Y-shaped oligonucleotides: a promising platform for enhanced therapy with siRNA and CpG Oligodeoxyribonucleotides

Nucleic acids (DNA and RNA) have been recognized as promising building blocks to fabricate a variety of well-defined two- and three-dimensional architectures through the programmable molecular self-assembly of multiple oligomeric strands. Y-shaped oligonucleotides are currently among the most widely employed nanostructures in the field of nucleic acid nanotechnology due to their unique features, including high structural stability, excellent biocompatibility, simplicity and ease of synthesis, and precisely controlled sizes. To functionalize biological activity, Y-shaped oligonucleotides can be incorporated with therapeutic genes such as small interfering RNA (siRNA) for target gene-specific silencing and CpG oligonucleotides (CpG ODN) for the activation of innate immune responses. Compared to the linear structures of siRNA and CpG ODN, Y-shaped siRNA and CpG ODN structures have demonstrated significant potential in the treatment of various diseases due to improved serum stability and intracellular uptake. Here, we review a broad spectrum of related topics, including the design, construction, and characteristics of Y-shaped oligonucleotides with a specific focus on their potential as a promising platform for enhancing the therapeutic efficacy of siRNA and CpG ODN.