Inhalable nucleic acid drug delivery systems have garnered increasing attention as a promising strategy for the treatment of chronic pulmonary diseases, such as asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), and idiopathic pulmonary fibrosis (IPF). These diseases are often characterized by chronic inflammation, airway remodeling, and progressive lung dysfunction, posing significant clinical challenges. Nucleic acid therapeutics, including plasmid DNA, messenger RNA (mRNA), microRNA (miRNA), small interfering RNAs (siRNAs), and antisense oligonucleotides (ASOs), offer the potential to correct genetic defects, modulate aberrant gene expression, or suppress pathogenic signaling pathways. The inhalation route enables direct, non-invasive access to the lungs, offering localized delivery, rapid onset of action, and reduced systemic side effects. However, the lung presents multiple biological barriers that limit the delivery and activity of nucleic acids, including mucus clearance, enzymatic degradation, alveolar macrophage uptake, and cellular membrane penetration. To address these challenges, various delivery vectors-ranging from viral vectors to non-viral systems such as lipid nanoparticles, polymeric carriers, and hybrid nanomaterials-have been engineered to enhance stability, targeting, and transfection efficiency. This review highlights recent advances in inhalable nucleic acid delivery platforms, discusses the critical physiological and pathological barriers in the pulmonary microenvironment, and outlines current clinical progress. Finally, we explore future directions and challenges toward clinical translation of these innovative therapies. STATEMENT OF SIGNIFICANCE: Chronic pulmonary diseases, including COPD, asthma, IPF, and CF, remain among the leading causes of morbidity and mortality worldwide, with limited treatment options that target disease pathogenesis at the molecular level. Nucleic acid therapeutics offer transformative potential to precisely regulate gene expression, correct mutations, and modulate inflammatory or fibrotic pathways. However, effective delivery to the lungs remains a critical barrier to clinical translation. This review highlights the emerging field of inhalable nucleic acid delivery systems, integrating recent advances in nanocarrier design, pulmonary targeting strategies, and the navigation of biological barriers. By bridging nucleic acid pharmacology with pulmonary drug delivery science, this review provides a comprehensive framework for the rational design and clinical development of next-generation genetic therapies for respiratory diseases. It also offers forward-looking perspectives on overcoming current translational hurdles, thereby accelerating the realization of precision gene therapy for chronic lung disorders.
