Special Lipid Nanoparticles with Two pH Levels for Targeted Lung mRNA Delivery and pH-Controlled Release Inside Cells

Dual pKa lipid nanoparticles (LNPs) produce lung-selective mRNA expression with higher potency than a cationic lipid comparator.

• The new synthetic ionizable lipid is retained in formulated LNPs and enhances mRNA delivery.
• After intravenous injection, these LNPs achieved robust pulmonary expression while remaining well tolerated.
• Molecular dynamics simulations indicate that the lipid's protonation state may enable efficient escape from endosomal membranes.
• The formulation provided therapeutic benefits in an acute lung inflammation model.
• A structure-property relationship was established, highlighting dual apparent pKa behavior as a key feature for effective RNA delivery.

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