The interactions between DNA nanostructures and cells: A critical overview from a cell biology perspective

Abstract

DNA nanotechnology has yielded remarkable advances in composite materials with diverse applications in biomedicine. The specificity and predictability of building 3D structures at the nanometer scale make DNA nanotechnology a promising tool for uses in biosensing, drug delivery, cell modulation, and bioimaging. However, for successful translation of DNA nanostructures to real-world applications, it is crucial to understand how they interact with living cells, and the consequences of such interactions. In this review, we summarize the current state of knowledge on the interactions of DNA nanostructures with cells. We identify key challenges, from a cell biology perspective, that influence progress towards the clinical translation of DNA nanostructures. We close by providing an outlook on what questions must be addressed to accelerate the clinical translation of DNA nanostructures. STATEMENT OF SIGNIFICANCE: Self-assembled DNA nanostructures (DNs) offers unique opportunities to overcome persistent challenges in the nanobiotechnology field. However, the interactions between engineered DNs and living cells are still not well defined. Critical systematization of current cellular models and biological responses triggered by DNs is a crucial foundation for the successful clinical translation of DNA nanostructures. Moreover, such an analysis will identify the pitfalls and challenges that are present in the field, and provide a basis for overcoming those challenges.

Keywords: Bionano interactions; Cellular uptake; Cytotoxicity; DNA nanotechnology; Nanotechnology; Protein corona.

Fig. 1.

Key examples of various DNA nanostructure designs. (A) DNA tetrahedron [35]. (B) Three-dimensional wireframe rabbit-shaped DNA structure designed from a polygonal mesh architecture [36]. (C) Two-dimensional DNA origami in the shape of a smiley face [38]. (D) Three-dimensional DNA origami vase structure featuring complex curvature [39]. (E) Modular DNA structures composed of 32-nucleotide “brick” motifs [41]. (F) Single-stranded DNA “tiles” acts as pixels in a two-dimensional array [187]. (G) A DNA box designed to be opened via toehold strand displacement to release a cargo of interest [44]. (H) pH-sensitive DNA i-motifs allow the assembly and disassembly of a DNA tetrahedral structure [45]. (I) Heteromultimeric assembly of complex DNA architectures via shape complementarity [46]. J) Homomultimeric assembly of DNA barrel structures into a hollow DNA tube via sticky end adhesion [47].

Fig. 2.

Historical timeline of the advancements in DNA nanotechnology research [2,24,27,34,61].

Fig. 3.

DNA nanostructures for biological applications. (A) BSA modified with positively charged dendrimers to adhere to a 60-helix bundle (60HB) nanostructure enables enhanced nanostructure stability, uptake, and immunoquiescence [68]. (B) Oligolysine-based peptide coating featuring two functional aurein 1.2 sequences that exhibits endosomal escape of the coated DNA nanostructure (EE-DN) in the absence of serum proteins [76]. (C) Cholesterol-bearing 6-helix bundle DNA nanostructures facilitate targeted uptake in white blood cells compared to red blood cells [188]. (D) A DNA origami sheet bearing MUC1-targeted aptamers capable of targeted intracellular delivery of active RNase A [189].

Fig. 4.

Schematic brief summary of DNA nanostructures interaction with living cells.