A Holistic Platform Approach for Developing Robust Pulmonary mRNA Delivery: Integrating Novel Phenolic Acid‐Derived Ionizable Lipids and Device Engineering

Abstract

The success of inhaled mRNA therapeutics remains limited by the absence of aerosol optimized ionizable lipids and incomplete understanding of formulation device interactions. Here we present an integrated platform for pulmonary mRNA delivery combining novel lipid chemistry, systematic formulation engineering, and device optimization. From a novel phenolic acid derived ionizable lipid library, we identified SY‐3 as a potent lead candidate, based on a biodegradable syringic acid‐based core. Design‐of‐experiments optimization yielded LNP 5, a formulation exhibiting potential for improved cytosolic delivery along with nebulization stability. Repeated nebulization of LNP 5 encapsulating human CFTR mRNA in Cftr ‐knockout mice produced robust protein expression and restored correct apical CFTR localization in airway epithelia. Device characterization revealed that vibrating‐mesh nebulizer selection critically influences LNP integrity, aerosol output, and mass median aerodynamic diameter (MMAD). Collectively, these results demonstrate an integrated development strategy encompassing ionizable lipid design, formulation optimization, and device engineering to enable efficient mRNA delivery to the lungs. While the work successfully shows robust mRNA expression, functional CFTR activity in vitro, and appropriate in vivo tissue localization, further validation is needed—specifically physiological assessments such as nasal potential difference and mucus clearance measurements—before advancing to clinical trials.