Therapeutic oligonucleotides revisited: Focus on siRNA and antisense technologies
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.