materials Review DNA Origami as Emerging Technology for the Engineering of Fluorescent and Plasmonic-Based Biosensors 1, , 2, , 1 2, Morgane Loretan * y, Ivana Domljanovic * y, Mathias Lakatos , Curzio Rüegg y and 1, Guillermo P. Acuna y 1 Photonic Nanosystems, Department of Physics, Faculty of Science and Medicine, University of Fribourg, Chemin du Musée 3, PER08, 1700 Fribourg, Switzerland; [email protected] (M.L.); [email protected] (G.P.A.) 2 Laboratory of Experimental and Translational Oncology, Department of Oncology, Microbiology and Immunology, Faculty of Science and Medicine, University of Fribourg, Chemin du Musée 18, PER17, 1700 Fribourg, Switzerland; [email protected] * Correspondence: [email protected] (M.L.); [email protected] (I.D.) These authors contributed equally to this work. y Received: 7 April 2020; Accepted: 5 May 2020; Published: 9 May 2020 Abstract: DNA nanotechnology is a powerful and promising tool for the development of nanoscale devices for numerous and diverse applications. One of the greatest potential fields of application for DNA nanotechnology is in biomedicine, in particular biosensing. Thanks to the control over their size, shape, and fabrication, DNA origami represents a unique opportunity to assemble dynamic and complex devices with precise and predictable structural characteristics. Combined with the addressability and flexibility of the chemistry for DNA functionalization, DNA origami allows the precise design of sensors capable of detecting a large range of different targets, encompassing RNA, DNA, proteins, small molecules, or changes in physico-chemical parameters, that could serve as diagnostic tools. Here, we review some recent, salient developments in DNA origami-based sensors centered on optical detection methods (readout) with a special emphasis on the sensitivity, the selectivity, and response time. We also discuss challenges that still need to be addressed before this approach can be translated into robust diagnostic devices for bio-medical applications. Keywords: DNA nanotechnology; DNA origami; biosensors; optics (plasmonic and fluorescence sensing) 1. Introduction 1.1. DNA Nanotechnology Nanotechnology allows applications of novel materials and devices at the nanoscale level in all disciplines of science. One emerging material for nanoscale engineering is DNA [1]. Some of the main characteristics of DNA are the high specificity, programmability, flexibility, and sub-nanometer precision. These characteristics allow DNA to be used for the construction of highly precise nanostructures, as demonstrated first by Seeman, in his ground-breaking research in the early 1980s [2]. Self-assembly of DNA nanostructures started with crossovers and branched junctions [3] followed by a variety of DNA objects such as polyhedral [4], prisms [5], and buckyballs [4]. Subsequently, self-assembly of DNA was further developed into an advanced order of design using DNA crossover tiles [6]. With this strategy, sticky ends are added to DNA for creating two-dimensional (2D) [7] and three-dimensional (3D) [8,9] periodic lattices. Another more advanced single-stranded DNA tiles strategy for DNA-based construction is DNA bricks that form large DNA structures in 2D and 3D [10]. All self-assemblies Materials 2020, 13, 2185; doi:10.3390/ma13092185 www.mdpi.com/journal/materials Materials 2020, 13, x FOR PEER REVIEW 2 of 25 Materials 2020, 13, 2185 2 of 24 structures in 2D and 3D [10]. All self-assemblies mentioned above are based on a combination of “short”mentioned single above-stranded are based DNA on aor combination pre-assembled of “short” DNA single-strandedmotifs. The structures DNA or assembled pre-assembled via these DNA methodsmotifs. The can structures be used as assembled programmable via these scaffo methodslds forcan the beorganization used as programmable of different nanoparticles scaffolds forthe or moleculesorganization [11] of, but diff areerent still nanoparticles limited by the or size molecules and the [11 complexity.], but are still In 2006, limited a method by the sizecalled and DNA the origamicomplexity. was Inintroduced 2006, a method by Rothemund called DNA [12] origami. This method was introduced enabled an by increase Rothemund in complexity [12]. This methodand the creatienabledon anof increaselarger nanostructures in complexity and(in the the range creation of hundreds of larger nanostructures of nm) [13,14] (in. 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Besides,precision DNA and origami accuracy, structures makes DNAare natural origami biopolymers a highly addressable that are biocompatible, tool with predictable biodegradable, conformation and minimally structures toxic [25]. [ 26Besides]. Thus,, DNA this origamiapproach structures has a great are potential natural biopolymers in biomedical tha applicationst are biocompatible, [26,27]. Furthermore, biodegradable, it was and shown minimally that toxicDNA [2 origami6]. Thus, structures this approach are more has a stable great than potential other in nucleic biomedical acid structures, applications facilitating [26,27]. Furthermore, their use for itbiological was shown and technicalthat DNA applications origami structures [28]. In addition, are more the stable development than other of DNA nucleic origami acid enabledstructures, the facilitatielaborationng their of “dynamic” use for biological structures and whose technical functions applications rely upon [28 conformational]. 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