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ABSTRACT
DNA's programmable, predictable, and precise self-assembly properties enable structural DNA
nanotechnology. DNA nanostructures have a wide range of applications in drug delivery, bioimaging,
biosensing, and theranostics. However, physiological conditions, including low cationic ions and the presence of nucleases in biological systems, can limit the efficacy of DNA nanostructures. Several
strategies for stabilizing DNA nanostructures have been developed, including i) coating them with
16 biomolecules or polymers, ii) chemical cross-linking of the DNA strands, and iii) modifications of the
nucleotides and nucleic acids backbone. These methods significantly enhance the structural stability of
DNA nanostructures and thus enable in vivo and in vitro applications. This study reviews the present
perspective on the distinctive properties of the DNA molecule and explains various DNA nanostructures,
their advantages, and their disadvantages. We provide a brief overview of the biomedical applications of
DNA nanostructures and comprehensively discuss possible approaches to improve their biostability.
Finally, the shortcomings and challenges of the current biostability approaches are examined.
Keywords: DNA nanostructures, Biostability, Biomedical applications, DNA nucleases
Hybrid nucleic acid-nanoparticles combine molecular recognition and programmability features of DNA with the efficient properties of nanoparticles. Different hybrid DNA nanostructures have emerged depending on the types of nanoparticles, including DNA-inorganic nanoparticles, DNA-lipid, and DNA- polymer hybrid nanosystems [41]. DNA-gold nanoparticles complex combines the high affinity and specificity of the DNA for a specific ligand with the optical features of the gold nanoparticles in biosensor development and drug delivery [42]. For instance, hybrid DNA-gold nanoparticles functionalized with human epidermal growth factor receptor 2 antibodies specifically target the breast cancer cells for co- delivery of the doxorubicin and 5-fluorouracil anticancer drugs [43]. DNA-calcium phosphate nanoparticles are biocompatible structures with high cellular uptake. These hybrid structures have shown strong immunological response, high transfection efficiency, and immunomodulatory function [44,45].