DNA Origami Penetration in Cell Spheroid Tissue Models is Enhanced by Wireframe Design

Abstract

As DNA origami applications in biomedicine are expanding, more knowledge is needed to assess these structures’ interaction with biological systems. Here, uptake and penetration in cell and cell spheroid tissue models (CSTMs) are studied to elucidate whether differences in internal structure can be a factor in the efficacy of DNA‐origami‐based delivery. Two structures bearing largely similar features in terms of both geometry and molecular weight, but with different internal designs—being either compact, lattice‐based origami or following an open, wireframe design—are designed. In CSTMs, wireframe rods are able to penetrate deeper than close‐packed rods. Moreover, doxorubicin‐loaded wireframe rods show a higher cytotoxicity in CSTMs. These results can be explained by differences in structural mechanics, local deformability, local material density, and accessibility to cell receptors between these two DNA origami design paradigms. In particular, it is suggested that the main reason for the difference in penetration dynamic arises from differences in interaction with scavenger receptors where lattice‐based structures appear to be internalized to a higher degree than polygonal structures of the same size and shape. It is thus argued that the choice of structural design method constitutes a crucial parameter for the application of DNA origami in drug delivery.

origamiFISH allows universal, label-free, single molecule visualization of DNA origami nanodevices across biological samples

“…5f ). These results corroborate previous observations of DN accessibility and penetration limits within cancer spheroids (Wang et al, 2021a), and prompt the need for more detailed characterizations of DN design rules for reaching deeper tissue regions within poorly vascularized organoid, spheroid, and tumor models. Taken together, our results demonstrate the utility of origamiFISH in capturing the faithful localization patterns of DNs within intact tissue systems, and offer a tool for characterizing DN design parameters for reaching deep tissue regions.…”

Myeloid cell‐specific topoisomerase 1 inhibition using DNA origami mitigates neuroinflammation

“…From a translational perspective, this could even enhance the effect of TPT on myeloid cells, and meanwhile, minimize the potential off‐target effects on other cell types when applying TOP1 inhibition therapy in patients. We took advantage of our previously designed wireframe‐stylized hexagonal rod (HR) DNA origami system (Benson et al , 2015 ; Wang et al , 2021 ). The superiority of using DNA origami as a drug delivery vehicle is the precision and reproducibility (Rothemund, 2006 ; Douglas et al , 2012 ).…”

Functionalizing Framework Nucleic‐Acid‐Based Nanostructures for Biomedical Application

“…Unlike other DNA nanostructures impeded by their dimension, improved tissue penetration could further extend the application of tFNA structures as drug delivery vehicles or sensor platforms. [37] Enhanced endocytosis and tissue penetration have been documented in many studies, although the mechanism remains under scrutiny. Fan's group has contributed the most in elaborating the cellular uptake process, [36] while Lin's group has contributed the most in extending the application of these structures based on the extraordinary merits explained above.…”