DNA Nanotechnology

DNA nanotechnology utilizes artificial nucleic acids as a material for the assembly of functionalized nanostructures. The field of DNA nanotechnology has been made possible thanks to the work of Robert Letsinger and Marvin Caruthers on synthetic DNA chemistry.1 The commercial availability of synthesized DNA strands of practically any sequence and the ability to position functional groups on DNA strands has contributed to the rapid emergence of this bottom-up approach since the 1990s. Now nearly all the materials required for DNA nanotechnology can be ordered, including modified DNA bases.2

Some of the emerging practical applications in DNA nanotechnology include:

  • Biosensing
  • Molecular imaging
  • Drug delivery

When it comes to DNA-based nanostructures, a wide range of building blocks are accessible as chemically modified oligonucleotides. Many modifications can be incorporated directly into oligonucleotides during solid-phase synthesis, but others rely on post-synthesis conjugation. The overview below highlights some of the functional groups available as reagents and used for the modification of oligonucleotides. For more information about the modifications that Glen Research offers, click on any of the categories below.

 Functional GroupDescription
 Amino-ModifiersAmino-modified oligonucleotides are reactive to a broad range of functional moieties such as suitably activated dyes, reporter groups or surfaces.
 Thiol-ModifiersThiol-modification of oligonucleotides is important for labeling with thiol-specific tags (iodoacetamides, maleimides), conjugation of enzymes, and attachment of oligos to gold surfaces. Dithiol Serinol, produced from lipoic acid and our patented serinol backbone, allows easy connection of multiple dithiol-labeled oligos to gold surfaces.
 Click and Copper-free Click   Chemistry

The use of copper(I)-stabilizing ligands has led to the use of click chemistry to functionalize alkyne-modified DNA nucleobases with extremely high efficiency. Alternatively, copper free click reactions are possible using highly strained alkyne groups. Glen Research supports two click techniques: copper (I) catalyzed azide-alkyne cycloaddition (CuAAC); and strained cyclooctyne cycloaddition with dibenzocyclooctyne (DBCO). Copper-assisted cycloadditions are efficient and, with the THPTA ligand, solution phase conjugation is complete in as little as 15 minutes. The reaction between DBCO and an azide is a simpler and equally efficient conjugation that avoids a copper catalyst.

 Aldehyde ModifiersAldehyde modifiers are electrophilic substitutions that can be reacted with amino groups to form a Schiff’s base, hydrazino groups to form hydrazones, and with semicarbazides to form semi-carbazones.
 NHS EstersAn NHS ester allows the functionalization of an amino moiety in a variety of molecules, including DNA and RNA oligonucleotides, as well as peptides or proteins. NHS esters are especially useful in situations where the equivalent phosphoramidites exhibit instability to the conditions of oligonucleotide synthesis and/or deprotection.

Modifications in DNA Nanostructures

A wide range of chemical modifications are available for oligonucleotides. These are some of the most common functional moieties introduced into DNA nanostructures.

Fluorescent Dyes and Quenchers

The most common modification found in DNA nanotechnology are fluorophores. These are widely used as markers in gels and microscopy, for sensing devices, to monitor dynamics and distances or kinetics, for light harvesting and energy transfer, and for single molecule microscopy.3

View Fluorescent Dyes and Quenchers


Avidin, streptavidin and other biotin-binding proteins have the ability to form an intense association with biotin-containing molecules. This association has been used for many years to develop systems designed to capture biotinylated biomolecules. Biotin-avidin affinity provides an established approach for protein-DNA attachment.

View Biotin Modifications


Cholesterol, tocoperol, and stearyl modifications can be incorporated into oligonucleotides during synthesis. The addition of lipophilic groups to an oligonucleotide would be expected to enhance cellular uptake/membrane permeation, which is necessary for optimal activity of potential therapeutic oligonucleotides.

View Cholesterol Modifications

View Tocoperol Modifications

View Stearyl Modifications


DNA nanostructures can be functionalized through the incorporation of electrochemical labels. Changes in the transfer of electrons can be detected and measured using modifications such as methylene blue and ferrocene as redox reporters. Ferrocene has been studied extensively and is available as a phosphoramidite for easy addition to oligonucleotides.

View Electrochemical Modifications


When a photo-responsive molecule is directly attached to DNA as a receptor, photo-regulation of the bioprocess regulated by that DNA molecule could, in principle, be achieved. Such photo-responsive DNA could also be used as a switch in a DNA-based nano-machine.

View Photo-regulation Modifications


Cross-linking is of interest to stabilize the interaction of two weakly bound biomolecules. Cross-linking may be initiated by a variety of chemical reactions, for example, disulfide formation, but the predominant procedure is photo-induced cross-linking.

View Crosslinking Modifications

Nucleoside Analogs

Nucleoside analogs typically increase chemical and biological stability. Chemical modifications of RNA that can alter nuclease resistance include locked nucleic acids (LNA), fluoroarabinonucleic acids (FANA), and 2’-fluoro RNA (2' F-RNA) monomers

View Nucleoside Analogs

  1. Y. Krishnan, N.C. Seeman, Chem. Rev., 2019, 119 (10), 6271-6272
  2. C. Fan, D. Li, Brief History of DNA Nanotechnology, 2013, 3-6
  3. M. Madsen, K. V. Gothelf, Chem. Rev., 2019, 119(10), 6384-6458