Stimuli Responsive, Programmable DNA Nanodevices for Biomedical Applications

Abstract

Of the multiple areas of applications of DNA nanotechnology, stimuli-responsive nanodevices have emerged as an elite branch of research owing to the advantages of molecular programmability of DNA structures and stimuli-responsiveness of motifs and DNA itself. These classes of devices present multiples areas to explore for basic and applied science using dynamic DNA nanotechnology. Herein, we take the stake in the recent progress of this fast-growing sub-area of DNA nanotechnology. We discuss different stimuli, motifs, scaffolds, and mechanisms of stimuli-responsive behaviours of DNA nanodevices with appropriate examples. Similarly, we present a multitude of biological applications that have been explored using DNA nanodevices, such as biosensing, in vivo pH-mapping, drug delivery, and therapy. We conclude by discussing the challenges and opportunities as well as future prospects of this emerging research area within DNA nanotechnology.

Keywords: DNA nanotechnology; biomedical applications; biosensing; stimulus responsive devices; therapeutics.

FIGURE 1

DNA-based stimuli-responsive nanodevices. (A). DNA i-motif based pH responsive nanodevice (Surana et al., 2011), (B). Light-responsive DNA-gold nano particles (Xiao et al., 2012), (C). Hydrogel crosslinked with DNA aptamer, which enables it’s conversion from gel to sol and triggers the release of embedded fluorescent particles (Yang et al., 2008), (D). Temperature sensitive DNA hydrogels, where GC content of the sticky ends decides the association-dissociation point (Xing et al., 2018), (E). Hydrogel monomers having disulfide linkages breaks apart due to enzyme activity of glutathione (GSH) (Li et al., 2015), and (F). Nucleic acid responsive nanotweezers act upon hybridization with target nucleic acid (Yurke et al., 2000).

FIGURE 2

Receptor binding and delivery of DNA nanodevices: In vivo delivery of (A) i-motif based pH-responsive DNA nanodevice (left), cargo loaded DNA icosahedron (right), and (B) DNA tetrahedron functionalized with folate-moieties for siRNA delivery.

FIGURE 3

Different kinds of motifs (A) A-motifs are pH-induced AH⁺–H⁺A base-paired right-handed symmetric parallel-stranded duplex form of poly dA sequences with a highly reversible nature. (B) I-motifs are pH-induced intercalated C-rich DNA quadruplex with C-C⁺ base pairing. (C) G-quadruplexes are formed by guanine tetrads stacked in G-rich DNA or RNA sequences.

FIGURE 4

(A) Schematic representation of aptamer-GNRs based cancer detection system, where mucin-1 aptamer-decorated GNRs detect breast cancer cells (MCF-7) specifically among other cells and generate a higher signal on LSPR spectra (Li et al., 2016a). (B) Molecular beacons, a hairpin loop DNA structure with a fluorophore, and a quencher attached on each end remain in proximity until a target DNA/RNA molecule hybridizes with it. Hybridization opens the hairpin structure and fluorescence can be seen as read-out (Tyagi and Kramer, 1996). (C) Representation of DNA nanoswitch based detection of a target viral RNA (Zhou et al., 2020). DNA nanoswitch changes structural configuration from linear strand to a loop, when introduced to a complementary target DNA/RNA molecule, which results into slower mobility on gel electrophoresis. Reproduced with permission from ref Zhou et al. (2020). Copyright 2020, American Association for the Advancement of Science (AAAS).

FIGURE 5

(A) Construction of the Apt/Dz constrained catenane nanostructure and (B) the representation of targeted delivery of the Apt/Dz nanostructure for gene silencing into cancer cells. Reproduced with permission from ref Li et al. (2020). Copyright 2020, The Royal Society of Chemistry (RSC).

FIGURE 6

DNA based hydrogels formation by (A) self-assembly of complimentary base pairing (Xing et al., 2011), (B) enzymatic ligation (Um et al., 2006), (C) polymerase chain reaction (Hartman et al., 2013), (D) DNA synthesized in situ via rolling circle amplification (RCA) having a large amount of physical entanglement (Lee et al., 2012b), (E) hybridization chain reaction (Wang et al., 2017b) and (F) DNA base pairing induced gelation of acrylamide (Nagahara and Matsuda, 1996). Reproduced with permission from ref Morya et al. (2020). Copyright 2020, American Chemical Society (ACS).