The findings, published in the November 26 online issue of Nature Biotechnology [DOI: 10.1038/s41587-025-02928-x], show that in preclinical studies in mice and human lung tissue in the lab, the therapy slowed bacterial growth, strengthened immune cell activity, and reduced lung tissue damage in models of multidrug-resistant pneumonia.
Antibiotic-resistant infections are a growing global threat, killing more than 1.2 million people each year and contributing to nearly 5 million deaths worldwide. In the United States alone, more than 3 million infections occur annually, causing up to 48,000 deaths and costing billions of dollars in health care. Experts warn that resistance is increasing across nearly all major bacterial species, putting routine surgeries, cancer treatments, and newborn care at risk.
“Our work suggests there may be a new path to tackling antibiotic-resistant infections by supporting the immune system more directly,” says Xucheng Hou, PhD, a lead author of the study and Assistant Professor of Immunology and Immunotherapy in the lab of Yizhou Dong, PhD, at the Icahn School of Medicine at Mount Sinai. “Although we’re still in the early stages and have only tested this approach in preclinical models, the results lay important groundwork for future therapies that could enhance how traditional antibiotics perform.”
The experimental therapy works by giving the patient mRNA that instructs their body to make a special infection-fighting protein called a “peptibody.” This peptibody is designed to do two things at the infection site: directly break down harmful bacteria and recruit immune cells to help clear them out.
To get the mRNA safely into the patient’s body, the researchers packaged it inside lipid nanoparticles—tiny fat-based bubbles commonly used in mRNA vaccines. These nanoparticles protect the mRNA as it travels through the body and help it enter cells. They also carry an extra ingredient that helps limit harmful inflammation by neutralizing excess reactive oxygen species, highly reactive molecules that the body produces during infection and that can damage tissues, often contributing to the severe symptoms of hard-to-treat infections.
In mouse models of multidrug-resistant Staphylococcus aureus and Pseudomonas aeruginosa, repeated doses of the therapy were well tolerated, reduced bacterial numbers in the lungs, decreased inflammation, and preserved normal lung structure, the investigators report. In addition, the laboratory tests with human lung tissue showed similar results, demonstrating that the therapy could work alongside human immune cells.
Next, the researchers plan to continue preclinical studies and eventually advance toward human clinical trials to evaluate safety, dosing, and efficacy. While the therapy is still in early stages, it represents an encouraging direction in the global fight against antibiotic-resistant infections.
“This is the first evidence that an mRNA-encoded antimicrobial peptide can directly kill bacteria while also turning on the immune system’s protective responses,” says Dr. Dong, the senior author and a co-corresponding author of the study, Mount Sinai Professor in Nanomedicine, and a member of the Icahn Genomics Institute and the Marc and Jennifer Lipzhultz Precision Immunology Institute (PrIISM) at the Icahn School of Medicine at Mount Sinai. “If future studies bear this out, it could open the door to a highly adaptable platform for developing new treatments against infections that no longer respond to today’s antibiotics.”
The paper is titled “Antimicrobial peptide delivery to lung as peptibody mRNA in anti-inflammatory lipids treats multidrug-resistant bacterial pneumonia.”
The study’s authors, as listed in the journal, are Yonger Xue, Xucheng Hou, Siyu Wang, Yuebao Zhang, Yichen Zhong, Diana D. Kang, Chang Wang, Haoyuan Li, Changyue Yu, Zhengwei Liu, Meng Tian, Dinglingge Cao, Ya Ying Zheng, Binbin Deng, Pauline Hamon, Miriam Merad, and Yizhou Dong.
This work is supported, in part, by the Maximizing Investigators’ Research Award (R35GM144117) from the National Institute of General Medical Sciences. See the journal paper for details on conflicts of interest: Nature Biotechnology [DOI: 10.1038/s41587-025-02928-x].
-####-
About the Icahn School of Medicine at Mount Sinai
The Icahn School of Medicine at Mount Sinai is internationally renowned for its outstanding research, educational, and clinical care programs. It is the sole academic partner for the seven member hospitals* of the Mount Sinai Health System, one of the largest academic health systems in the United States, providing care to New York City’s large and diverse patient population.
The Icahn School of Medicine at Mount Sinai offers highly competitive MD, PhD, MD-PhD, and master’s degree programs, with enrollment of more than 1,200 students. It has the largest graduate medical education program in the country, with more than 2,600 clinical residents and fellows training throughout the Health System. Its Graduate School of Biomedical Sciences offers 13 degree-granting programs, conducts innovative basic and translational research, and trains more than 560 postdoctoral research fellows.
Ranked 11th nationwide in National Institutes of Health (NIH) funding, the Icahn School of Medicine at Mount Sinai is among the 99th percentile in research dollars per investigator according to the Association of American Medical Colleges. More than 4,500 scientists, educators, and clinicians work within and across dozens of academic departments and multidisciplinary institutes with an emphasis on translational research and therapeutics. Through Mount Sinai Innovation Partners (MSIP), the Health System facilitates the real-world application and commercialization of medical breakthroughs made at Mount Sinai.
-------------------------------------------------------
* Mount Sinai Health System member hospitals: The Mount Sinai Hospital; Mount Sinai Brooklyn; Mount Sinai Morningside; Mount Sinai Queens; Mount Sinai South Nassau; Mount Sinai West; and New York Eye and Ear Infirmary of Mount Sinai
END