Acacetin-incorporated lipid nanoparticles for inhaled mRNA vaccines

pulmonary delivery assays, we find acacetin-incorporated LNPs increased lung transfection by 10.82-fold. A mechanistic study showed that acacetin reshaped the intracellular environment of lung cells by activating antioxidant stress pathways and suppressing pro-inflammatory signaling, thereby maintaining high levels of mRNA translation. Inhaled administration of acacetin-incorporated LNPs, delivering mRNA encoding the SARS-CoV-2 spike protein, induced higher antigen-specific IgG (14.95-fold) and IgA (2.38-fold) levels than a conventional LNP formulation, without inducing toxicity. We demonstrate that acacetin-incorporated LNPs offer a simple and scalable strategy to improve the efficacy of inhaled mRNA vaccines.