Inhaled lipid nanoparticle–RNA delivery systems: Challenges and breakthroughs

Inhaled RNA therapeutics offer a promising strategy for treating respiratory diseases through potent and highly specific modulation of disease-relevant genes. Lipid nanoparticles (LNPs) represent the most advanced and clinically validated platform for RNA delivery, owing to mature manufacturing processes, high encapsulation efficiency, biocompatibility, and clinical approvals. However, inhaled LNP–RNA delivery faces interconnected challenges from formulation to clinical translation. This review systematically examines these barriers and recent advances, including lipid formulation optimization, device selection, stabilizing excipients, nebulization-medium engineering, and solid-state stabilization to improve storage and nebulization stability; surface-property modulation to overcome mucociliary clearance and regulate alveolar macrophage uptake; active targeting, pulmonary surfactant-inspired biomimetic design, and responsiveness to reactive oxygen species, disease-associated proteases, and hypoxia for cell- and lesion-selective delivery; and control of LNP internal phase behavior, lipid molecular geometry, and functional components to enhance endosomal escape. We further discuss pulmonary safety risks associated with long-term or repeated inhalation and corresponding mitigation strategies. Drawing on current inhaled LNP–mRNA clinical programs, we also analyze translational challenges in scale-up manufacturing, batch-to-batch consistency, formulation–device compatibility, quality control, and regulatory evaluation. This review establishes an integrated framework for developing inhaled LNP–RNA therapeutics that balances delivery efficiency, long-term safety, manufacturability, and clinical translatability.