Upgrading nucleic acid and antisense therapeutics: challenges, solutions, and future directions

Only a small fraction of disease-modifying proteins present druggable pockets for conventional small-molecule or biologic therapies, underscoring the urgent need for innovative strategies such as nucleic acid–based antisense therapeutics. Antisense approaches—including antisense oligonucleotides (ASOs), RNA interference (RNAi), and decoy oligodeoxynucleotides (ODNs)—offer powerful means to directly modulate gene expression at the RNA level. Over the past four decades, these modalities have advanced from early proof-of-concept studies to numerous FDA- and EMA-approved therapies for neuromuscular, metabolic, and neurodegenerative diseases. Despite these successes, critical barriers remain. Antisense drugs face challenges related to nuclease degradation, off-target binding, dose-dependent toxicities, limited tissue penetration, and inefficient endosomal escape. Addressing these limitations will require advances in nucleotide chemistry, conjugation strategies, and delivery platforms. Personalized "N-of-1" therapies further highlight the promise of customized oligonucleotides but also raise ethical and cost considerations. This review synthesizes the current state of antisense modalities, the obstacles impeding their broader application, and the innovative approaches needed to upgrade existing platforms and expand their therapeutic potential across a wider range of genetic and acquired diseases.