The facile self-assembly and nanomanipulation of nucleic acids hold great promise in the design of innovative,
programmable materials, with applications ranging from biosensing to cellular targeting and drug delivery. Little is
known, however, of the effects of confinement on biochemical reactions within such systems, in which the level of packing
and crowding is similar to that of intracellular environments. In this review article we outline novel, unexpected properties
of nucleic acids that arise from nanoscale confinement, as mainly revealed by atomic force and electron microscopy,
electrochemistry, fluorescence spectroscopy, and gel electrophoresis. We review selected scientific studies over the last
decade that describe the novel behavior of nanoconfined nucleic acids with respect to hybridization, denaturation, conformation,
stability, and enzyme accessibility. The nanoscale systems discussed include self-assembled, water-soluble,
DNA or RNA nanostructures, ranging in width from a few to several tens of nm; gold nanoparticles coated with DNA
monolayers; and self-assembled monolayers of DNA, from a few to several hundreds of bp in length. These studies reveal
that the functionality of nucleic acid-based nanosystems is highly dependent upon the local density, molecular flexibility
and network of weak interactions between adjacent molecules. These factors significantly affect steric hindrance, molecular
crowding and hydration, which in turn control nucleic acid hybridization, denaturation, conformation, and enzyme accessibility.
The findings discussed in this review article demonstrate that nucleic acids function in a qualitatively different
manner within nanostructured systems, and suggest that these novel properties, if better understood, will enable the development
of powerful molecular tools for nanomedicine.
Keywords: Atomic force microscopy, crowding, denaturation, detection, DNA, electrochemistry, enzymes, fluorescence, hybridization,
molecular device, nanoarray, nanomanipulation, nanomedicine, nanotechnology, nucleic acids, nucleases, RNA,
self-assembled monolayers, self-assembly, steric hindrance, surfaces.
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