Nanoscale horizonsJun 16, 2026

Lipid Nanoparticles with Acacetin for Inhaled mRNA Vaccines

mRNA Technology Weekly Brief ↗PubMed ↗DOI ↗

Updated Jun 17, 2026

Abstract

Acacetin incorporation into lipid nanoparticles increased lung transfection by 10.82-fold.

Inhaled mRNA vaccines face challenges such as oxidative stress and rapid clearance from the lungs.
A compound library screening identified acacetin as significantly enhancing mRNA expression in lung cells.
Acacetin reshaped the intracellular environment by activating antioxidant pathways and reducing inflammation.
Inhaled acacetin-incorporated LNPs delivering mRNA for the SARS-CoV-2 spike protein resulted in 14.95-fold higher antigen-specific IgG and 2.38-fold higher IgA levels compared to standard formulations.
No toxicity was associated with the acacetin-incorporated LNPs.

Simplified

Inhaled mRNA vaccines have shown great promise for the prevention of respiratory diseases. However, their broad application is still restricted by lipid nanoparticle (LNP)-induced oxidative stress, rapid clearance of LNPs from the lung, and limited mRNA expression. Here, we show that incorporating a natural compound, acacetin, into the LNP formulation can overcome these delivery barriers and greatly improve inhaled vaccine effectiveness. A natural compound library containing 242 compounds was used in anscreening experiment, and acacetin was identified as the lead compound that substantially increased LNP-mediated mRNA expression in A549 cells. We then incorporated acacetin in LNPs as a fifth component. After optimizing the formulation of LNPs intransfection assays andpulmonary 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. in vitro in vitro in vivo

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Lipid Nanoparticles with Acacetin for Inhaled mRNA Vaccines

Abstract

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