A review of mRNA vaccines and host-directed therapeutics for multidrug-resistant ESKAPE pathogens

Abstract The persistent threat of multidrug-resistant (MDR) pathogens— Enterococcus faecium , Staphylococcus aureus , Klebsiella pneumoniae , Acinetobacter baumannii , Pseudomonas aeruginosa , and Enterobacter species (ESKAPE)—has necessitated messenger ribonucleic acid (mRNA) strategies beyond conventional antibiotics. We review two mRNA modalities: prophylactic vaccines targeting ESKAPE antigens and host-directed therapeutics encoding antibacterial effectors. mRNA platforms offer rapid design, potential broad-spectrum activity, and intracellular delivery of host proteins unavailable as recombinant biologics. This review assesses both approaches for MDR ESKAPE by examining advances, delivery barriers, and translational gaps. Vaccine candidates against S. aureus and P. aeruginosa have reached Phase 1/2, while preclinical studies show mRNA-encoded host factors limit bacterial burden in murine models, but no clinical-stage therapeutic candidates exist for bacterial infection. Key challenges include extrahepatic targeting, nuclease degradation in infected tissues, and stability during global distribution. We contrast vaccine vs. therapeutic mRNA delivery requirements and evaluate regulatory hurdles specific to acute bacterial disease. Rather than projecting broad clinical impact, we identify where mRNA may complement existing antimicrobials and where current data do not support development. Targeted research on lung-specific lipid nanoparticles (LNPs) and pathogen-specific host targets is required before mRNA can address MDR ESKAPE.