Introduction
Acyclic threoninol nucleic acid (aTNA) and serinol nucleic acid (SNA) are synthetic nucleic acid analogs developed to enhance the stability, binding behavior, and functional utility of oligonucleotides. Both belong to the broader family of xeno nucleic acids (XNAs) and differ from DNA and RNA by replacing the natural ribose sugar with flexible, acyclic backbone architectures. These structural modifications can improve resistance to enzymatic degradation and broaden the potential of oligonucleotides in therapeutic, diagnostic, and nanotechnology-based applications. [1,2] Structure of aTNA and SNA oligo modifications
Structure of aTNA and SNA oligo modifications
Technology Overview
aTNA is an artificial phosphodiester-linked nucleic acid built on a threoninol-derived scaffold attached to canonical nucleobases. In contrast to the rigid cyclic sugar framework of DNA and RNA, aTNA contains a flexible acyclic backbone that can still support highly ordered duplex and higher-order structures. Studies have shown that aTNA maintains good aqueous solubility, resists serum nucleases, and can be used to assemble compact and stable 3D nanostructures. [2,3] SNA is another acyclic nucleic acid platform designed with similar goals, but its structural behavior differs in important ways. Although SNA can hybridize with complementary DNA and RNA strands, its more flexible scaffold is less preorganized than that of aTNA. As a result, SNA may be easier to adapt into standard oligonucleotide workflows, whereas aTNA often provides stronger structural control and higher order organization in selected systems.
Structural and Binding Characteristics
The key distinction between these two systems lies in how they interact with natural nucleic acids. L-aTNA has been reported to cross-pair strongly with complementary DNA and RNA, often showing greater thermal stability than SNA. This behavior suggests that its backbone geometry is well suited for productive hybridization and the formation of stable duplexes, triplexes, and other ordered nucleic acid assemblies. [1-3]
By comparison, SNA is more flexible and less stereochemically constrained. It can still form stable hybrids, but sequence-specific substitutions may lead to localized destabilization depending on the context. From a design perspective, this means that aTNA is generally preferred when high affinity and structural rigidity are important, while SNA may be more practical for conventional hybridization-based applications.
Technical Advantages
The most important advantage of aTNA is its combination of biochemical stability and structural versatility. Because the backbone is acyclic, it is less susceptible to nuclease-mediated cleavage, which may improve persistence in biological systems. This makes aTNA especially attractive for antisense strategies, gene regulation, and other nucleic acid-based therapeutic approaches.
aTNA is also highly relevant to nanotechnology. Recent studies have demonstrated its ability to self-assemble into ultrasmall 3D architectures such as cubes and pyramids with high thermal and serum stability. These properties make aTNA a promising scaffold for molecular delivery systems, biosensors, and other nanoscale platforms that require durable and programmable structural elements. [3,4]
Conclusion
Overall, aTNA and SNA illustrate how backbone engineering can expand the chemical and biological performance of oligonucleotides. aTNA is distinguished by stronger binding, higher nuclease resistance, and the ability to form stable higher-order structures, whereas SNA offers a more flexible scaffold with distinct hybridization behavior. For advanced antisense, nanostructure, and delivery applications, aTNA currently appears to be the more powerful platform, although both remain important research tools in the XNA field.
References
1. https://pubs.rsc.org/cc/article-abstract/51/30/6500/429226/Acyclic-l-threoninol-nucleic-acid-l-aTNA-with?redirectedFrom=fulltext
2. https://www.nature.com/articles/pj201639
3. https://pubs.acs.org/doi/10.1021/jacs.4c04919