Sepsis, the body’s excessive reaction to an infection, affects more than 1.5 million people and kills at least 270,000 people each year in the United States alone. Standard treatment with antibiotics and fluids is ineffective for many patients, and those who survive face a higher risk of death.
In a new research published in the journal Nature’s nanotechnology The laboratory of Shoukin “Sarah” Jung, a professor at the Wisconsin Discovery Institute at the University of Wisconsin-Madison, has reported a new nanoparticle-based treatment that delivers anti-inflammatory and antibiotic molecules.
The new system saved the lives of mice with an inducible sepsis version intended to serve as a model for human infection, and is a promising proof of concept for a potential new treatment, pending further research.
New nanoparticles transported the chemical NAD+ Or its reduced form NAD (H), a molecule that is essential in biological processes that generate energy, preserve genetic material and help cells adapt and cope with stress. While NAD (H) is well known for its anti-inflammatory function, clinical application has been hampered because NAD (H) cannot be directly taken up by cells.
“To enable clinical translation, we need to find a way to efficiently deliver NAD (H) to target organs or cells. To achieve this goal, we designed nanoparticles that can transport and release NAD (H) directly into the cell, while preventing early drug release and degradation in the bloodstream,” Jung, who also holds positions in the Department of Biomedical Engineering and the College of Ophthalmology in the Department of Ophthalmology and Visual Sciences at the University of Washington, says.
Gong led the interdisciplinary work with Mingzhou Ye and Yi Zhao, two postdoctoral fellows in Gong’s lab. John Demian Sawyer, a professor in the Department of Medical Microbiology and Immunology, also collaborated on the project.
Sepsis can be fatal in two stages. First, the infection begins in the body. The immune system responds by inducing severe inflammation that obstructs blood flow and leads to the formation of blood clots, which can cause tissue death and trigger a chain reaction that leads to organ failure. Then, the body overcorrects itself by suppressing the immune system, which in turn increases susceptibility to infections. Controlling complications from inflammation is vital in treating sepsis.
Calcium phosphate coated with lipids or metal-organic framework nanoparticles designed by Gong Laboratory can be used to jointly deliver NAD(H) and antibiotics. Gong’s lab tested NAD(H)-loaded nanoparticles in multiple mouse models including endotoxemia, drug-resistant multi-microbial bacteremia, as well as a perforation-induced sepsis model with secondary infection by a common pathogenic bacteria called P. aeruginosa.
The performance of nanoparticle treatment was significantly better than using NAD(H) alone. For example, in a mouse model of endotoxemia, mice died without any treatment or treated with free NAD(H) within 2 days. In contrast, mice treated with NAD(H)-loaded nanoparticles survived. These animal studies have shown that NAD(H) nanoparticles can help maintain a healthy immune system, support blood vessel function and prevent injury to many organs.
This technology may pave the way for the development of a new clinical treatment for sepsis that can also be applied in other infection-related scenarios, such as the treatment of COVID-19. An additional benefit of this treatment is the ability to treat the infection with smaller amounts of antibiotics, which reduces their overuse. More research in larger animal models will be necessary before clinical trials in humans can begin.
“NAD(H) nanoparticles have the potential to treat many other diseases because NAD(H) is involved in many biological pathways. There is strong evidence for the use of NAD(H) as an intervention or aid in serious diseases,” says Gong.
Researchers develop intravenous treatment for sepsis
Shaoqin Gong, NAD(H) Loaded Nanoparticles for Effective Treatment of Sepsis by Modulating Immune and Vascular Balance, Nature’s nanotechnology (2022). DOI: 10.1038/s41565-022-01137-w. www.nature.com/articles/s41565-022-01137-w
Provided by University of Wisconsin-Madison
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