MicroRNAs as novel therapeutics against multidrug-resistant ESKAPE pathogens: mechanisms, challenges, and future directions.

BACKGROUND: Multidrug-resistant (MDR) ESKAPE pathogens, including Enterococcus faecium, S. aureus, Klebsiella pneumoniae, Acinetobacter baumannii, P. aeruginosa, and Enterobacter spp., pose a critical global health threat. OBJECTIVE: This narrative review evaluates microRNAs (miRNAs) as novel antibacterial agents against MDR ESKAPE, focusing on their mechanisms of action, preclinical efficacy, delivery innovations, and translational barriers. METHODS: PubMed and Google Scholar were searched using terms related to miRNA biology, antibacterial activity, ESKAPE pathogens, and delivery platforms RESULTS: miRNAs exert antibacterial effects through three mechanisms: innate and adaptive immune modulation, regulation of host antibacterial pathways (including antimicrobial peptide production), and direct cross-kingdom bacterial mRNA silencing with biofilm disruption. Preclinical evidence highlights key candidates: let-7b-5p achieved a 90% reduction in P. aeruginosa biofilm and restored aztreonam sensitivity, and miR-101-3p, delivered via DNA tetrahedron nanostructures, suppressed polymicrobial biofilms in cystic fibrosis (CF) models. The Rocket-miR platform identified miRNA candidates across all ESKAPE organisms, including miR-877-5p and miR-3127-5p, which target carbapenem-resistant K. pneumoniae and vancomycin-resistant E. faecium. The core translational challenges include miRNA instability, limited cellular uptake, off-target effects, and undefined regulatory pathways. Nanocarrier-based delivery, exosomal platforms, and machine learning-assisted target prediction offer promising solutions to these challenges. CONCLUSION: Current preclinical evidence suggests that miRNAs hold promise as early-stage candidate antibacterial agents through immunomodulation, host pathway regulation, and direct bacterial gene silencing with biofilm disruption. However, no miRNA-based antibacterial therapy has entered clinical evaluation, and substantial translational barriers, including delivery challenges, off-target effects, and undefined regulatory pathways, must be addressed before clinical application can be considered.