The Versatile Applications of Antisense Oligonucleotides in Modern Medicine

Antisense oligonucleotides (ASOs) are a class of nucleic acid therapeutics that modulate gene expression through diverse mechanisms. Since their initial demonstration in inhibiting viral genes, advances in medicinal chemistry, pharmacology, and delivery have enabled robust and durable target engagement across multiple tissues. Chemical modifications to the backbone, ribose, and nucleobases have improved nuclease resistance, binding affinity, and pharmacokinetics, while conjugation and delivery technologies have expanded tissue accessibility. Beyond classical RNase H–mediated RNA degradation, ASOs regulate gene expression via splicing modulation, microRNA inhibition, transcriptional activation, and translation modulation, supporting both gene silencing and upregulation strategies. Multiple ASO drugs are now approved, particularly for genetic diseases, with many more in clinical development. This review outlines the evolution of antisense technology, key chemical and delivery innovations, ASO pharmacokinetics and intracellular trafficking, the mechanisms underlying gene regulation, and current clinical applications and future opportunities.