DNA origami applications in cancer therapy

Abstract

Due to the complexity and heterogeneity of cancer, the development of cancer diagnosis and therapy is still progressing, and a complete understanding of cancer biology remains elusive. Recently, cancer nanomedicine has gained much interest as a promising diagnostic and therapeutic strategy, as a wide range of nanomaterials possess unique physical properties that can render drug delivery systems safer and more effective. Also, targeted drug delivery and precision medicine have now become a new paradigm in cancer therapy. With nanocarriers, chemotherapeutic drugs could be directly delivered into target cancer cells, resulting in enhanced efficiency with fewer side-effects. DNA, a biomolecule with molecular self-assembly properties, has emerged as a versatile nanomaterial to construct multifunctional platforms; DNA nanostructures can be modified with functional groups to improve their utilities as biosensors or drug carriers. Such applications have become possible with the advent of the scaffolded DNA origami method. This breakthrough technique in structural DNA nanotechnology provides an easier and faster way to construct DNA nanostructures with various shapes. Several experiments proved that DNA origami nanostructures possess abilities to enhance efficacies of chemotherapy, reduce adverse side-effects, and even circumvent drug resistance. Here, we highlight the principles of the DNA origami technique and its applications in cancer therapeutics and discuss current challenges and opportunities to improve cancer detection and targeted drug delivery.

Keywords: Cancer; DNA origami; drug delivery; nanotechnology; targeted therapy.

Figure 1

DNA origami technique and nanostructures. (a) Principles of DNA origami technique. Hundreds of staples (red) fix the scaffold (gray) to create a desired shape. Reproduced from Sandersen (2010), with permission from [Nature Publishing Group].17 (b) First examples of DNA origami nanostructures from Rothemund. Top panels are the designed shapes and bottom panels are atomic force microscope (AFM) images. Reproduced from Rothemund (2006), with permission from [Nature Publishing Group].16 (c) Multilayered DNA origami nanostructures. Top panels, designed shapes; bottom panels, AFM images. Reproduced from Douglas et al. (2009), with permission from [Nature Publishing Group].18 (d) Wireframe DNA origami nanostructures. Top panels, designed shapes; bottom panels, AFM images. Reproduced from Benson et al. (2015), with permission from [Nature Publishing Group].19 (e) Movable DNA origami nanostructures. Reproduced from Marras et al. (2015), with permission from [US National Academy of Sciences].20

Figure 2

Functionalized DNA origami nanostructures. (a) Anti‐Pf LDH aptamer‐modified DNA origami rectangles as a diagnostic tool for malaria. Reproduced from Godonoga et al. (2012), with permission from [Nature Publishing Group].7 (b) DNA origami monoliths modified with cholesterols (yellow) and fluorescent molecules (green). Reproduced from Czogalla et al., with permission from [John Wiley and Sons].9 (c) Transferrin‐modified DNA origami rectangles for enhanced cellular internalization. Reproduced from Schaffert et al. (2016), with permission from [John Wiley and Sons].12 (d) Silver nanoparticles (AgNP) (yellow) and gold nanoparticles (AuNP) (red) precisely organized onto DNA origami triangles. Reproduced from Pal et al. (2010), with permission from [John Wiley and Sons].32 (e) Azo‐benzene modified DNA origami nanocapsules which their conformational changes could be controlled by light. Reproduced from Takenaka et al. (2014), with permission from [John Wiley and Sons].26

Figure 3

DNA origami nanostructures as drug carriers. (a) DNA octahedron (blue) encapsulated inside lipid bilayer. Top panels, transmission electron microscopy images of free octahedrons; bottom panels, transmission electron microscopy images of lipid encapsulated octahedrons. Reproduced from Perrault and Shih (2014), with permission from [American Chemical Society].49 DOPC, 1,2‐dioleoyl‐sn‐glycero‐3‐ phosphocholine; PEG‐PE, polyethylene glycol‐ phosphatidylethanolamine. (b) Fluorescently labeled DNA origami tubes for cellular tracking. Reproduced from Shen et al. (2012), with permission from [American Chemical Society].47 (c) Virus capsid protein (CP; blue) covered DNA origami rectangles (orange). Reproduced from Mikkila et al. (2014), with permission from [Royal Society of Chemistry].35 (d) Doxorubicin (DOX)‐containing DNA origami triangles showing enhanced permeability and retention (EPR) effects. Reproduced from Zhang et al. (2014), with permission from [American Chemical Society].15

Figure 4

Additional applications of DNA origami nanocarriers. (a) Doxorubicin (Dox)‐loaded DNA origami tubes and triangles exhibited drug resistance circumvention when treated with resistant MCF‐7 cells. Reproduced from Jiang (2012), with permission from [American Chemical Society].^{(45 )} (b) Gold nanorod (AuNR)‐functionalized DNA origami tubes and triangles used in photothermal dynamic therapy showed lower percentage cell viability of tumor cells in mice. Reproduced from Jiang et al. (2015), with permission from [John Wiley and Sons].50 DO‐GNR, DNA origami‐gold nanorod; dsDNA, double‐stranded DNA; GNR, gold nanorod; IR, infrared.