Therapeutic oligonucleotides revisited: Focus on siRNA and antisense technologies
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PUBLIC SUMMARY
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siRNA and antisense oligonucleotide can precisely “seal off” faulty-gene for disease treatment.
They often offer long-lasting effects and can treat previously "undruggable" genetic disorders.
Approved drugs now help patients with ATTR amyloidosis, hemophilia, and Duchenne muscular dystrophy.
A key challenge is delivering these drugs beyond the liver to other tissues like brain.
New delivery technologies and multi-targeting approach aim to enable broader application in future.
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ABSTRACT
Oligonucleotide therapeutics have demonstrated unique advantages, including the capacity to target traditionally undruggable disease targets and achieve prolonged pharmacological effects that can last up to months. This fast-evolving drug modality has been gaining momentum over the past two decades, evidenced by regulatory approval on multiple entities which mostly target liver. Nevertheless, further extending its application to extrahepatic targets is largely confined by corresponding delivery systems. This review first provides a concise overview of the mechanistic principles underlying oligonucleotide function and commonly employed chemical modification techniques. It then highlights recent advancements in receptor-mediated delivery systems for extrahepatic targeting, and dual-targeting oligonucleotide engagement strategies encompassing design principles and outcomes in complex disease condition. Finally, we discuss key challenges and future directions in the field. Collectively, ongoing innovations in chemical modification and delivery technologies are expected to broaden the therapeutic scope of oligonucleotide agents, paving the way for improved clinical outcomes across a wider range of diseases. -
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REFERENCES
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Chen L., Xu J., Li J., et al. (2026). Therapeutic oligonucleotides revisited: Focus on siRNA and antisense technologies. The Innovation Drug Discovery 1:100007. https://doi.org/10.59717/j.xinn-drugdisc.2026.100007
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Chen L., Xu J., Li J., et al. (2026). Therapeutic oligonucleotides revisited: Focus on siRNA and antisense technologies. The Innovation Drug Discovery 1:100007. https://doi.org/10.59717/j.xinn-drugdisc.2026.100007
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Figure 1.
Statistics on marketed and clinical-stage oligonucleotide drugs
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Figure 2.
Milestones in the development of ASO and siRNA
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Figure 3.
Mechanism of ASO and siRNA
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Figure 4.
Chemical modification strategies of nucleic acid monomers
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Figure 5.
Receptor-mediated oligonucleotide delivery system
