Nucleic acid nanostructures for in vivo applications: The influence of morphology on biological fate

Abstract

The development of programmable biomaterials for use in nanofabrication represents a major advance for the future of biomedicine and diagnostics. Recent advances in structural nanotechnology using nucleic acids have resulted in dramatic progress in our understanding of nucleic acid-based nanostructures (NANs) for use in biological applications. As the NANs become more architecturally and functionally diverse to accommodate introduction into living systems, there is a need to understand how critical design features can be controlled to impart desired performance in vivo. In this review, we survey the range of nucleic acid materials utilized as structural building blocks (DNA, RNA, and xenonucleic acids), the diversity of geometries for nanofabrication, and the strategies to functionalize these complexes. We include an assessment of the available and emerging characterization tools used to evaluate the physical, mechanical, physiochemical, and biological properties of NANs in vitro. Finally, the current understanding of the obstacles encountered along the in vivo journey is contextualized to demonstrate how morphological features of NANs influence their biological fates. We envision that this summary will aid researchers in the designing novel NAN morphologies, guide characterization efforts, and design of experiments and spark interdisciplinary collaborations to fuel advancements in programmable platforms for biological applications.

DNA nanostructure decoration: a how-to tutorial

“…Numerous other commercially available modified bases exist to support biochemical assays for applications ranging from fluorescent reporting to nuclease resistance and photo crosslinking. See the cited review for a more thorough description of modified bases relevant to biological applications [39].…”

Dynamic RNA synthetic biology: new principles, practices and potential

“…RNA biomaterials are ordered structural networks that span multiple-length scales, from nanostructures to larger mesoscale materials [ 103 ]. While much of the work in nucleic acid nanomaterials originated with DNA, recently researchers have recognized the potential for RNA’s wider range of structural motifs to expand nanomaterial functionality [ 103 ], such as metabolic pathway scaffolding [ 104 ].…”

“…In application spaces, nucleic acid-based biomaterials are being pursued for therapeutics, where they are used in drug and vaccine delivery, tissue engineering and other applications [ 112 ]. The complexity of in vivo environments, however, presents challenges with stability and toxicity [ 103 ]. RNA modifications, such as fluorination of the 2’ ribose position, can improve resistance to nucleases while retaining RNA structure and biological activity [ 113 ].…”

Membrane and glycocalyx tethering of DNA nanostructures for enhanced uptake

“…Nanoscaled platforms have drawn enormous research effort in the past decade for imaging, biosensing and drug delivery. [1][2][3][4][5][6][7][8] These nanoplatforms can carry molecular loads, including diagnostic and therapeutic agents, serving as effective delivery vehicles to target specific cell-types and intracellular compartments. 9,10 Nevertheless, their internalization and accumulation inside of cells have raised concerns over cytotoxicity.…”

“…14,15 Structural DNA nanotechnology is recognized as a practicable candidate to potentially overcome the aforementioned obstacles because of its biocompatibility, biodegradability, programmability and ease of functionalization. 7,8,[16][17][18][19][20][21] Since its emergence, various DNA nanostructures (DNs) have been designed and synthesized with nanoscale precision, and modified with chemical and biological conjugates. 20,[22][23][24][25] For example, recent studies show the potential of DNs to enable robust expression genetic cargo for therapeutics.…”