Towards XNA nanotechnology: new materials from synthetic genetic polymers

Abstract

Nucleic acids display remarkable properties beyond information storage and propagation. The well-understood base pairing rules have enabled nucleic acids to be assembled into nanostructures of ever increasing complexity. Although nanostructures can be constructed using other building blocks, including peptides and lipids, it is the capacity to evolve that sets nucleic acids apart from all other nanoscale building materials. Nonetheless, the poor chemical and biological stability of DNA and RNA constrain their applications. Recent advances in nucleic acid chemistry and polymerase engineering enable the synthesis, replication, and evolution of a range of synthetic genetic polymers (XNAs) with improved chemical and biological stability. We discuss the impact of this technology on the generation of XNA ligands, enzymes, and nanostructures with tailor-made chemistry.

Figure 1

The potential of nucleic acid-like synthetic genetic polymers (XNA) as polymerase substrates, genetic materials, and functional nucleic acids. Each modification is scored for its potential as a polymerase (natural or engineered) substrate as monomers (red) or as templates (blue). Modifications are also scored for their highest reported functional complexity (green). Nucleotide triphosphates or the closest suitable analogue were scored as: , no reported incorporation or extension; , single or sparse incorporations; , multiple incorporations or partial substitution; , full substitution. The suitability of XNAs as templates are scored as: , no reported replication; , DNA synthesis from XNA template; , XNA synthesis from DNA/XNA hybrid template; , XNA replication. Functional complexity was scored as: , no proven function; , functional genetic material; , functional ligands or enzymes. The relevant references are indicated by the XNA shown [10,12–18,20,21,23,30–33,35,42–44,47–49,89–109].

Figure 2

Information complexity in nucleic acid materials. As a material, nucleic acids encode more information than what is stored in the aperiodic polymer [110–113]. Topological arrangements that deviate from the linear molecule, such as nanoparticles like spherical nucleic acids or precise structures such as DNA origami [Protein Data Bank (PDB): 2YMF, 2YMG, 2YMH, 2YMI, and 2YMR] increase the complexity of the stored information and can lead to novel physicochemical properties, such as spherical nucleic acid (SNA) efficient cellular uptake or nucleic acid structures that function as pores in lipid bilayers . Even higher information complexity can be obtained through the isolation of individual sequences capable of high affinity and specific binding to ligands (aptamers) such as an aptamer against thrombin (PDB: 3DD2) or with catalytic activity such as an RNA ligase ribozyme (PDB: 3HHN) . Structures are drawn to scale with the bar representing approximately 12.5 Å.