Antimicrobial peptide delivery to lung as peptibody mRNA in anti-inflammatory lipids treats multidrug-resistant bacterial pneumonia.

The efficacy of antimicrobial peptides (AMPs) is limited by challenges of delivery and potency. We enhance AMP performance in the lung by converting AMPs to a peptibody format that fuses AMPs with fragment crystallizable domains to activate innate immunity and cathelin domains for infection-responsive activation, with their mRNA constructs delivered by anti-inflammatory lipid nanoparticles. The highest-scoring design outperforms antibiotic therapy approved by the US Food and Drug Administration in multidrug-resistant pneumonia models, eradicating representative MDR bacteria while mitigating inflammation.