Transient Cyclic Structured Oligonucleotide Designs for Therapeutic Applications

Oligonucleotide-based therapeutics are now widely used in clinical settings. From the late 1980s to the mid-1990s, efforts to improve therapeutic efficacy focused on imparting drug-like properties to oligonucleotides, emphasizing nuclease stability and target sequence affinity. These efforts resulted in the standard gapmer design for RNase H-mediated antisense and the prevalent use of chemical modification such as phosphorothioate and 2'-substituted oligoribonucleotides in oligonucleotide therapeutics. Progress made in the antisense field also enabled the development of splice-modulating oligonucleotide therapeutics and later siRNA therapies. All three modes of action are now widely employed in >25 approved drugs. Since then, we have learned that oligonucleotides and their chemical modifications can interact with pattern recognition receptors as well as various other proteins. This can have both positive and negative effects, such as aiding in oligonucleotide delivery or activating the intracellular innate immune system. My current work aims to optimize the drug-like properties of oligonucleotides by combining the early chemical advances with the more recent insights into off-target protein binding. The present article describes how this resulted in several different cyclic structured oligonucleotide designs, in which 3' and 5' ends are transiently held together via Watson-Crick base pairing. The transient nature of these cyclic structures protects the functional parts of the structure against nucleases during delivery and cell entry while allowing effective release of the oligonucleotide drug into the intracellular environment. These cyclic designs demonstrate significant improvements in potency and specificity over gapmer antisense and are broadly applicable to potentially all types of RNA therapeutics, irrespective of their mechanism of action. © 2026 Wiley Periodicals LLC.