ANTIBIOTIC-resistant infections represent a growing global health threat, causing over 1.2 million deaths annually and contributing to nearly 5 million deaths worldwide. In the USA, more than 3 million infections occur each year, resulting in approximately 48,000 deaths and massive healthcare costs. Resistance across major bacterial species increasingly jeopardises routine surgeries, cancer treatments, and neonatal care. Novel therapeutic approaches are urgently needed to combat these pathogens.
mRNA Peptibody Approach: Mechanism and Design
Researchers at the Icahn School of Medicine at Mount Sinai have developed an experimental therapy using mRNA to encode a “peptibody,” an engineered protein that simultaneously kills bacteria and activates host immune defences. The mRNA is delivered via lipid nanoparticles, which protect it during systemic administration and facilitate cellular uptake. These nanoparticles also contain anti-inflammatory agents to neutralise reactive oxygen species, minimising tissue damage commonly associated with severe infections.
Preclinical Efficacy: Mouse and Human Lung Models
In preclinical studies, mice infected with multidrug-resistant Staphylococcus aureus and Pseudomonas aeruginosa received repeated doses of the therapy. Results demonstrated significant reductions in pulmonary bacterial load, attenuated inflammation, and preservation of lung architecture. Complementary experiments in ex vivo human lung tissue confirmed that peptibody mRNA enhanced bacterial clearance while supporting immune cell activation.
Clinical Implications and Next Steps
This therapy represents the first evidence that an mRNA-encoded antimicrobial peptide can provide dual action: direct bacterial killing and immune activation. By complementing traditional antibiotics, the approach could overcome limitations of current therapies. The team plans to advance toward human clinical trials to evaluate safety, dosing, and efficacy, potentially establishing a versatile platform to address multidrug-resistant infections.
Takeaways
The study demonstrates a breakthrough strategy using mRNA-encoded peptibodies to tackle multidrug-resistant bacterial pneumonia. If successfully translated to humans, this approach could transform treatment paradigms for antibiotic-resistant infections and offer a scalable, adaptable platform for emerging bacterial threats.
Reference
Xue Y et al. Antimicrobial peptide delivery to lung as peptibody mRNA in anti-inflammatory lipids treats multidrug-resistant bacterial pneumonia. Nat Biotechnol. 2025; DOI:10.1038/s41587-025-02928-x.
