Scientists say they have developed a method to prop up a struggling immune system to enable its fight against sepsis. The team used nanotechnology to transform donated healthy immune cells into a drug with enhanced power to kill bacteria.
In experiments treating mice with sepsis, the engineered immune cells eliminated bacteria in blood and major organs, dramatically improving survival rates, according to the researchers. This work focuses on a treatment for late-stage sepsis, when the immune system is compromised and unable to clear invading bacteria. The scientists are collaborating with clinicians specializing in sepsis treatment to accelerate the drug-development process.
“Sepsis remains the leading cause of death in hospitals. There hasn’t been an effective treatment for late-stage sepsis for a long time. We’re thinking this cell therapy can help patients who get to the late stage of sepsis,” said Yizhou Dong, PhD, senior author and associate professor of pharmaceutics and pharmacology at the Ohio State University. “For translation in the clinic, we believe this could be used in combination with current intensive-care treatment for sepsis patients.”
The study (“Vitamin lipid nanoparticles enable adoptive macrophage transfer for the treatment of multidrug-resistant bacterial sepsis”) is published in Nature Nanotechnology.
“Sepsis, a condition caused by severe infections, affects more than 30 million people worldwide every year [1.7 million adults in the United States alone, according to the CDC] and remains the leading cause of death in hospitals. Moreover, antimicrobial resistance has become an additional challenge in the treatment of sepsis, and thus, alternative therapeutic approaches are urgently needed. Here, we show that adoptive transfer of macrophages containing antimicrobial peptides linked to cathepsin B in the lysosomes (MACs) can be applied for the treatment of multidrug-resistant bacteria-induced sepsis in mice with immunosuppression,” the investigators wrote.
“The MACs are constructed by transfection of vitamin C lipid nanoparticles that deliver antimicrobial peptide and cathepsin B (AMP-CatB) mRNA. The vitamin C lipid nanoparticles allow the specific accumulation of AMP-CatB in macrophage lysosomes, which is the key location for bactericidal activities. Our results demonstrate that adoptive MAC transfer leads to the elimination of multidrug-resistant bacteria, including Staphylococcus aureus and Escherichia coli, leading to the complete recovery of immunocompromised septic mice. Our work provides an alternative strategy for overcoming multidrug-resistant bacteria-induced sepsis and opens up possibilities for the development of nanoparticle-enabled cell therapy for infectious diseases.”
The research combined two primary types of technology: using vitamins as the main component in making lipid nanoparticles and using those nanoparticles to capitalize on natural cell processes in the creation of a new antibacterial drug. Macrophages are one of the first responders in the immune system, with the job of “eating” invading pathogens. However, in patients with sepsis, the number of macrophages and other immune cells are lower than normal, and they don’t function as they should.
In this study, Dong and colleagues collected monocytes from the bone marrow of healthy mice and cultured them in conditions that transformed them into macrophages. The lab also developed vitamin-based nanoparticles that were especially good at delivering messenger RNA, molecules that translate genetic information into functional proteins. The scientists, who specialize in messenger RNA for therapeutic purposes, constructed a messenger RNA encoding an antimicrobial peptide and a signal protein. The signal protein enabled the specific accumulation of the antimicrobial peptide in internal macrophage structures called lysosomes, the key location for bacteria-killing activities. From here, researchers delivered the nanoparticles loaded with that messenger RNA into the macrophages they had produced with donor monocytes, and let the cells take it from there to “manufacture” a new therapy.
“Macrophages have antibacterial activity naturally. So if we add the additional antibacterial peptide into the cell, those antibacterial peptides can further enhance the antibacterial activity and help the whole macrophage clear bacteria,” Dong said.
After seeing promising results in cell tests, the researchers administered the cell therapy to mice. The mouse models of sepsis in this study were infected with multidrug-resistant S. aureus and E. coli and their immune systems were suppressed. Each treatment consisted of about four million engineered macrophages. Controls for comparison included ordinary macrophages and a placebo. Compared to controls, the treatment resulted in a significant reduction in bacteria in the blood after 24 hours—and for those with lingering bacteria in the blood, a second treatment cleared them away.
Dong considers the lipid nanoparticle delivery of messenger RNA into certain kinds of immune cells applicable to other diseases, and his lab is currently working on the development of cancer immunotherapy using this technology.