Lung-targeted RNA delivery systems: strategies and therapeutic applications

Pulmonary diseases, encompassing asthma, lung cancer, chronic obstructive pulmonary disease (COPD), and pulmonary fibrosis, constitute major contributors to global morbidity and mortality, imposing substantial burdens on healthcare systems worldwide. While RNA-based therapeutics have emerged as promising tools for modulating disease pathophysiology at the molecular level, achieving efficient and lung-specific RNA delivery remains a significant challenge that limits clinical translation. Unlike previous reviews that primarily catalog delivery system performance metrics, this review uniquely integrates structure-function design principles with clinical translation insights, providing mechanistic understanding of how specific physicochemical parameters govern pulmonary tropism and therapeutic efficacy. We systematically examine both synthetic and biologically derived carriers, with particular focus on lung-targeted delivery strategies including inhalation, intravenous targeting, and local pulmonary administration. We critically analyze lessons learned from clinical trial failures, including ALN-RSV01 and MRT-5005, to identify key barriers to successful translation. Furthermore, we discuss the translational outlook of these systems, encompassing formulation stability, immunological compatibility, and scalable manufacturing considerations. By bridging mechanistic understanding with clinical development challenges, this review provides a roadmap for accelerating the clinical translation of RNA therapeutics for pulmonary diseases.