ABSTRACT The two fields of structural DNA nanotechnology and functional nucleic acids have been independently coevolving, with the former seeking to arrange and bring about movement of nucleic acid modules precisely and with control in space and the latter producing modules with incredible diversity in effective recognition and function. Here, we track the key developments in structural DNA nanotechnology that reveal a current trend that is seeing the integration of functional nucleic acid modules into their architectures to access a range of new functions. This contribution will seek to provide a perspective for the field of structural DNA nanotechnology where the integration of such functional modules on precisely controlled architectures can uncover phenomena of interest to physical chemists. D NA has proven to be a powerful material for construction on the nanoscale on the basis of the following properties: (i) the availability of automated synthetic methods and continually dropping costs, (ii) chemical robustness that confers stability on the resultant architectures and their subsequent ability to be functional under a variety of environmental conditions, (iii) the uniformly rodlike nature of the DNA double helix irrespective of its primary sequence, (iv) the specificity of Watson-Crick base pairing, which functions as an easily engineerable, site-specific, molecular-scale glue applicable to any DNA double helix, (v) the periodic nature of the DNA double helix and the predictable nature of sequence-specific thermal stability, both of which predispose it to computational methods to design and fabricate superarchitectures, (vi) the availability of well-characterized biochemical and molecular biological methods to cut, copy, and covalently link B-DNA double helices sequencespecifically, which allows manipulation of the construction material, (vii) the modular nature of the DNA scaffold that allows fabrication of architectures that are complex in terms of both structure and function when multiple modules are appended to each other, and (viii) single-stranded DNA sequences, called functional nucleic acids, which can fold and offer three-dimensional cavities suited to bind with great specificity a range of molecular entities with diverse function. In 1982, Ned Seeman proposed that DNA, which until then had been thought of as a linear polymer, could be used to make branched architectures by using stable artificial junctions with helical DNA limbs radiating from a central node. 1 These structures were analogous to metastable naturally occurring DNA motifs, such as the replication fork and Holliday junction. "It appears to be possible to generate covalently joined...networks of nucleic acids which are periodic in connectivity and perhaps in space." 1 This marked the origin of structural DNA nanotechnology that seeks to create defined architectures on the nanoscale using sequences of DNA that self-assemble into rigid rods that are, in turn, connected to form superarchitectures of precise dimensions. In 1999, it was shown that DNA could switch between two forms (the B-form and the Z-form), and this motion could be transduced along a DNA architecture, making it undergo a twisting motion. 2 Thus began a complementary aspect of structural DNA nanotechnology, of bringing about defined molecular-scale movements of DNA architectures triggered by the addition of input stimuli that are chemical, photonic, thermal, or electrical in nature. Functional nucleic acids are obtained from a test tube evolution method called SELEX independently conceptualized by the Szostak and Gold groups. 3,4 It uses molecular biology tools to pick out from a library of ∼10 15 different DNA (or RNA) sequences, a subset of sequences based on a given selection criterion and amplify them. 5 When subjected to the same selection criterion repeatedly with progressively higher stringencies, it is possible to progressively enrich from the library, a pool of DNA (or RNA) sequences with a specific functionality. If the selection criterion is the recognition of a target molecule, then selected single-stranded DNA (ssDNA) sequences are capable of binding to the target with high specificity and affinity. Thus, SELEX has yielded DNA sequences that can bind a huge variety of chemical entities ranging from small molecules to proteins, peptides, transition-stat
