Delivering a particular drug at a targeted site has always been a challenge for researchers. Many of the available techniques lack specificity and thereby, end up harming the healthy tissues or cells.
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For many years, researchers have worked extensively on developing various novel techniques to formulate an effective drug delivery system. Currently, scientists have developed a DNA nanostructure that promises permeability, programmability, and biocompatibility that are all essential for efficient drug delivery and the treatment of several diseases.
The combination of DNA structures with nanotechnology has paved the way to create DNA nanostructures. The innate complementary base-pairing system of DNA allows the first-rate programmability for DNA, making them an ideal ingredient for building complex nanostructures. Further, their high permeability, biocompatibility, and ability to accurately assemble quickly (within hours) at a specific site make them the most effective candidate for drug delivery.
Currently, researchers at the Wyss Institute for Biologically Inspired Engineering, at Harvard University in the United States, have established two methods for developing nanostructures (random shaped) using DNA. The main aim of creating these DNA nanostructures is to develop effective technology for drug delivery applications and nanofabrication. The technologies developed at the Wyss Institute are described below:
This DNA nanofabrication technique uses small synthetic DNA strands whose characteristic features are similar to that of Lego bricks, i.e., how one Lego block interlocks with the other. Researchers have exploited the natural tendency of DNA to form specific shapes, for example, the DNA base pair follows the rule of thumb where adenosine only binds to thymine and cytosine binds to guanine.
This DNA nanofabrication also capitalizes on the self-assembly and programmable nature of DNA. The DNA double-helical strands are customized to form specific shapes. In this process, one large single strand of DNA is used as a “scaffold”, which is modified by manipulating the numerous small, synthetic DNA strands (lattice), that are developed using computer software. DNA origami is used to create 3-dimensional structures, that are useful for designing an effective drug delivery system and nanoscale tools.
Researchers also believe that nanomaterials-based therapeutics could help overcome some of the technical challenges of immunotherapy. The small size of nanomaterials promotes efficient cellular uptake, for example, infiltration into antigen-presenting cells (APCs) via the surrounding mucosal barrier and mesenchyme.
Several nanomaterials are widely used to transport a variety of biologically active immune-related antigens and adjuvants. Scientists have created different types of DNA nanostructures, such as DNA cages, DNA particles, DNA polypods, and DNA hydrogel, that are used to develop novel nano-systems for effective drug delivery. Some such DNA nanostructures used for drug delivery are discussed below:
The wireframe architectures that are formed by the assembly of DNA strands are known as DNA cages. There are many types of DNA cages such as DNA polyhedrons, DNA nanotube, etc. A DNA polyhedron is a non-cytotoxic, stable, mechanically strong, and 3D cage-like compacted structure which is easily absorbed by cells.
In many immune therapies, DNA tetrahedron is the most widely used nanostructure to load various immune moieties that includes peptides, and CpG. DNA tetrahedra are composed of DNA-lipid micellar nanoparticles and can be effectively used as a drug delivery system.
One of the common DNA based nanoparticles is a spherical nucleic acid. It consists of two components, a dense radially surrounding nucleic acid shell and a solid or hollow nanoparticle core. In the drug delivery system, spherical nucleic acids have more advantages than linear nucleic acids. This is because the affinity of spherical nucleic acids to complementary nucleic acids is higher than that of linear counterparts due to their special geometry.
Owing to this structure, the spherical nucleic acids are more stable than their linear form. Also, spherical nucleic acids can penetrate a variety of cells and with excellent cellular uptake in the absence of an auxiliary transfection agent.
Spherical nucleic acids are biologically compatible and are non-cytotoxic. They can bind with effective ligands and thereby serve as a powerful platform for the application of molecular diagnostic, gene regulation, and immunomodulatory therapy.
Currently, liposomal spherical nucleic acids are used in immunotherapy.
Polypod-like DNA Nanostructure
Scientists have reported various kinds of polypod-like DNA nanostructure, such as DNA nano-centipede, and polypodna. Polypod nanostructures have a long backbone that provides structural stability and contains numerous branched structures that greatly increases drug binding sites.
In comparison to DNA tetrahedron, polypod-shaped DNA has better geometrical flexibility. Polypodna by itself acts as an immunostimulatory agent. Scientists have reported that Y-shaped polypodna can induce great amounts of cytokines TNF-a and IL-6 than normal native double-stranded DNA.
DNA nano-centipede is also considered a powerful drug delivery platform. Their structure is analogous to centipede and consist of “trunk” and “legs”. Its structural construction promotes high loading capacity and cytotoxicity only to target cancer cells.
Nanohydrogels are polymeric nanoparticles that possess high mechanical stability, biocompatibility, great payload capacity, and flexibility. These characteristic features make nanohydrogels a strong drug carrier and are used in many cancer treatments. Their drug loading volume is much greater than traditional DNA nanostructures.
Scientists have also built multifunctional DNA nanoflowers that contain bioimaging agents, therapeutic drugs, and genes. Owing to these properties, the DNA nanoflowers can be used as excellent nanocarriers. These structures are biocompatible and do not get degraded by nuclease.
DNA nanoflowers are easily internalized by macrophages mainly due to their nanoscale size. They are considered excellent nanocarriers for the intracellular delivery of CpG for immunotherapy treatment of cancer.
This article shows how the application of various types of DNA nanostructures in biomedical applications could be an excellent alternative to conventional therapies for many diseases such as cancer. The excellent biological compatibility and programmability of DNA nanostructures have shed new light on DNA-based drug delivery systems that are yet to be exploited to their full potential.
References and Further Readings
- DNA Nanostructures for Drug Delivery. (2020). https://wyss.harvard.edu/technology/dna-nanostructures-for-drug-delivery/
- Chi, Q. et al. (2020). DNA Nanostructure as an Efficient Drug Delivery Platform for Immunotherapy. Frontiers in Pharmacology. 10,1585. https://doi.org/10.3389/fphar.2019.01585
- Wu, N., Zhao, Y. DNA Nanostructures as Drug Carriers for Cellular Delivery. Chem. Res. Chin. Univ. 36, 177–184 (2020). https://doi.org/10.1007/s40242-020-9070-0