanostructures for biomedical applications have been addressed and overcome, including low-scale inefficient production, poor structural integrity in physiological fluids and degradation by nuclease activity, making DNA origami-based nanostructures a potential platform for the design of tailored nanomedicines. [35][36][37][38][39][40][41][42] To maximize the potential of DNA nanostructures as a generic platform for precision medicine it is essential to analyze all parameters that influence nanostructure performance. While the parameters that modulate cellular uptake are relatively well understood, it is currently unclear if DNA nanostructures interfere with the interaction between ligands and cellular surface receptors.…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Determinants of ligand-functionalized DNA nanostructure-cell interactions

Cremers

Rosier

Meijs

et al. 2021

Preprint

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Synthesis of ligand-functionalized nanomaterials with control over size, shape and ligand orientation, facilitates the design of tailored nanomedicines for therapeutic purposes. DNA nanotechnology has emerged as a powerful tool to rationally construct two- and three-dimensional nanostructures, enabling site-specific incorporation of protein ligands with control over stoichiometry and orientation. To efficiently target cell surface receptors, exploration of the parameters that modulate cellular accessibility of these nanostructures is essential. In this study we systematically investigate tunable design parameters of antibody-functionalized DNA nanostructures binding to therapeutically relevant receptors. We show that, although the native affinity of antibody-functionalized DNA nanostructures remains unaltered, the absolute number of bound surface receptors is lower compared to soluble antibodies and is mainly governed by nanostructure size and DNA handle location. The obtained results provide key insights in the ability of ligand-functionalized DNA nanostructures to bind surface receptors and yields design rules for optimal cellular targeting.

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Nucleic acid constructs for the interrogation of multivalent protein interactions

Abstract: Sequence-programmed self-assembly provides multivalent nucleic acid–ligand constructs used as tailor-made probes for unravelling and exploiting the mechanisms of multivalency-enhanced interactions on protein receptors.

Cited by 48 publications

References 55 publications

Modular Assembly of Tumor‐Penetrating and Oligomeric Nanozyme Based on Intrinsically Self‐Assembling Protein Nanocages

Modular Assembly of Tumor‐Penetrating and Oligomeric Nanozyme Based on Intrinsically Self‐Assembling Protein Nanocages

Orthogonal coiled coils enable rapid covalent labelling of two distinct membrane proteins with peptide nucleic acid barcodes

Determinants of ligand-functionalized DNA nanostructure-cell interactions

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