Inhaled Formulations of mRNA – Lipid Nanoparticles (LNPs): Barriers and Formulation Strategies

Inhaled mRNA therapy holds significant promise for the treatment of various respiratory diseases by directly delivery of mRNA therapeutics to the target organ. Lipid nanoparticles (LNPs), which have gained widespread attention following their successful use in mRNA vaccines, are now becoming the leading mRNA delivery system for pulmonary delivery. However, the fragile nature of both LNPs and mRNA presents substantial challenges during aerosolization, compromising their stability and efficiency. Several early-phase clinical trials are currently evaluating nebulized delivery of LNPs for lung diseases such as cystic fibrosis (CF) with the initial results indicating a favourable safety profile. The therapeutic potential of inhaled mRNA extends beyond vaccines and genetic diseases, and optimizing delivery system for inhalation remains critical. While conventional LNPs are primarily designed for systemic administration, pulmonary delivery requires specific formulation strategies, such as modification of lipid composition and the use of protective excipients to enhance stability during aerosolization. Device selection also plays a pivotal role in maintaining LNP integrity and maximizing delivery efficiency. This chapter provides an in-depth analysis of factors influencing LNP stability and transfection following aerosolization, reviews formulation optimization and device selection, and discusses biological barriers and strategies to advance inhaled mRNA therapies toward clinical translation.