Inhaled nucleic acid therapeutics for respiratory diseases: delivery barriers, translational challenges, and emerging solutions

Abstract Pulmonary delivery of nucleic acid therapeutics represents a transformative strategy for treating a broad spectrum of respiratory diseases, including lung cancer, pulmonary fibrosis, chronic obstructive pulmonary disease, and acute lung injury. Despite their promise, effective clinical translation is hampered by a cascade of physiological barriers spanning the airway mucus layer, mucociliary clearance, alveolar macrophage uptake, cellular internalization, and endosomal sequestration. In this review, we adopt a barrier-oriented framework to systematically dissect these extracellular, cellular, and intracellular obstacles, highlighting how disease-specific microenvironments further modulate delivery efficiency. We then critically examine emerging engineering strategies-including nanocarrier surface modifications, biomimetic vesicles, aerosol optimization, and stimuli responsive formulations that are designed to overcome these barriers. Integrating mechanistic insights with disease-specific considerations, we analyze how distinct pulmonary pathologies necessitate tailored delivery solutions, emphasizing that successful translation requires coupling nanoengineering with the unique cellular and molecular landscapes of target tissues. Finally, we discuss translational challenges, including manufacturing scalability, long-term safety, and regulatory constraints, and outline emerging solutions that may enable next-generation inhaled nucleic acid therapies. By providing a synthesis of barrier-oriented design principles and disease-driven targeting strategies, this review offers a comprehensive roadmap for accelerating the clinical adoption of inhaled nucleic acid therapeutics.