Antimicrobial peptide-derived lipid nanoparticles enable lung-targeted mRNA therapy for multidrug-resistant bacterial pneumonia.

Multidrug-resistant (MDR) bacterial pneumonia presents a critical and growing clinical challenge, necessitating new therapeutic strategies. Here, we report an antimicrobial peptide-derived lipid nanoparticle system for lung-targeted delivery of mRNA encoding cathelicidin, a secreted host defense peptide with broad antimicrobial activity. This design enables the coordinated killing of both intracellular and extracellular bacteria, addressing a barrier in treating bacterial infections. A single systemic administration achieves robust pulmonary accumulation, leading to reduced bacterial burden, suppressed inflammatory cytokines, and improved clinical outcomes and survival in mice with MDR bacterial pneumonia. Together, this platform offers a novel strategy for treating MDR bacterial pneumonia and may provide a generalizable framework for developing mRNA-based antimicrobials against recalcitrant respiratory infections.