Abstract Oligonucleotide-based therapeutics, including antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs), have emerged as promising precision medicines capable of modulating gene expression at the RNA level. Their site-specific and reversible modes of action make them particularly suitable for respiratory disorders, where direct pulmonary delivery can maximize therapeutic concentrations while limiting systemic exposure. This review summarizes the molecular mechanisms, advances in delivery systems, current clinical development, and future potential of oligonucleotide-based therapies for pulmonary diseases. A structured literature search was conducted across PubMed, Scopus, and Web of Science for indexed articles published between 2018 and 2025 using the keywords “oligonucleotide therapy,” “antisense,” “siRNA,” “RNA therapeutics,” and “pulmonary diseases.” Only peer-reviewed, indexed journal articles were included. Preclinical and early clinical studies have demonstrated encouraging outcomes for inhaled ASOs in cystic fibrosis, siRNAs targeting inflammatory cytokines in asthma, and oligonucleotide-based approaches against fibrotic mediators in idiopathic pulmonary fibrosis. Although delivery remains a major barrier, inhaled lipid nanoparticles and mucus-penetrating nanocarriers have shown considerable promise in overcoming lung-specific obstacles. Oligonucleotide-based therapeutics hold transformative potential in pulmonary medicine. Successful translation into clinical practice will depend on optimizing delivery systems, ensuring long-term safety, and integrating mutation-targeted companion diagnostics.
Avinash A. Nair (Thu,) studied this question.