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WIREs Nanomed Nanobiotechnol
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Functionalizing DNA nanostructures for therapeutic applications

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Abstract Recent advances in nanotechnology have enabled rapid progress in many areas of biomedical research, including drug delivery, targeted therapies, imaging, and sensing. The emerging field of DNA nanotechnology, in which oligonucleotides are designed to self‐assemble into programmable 2D and 3D nanostructures, offers great promise for further advancements in biomedicine. DNA nanostructures present highly addressable and functionally diverse platforms for biological applications due to their ease of construction, controllable architecture and size/shape, and multiple avenues for chemical modification. Both supramolecular and covalent modification with small molecules and polymers have been shown to expand or enhance the functions of DNA nanostructures in biological contexts. These alterations include the addition of small molecule, protein, or nucleic acid moieties that enable structural stability under physiological conditions, more efficient cellular uptake and targeting, delivery of various molecular cargos, stimulus‐responsive behaviors, or modulation of a host immune response. Herein, various types of DNA nanostructure modifications and their functional consequences are examined, followed by a brief discussion of the future opportunities for functionalized DNA nanostructures as well as the barriers that must be overcome before their translational use. This article is categorized under: Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Therapeutic Approaches and Drug Discovery > Emerging Technologies Biology‐Inspired Nanomaterials > Nucleic Acid‐Based Structures
Electrostatic coating strategies for in vivo DNA nanostructure stabilization. (a) Schematic of PEGylated oligolysine coating and subsequent crosslinking by glutaradehyde. Figure adapted from Ponnuswamy et al. (Ponnuswamy et al., 2017) and Anastassacos et al. (Anastassacos et al., 2020). (b) Block copolymer protection strategy. DNA origami is degraded in the absence of polymer (shown in gray/green) but protected from nucleases after polymer complexation. Decomplexation is made possible via competition with dextran sulfate (shown in red). Figure adapted from Agarwal et al. (Agarwal et al., 2017). (c) Schematic view of the two types of peptoid surface coatings of octahedral DNA origami (brush‐type and block‐type) and their chemical structures. Figure adapted from Wang, Gray, et al. (2020); Wang, Song, et al. (2020). (d) Lipid micellization of an octahedral DN with lipid‐conjugated DNA handles in a solution of surfactant and lipids (liposomes, DOPC, and PEG‐PE). Figure adapted from (Perrault & Shih, 2014). (e) Schematic of BSA conjugated to a synthetic binding domain (G2) and its dendritic chemical structure. Figure adapted from (Auvinen et al., 2017)
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Immune modulation methods using DN functionalization. (a) TLR9‐induced immunostimulation by DNA nanotubes modified with three kinds of orthogonal cytosine‐phosphate‐guanine (CpG) oligonucleotides and handle sequences (CpG‐H's). CpG‐h′ PTO‐labeled strands feature stabilizing phosphorthioate (PTO)‐modified backbones, and CpG‐H′ chimera strands feature a PTO‐modified CpG segment and a handle sequence whose backbone is unmodified. Figure adapted from (Schüller et al. Schüller et al., 2011). (b) CpG oligonucleotides arranged in polypod‐like structures comprised of three (top left), four (top right), six (bottom left), or eight (bottom right) oligonucleotides. Adapted from Mohri et al. (Mohri et al., 2012). (c) A DNA tetrahedron bearing CpG motifs that induces TLR9‐dependent immune activation. Adapted from Li et al. (Li et al., 2011). (d) Schematic of a synthetic DNA vaccine co‐delivering CpG adjuvants and model antigens and the subsequent DN‐mediated antigen presentation and activation of B and T cells. Figure adapted from Liu et al. (Liu et al., 2012). (e) Fabrication of a dual adjuvant (dsRNa and CpG loop motif) and antigen‐carrying DNA delivery vehicle (top) and atomic force microscopy images (bottom) of its unloaded open (left), cargo‐loaded open (middle), and cargo‐loaded closed state (right). Figure adapted from Liu et al. (Liu et al., 2020)
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Stimulus‐responsive moieties in DNA nanostructures. (a) Chemical structure of DNA i‐motif cytosine‐cytosine+ base pairing (left) and a schematic of an i‐motif‐incorporated, DNA tetrahedron that dissociates in an acidic environment (right). Adapted from Keum & Bermudez (Keum & Bermudez, 2012). (b) Chemical structures of pH‐dependent Hoogsteen triplex thymine‐adenine‐thymine (TAT, top left) and cytosine+‐guanosine‐cytosine (C+GC, bottom left) base pairing and a schematic of a DNA tetrahedron designed to utilize these interactions to assemble and disassemble according to environmental pH (right). Figure adapted from Liu et al. (Liu et al., 2013). (c) DNA tetrahedron assembly via oxidation of cysteamine‐modified DNA. Subsequent disassembly can be achieved via glutathione (GSH)‐mediated reduction of the resulting disulfide bond. Figure adapted from Wang et al. (Wang et al., 2019). (d) Azobenzene UV‐triggered trans to trans cis isomerization (left) and a schematic of the light‐droven opening and closing of azobenzene‐incorporated DNA nano‐tweezers (right). Adapted from Liang et al. (Liang et al., 2008)
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DNA nanostructure‐mediated cargo delivery methods. (a) siRNA hybridized to a tetrahedral DN during assembly to enable cellular delivery of the RNAi therapeutic. Adapted from Lee et al. (Lee et al., 2012). (b) Antisense oligonucleotides (ASOs) with phosphorothioate (PS)‐modified backbones are hybridized to DNA cage in varying amounts. Adapted from Fakhoury et al. (Fakhoury et al., 2014). (c) A kite‐shaped, Dox‐intercalated triangular DN outfitted with two disulfide‐linked tumor suppressor genes (p53) for the delivery of a combination gene and chemotherapy. Figure adapted from Liu et al. (Liu et al., 2018). (d) Cross‐sectional and perspective view of an aptamer‐gated DNA nanorobot loaded with a protein payload. Image adapted from Douglas et al. (Douglas et al., 2012). (e) “Mirror‐image” DNA tetrahedron assembled from L‐DNA outfitted with streptavidin that enables modular loading of biotinylated species onto the DN. Figure adapted from Kim et al. (Kim et al., 2018). (f) Luciferase‐loaded DNs are taken up into cells and their uptake efficiency is measured by a luminescence assay performed on cell lysate. Adapted from Ora et al. (Ora et al., 2016). (g) Triangular DN intercalated with Dox and delivered via tail vein injection into murine models. Figure adapted from Zhang et al. (Zhang et al., 2014). (h) DNA tetrahedron self‐assembled from cholesterol‐ and chemotherapeutic 5‐fluoro‐2′‐deoxyuridine (FdU)‐modified DNA strands. Adapted from Jorge et al. (Jorge et al., 2018)
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Methods for cell‐specific targeting and uptake of DNA nanostructures. (a) Viral capsid proteins for electrostatic coating and enhancement of cellular uptake of DNA origami structures. Figure adapted from (Mikkila et al., 2014). (b) DNA nano‐bundles modified with a varying number of cholesterol moieties (depicted in orange) to enhance DN interaction with the cell membrane and increase internalization. Figure adapted from Whitehouse et al. (Whitehouse et al., 2019). (c) Tumor penetrating peptide conjugation with a Dox‐intercalated DNA tetrahedron that allows for cancer‐specific DN uptake. Figure adapted from Xia et al. (Xia et al., 2016). (d) Folate‐modified DNA nanotube labeled with a fluorescent dye (Cy3) capable of targeting folate receptor‐overexpressing cancer cells. Image adapted from Ko et al. (Ko et al., 2008). (e) Nucleolin‐specific aptamer (AS1411)‐modified tetrahedral DNs (TDN) elicit increased internalization into cancer cell lines compared to nonaptamer modified TDNs. Adapted from Li et al. (Li et al., 2017)
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Biology-Inspired Nanomaterials > Nucleic Acid-Based Structures
Therapeutic Approaches and Drug Discovery > Emerging Technologies
Nanotechnology Approaches to Biology > Nanoscale Systems in Biology

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