Advances in Nebulized Lipid Nanoparticles (LNPs) for Nucleic Acid Delivery

Lipid nanoparticles (LNPs) exhibit significant potential as highly efficient carriers for nucleic acid therapeutics in the treatment of pulmonary diseases. Nebulized inhalation delivery, which directly targets the lungs through respiratory tract, represents an ideal pulmonary administration route. However, the clinical translation of nebulized LNP-based delivery still faces several critical challenges. Intense shear forces during nebulization impair the structural integrity and stability of LNPs, leading to nucleic acid leakage. The mucin network within the pulmonary mucus layer forms a physical barrier that restricts LNP diffusion, while non-specific phagocytosis by alveolar macrophages further decreases delivery efficiency. In recent years, various design strategies have been developed to address these limitations. Modifying LNP component ratios, optimizing buffer formulations, and functionalizing LNP components have collectively improved stability, enhanced mucus penetration, reduced macrophage uptake, and increased cellular uptake by epithelial cells. This systematic review analyzes the key challenges of nebulized LNP delivery, summarizes recent breakthrough, and outlines future research directions, thereby providing theoretical insights for developing efficient pulmonary nucleic acid delivery systems.