Antisense Oligonucleotides: Technological Advances, Clinical Progress, and Expanding Therapeutic Frontiers

Antisense oligonucleotides (ASOs) are emerging therapeutic agents that modulate gene expression at the RNA level, offering distinct therapeutic advantages over conventional small-molecule drugs and biologics. By directly targeting RNA, ASOs expand the spectrum of druggable targets to include those previously considered “undruggable”, and enable shorter development timelines with improved research and development efficiency. These attributes position ASOs as a highly promising platform for precision and personalized medicine. Recent advances in chemical modification strategies and delivery technologies have markedly accelerated their clinical translation. This review systematically examines the technological evolution of ASO therapeutics, detailing their mechanisms of action, key chemical modification strategies, and advanced delivery systems. It also provides a comprehensive overview of the current global clinical landscape, including approved drugs, discontinued candidates, and ongoing clinical trials. Finally, this review discusses the major challenges facing the field and outlines future directions, with the aim of informing subsequent basic research and clinical development efforts.