Dual pKa Lipid Nanoparticles for Lung‐tropic mRNA Delivery and pH‐Programmed Endosomal Escape

Abstract

ABSTRACT Lipid nanoparticles (LNPs) have enabled the clinical application of RNA therapeutics, including approved mRNA vaccines and siRNA medicines. However, their predominant accumulation in liver after systemic administration and inefficient endosomal escape remain key bottlenecks for productive cytosolic delivery and gene expression. Here, we introduce a synthetic ionizable lipid with a dual pKa property that is retained in formulated LNPs. We show that after intravenous injection, these dual pKa LNPs produce lung‐selective mRNA expression with higher potency than a cationic lipid‐rich comparator while remaining well tolerated. Using molecular dynamics simulations, we find that protonation state can support two distinct interaction modes between the ionizable lipid and endosomal membranes, suggesting a mechanistic basis for efficient endosomal escape. Moreover, the formulation maintains robust pulmonary expression and delivers therapeutic benefit in an acute lung inflammation model. These results establish a structure‐property relationship within the ionizable lipid‐based LNPs investigated here and identify dual apparent pKa behavior as a promising feature for potent and tolerable lung‐targeted RNA delivery.