In the United States alone, sepsis, or the body’s overreaction to an infection, strikes more than 1.5 million individuals and kills nearly 270,000 people every year. Many patients do not respond to the traditional therapy of antibiotics and fluids, and those who do recover face an increased risk of mortality.
Shaoqin “Sarah” Gong. Image Credit: University of Wisconsin–Madison
The team of Shaoqin “Sarah” Gong, a professor at the University of Wisconsin–Wisconsin Madison’s Institute for Discovery, described a new nanoparticle-based treatment that distributes anti-inflammatory chemicals and antibiotics in a new study published in the journal Nature Nanotechnology.
The new approach improved the lives of mice with an induced type of sepsis that was intended to be used as a model for human infections, and it is a piece of potential evidence for a prospective future medicine, which is awaiting further research.
The novel nanoparticles transported the chemical NAD+ or its reduced form NAD(H), a molecule that plays an important role in biological activities such as energy generation, genetic material preservation, and cell adaptation and stress resistance. NAD(H) is well known for its anti-inflammatory properties, but its clinical application has been hampered by the fact that it cannot be taken up directly by cells.
To enable clinical translation, we need to find a way to efficiently deliver NAD(H) to the targeted organs or cells. To achieve this goal, we designed a couple of nanoparticles that can directly transport and release NAD(H) into the cell, while preventing premature drug release and degradation in the bloodstream.
Shaoqin “Sarah” Gong, Professor, Madison’s Institute for Discovery, University of Wisconsin
Gong also holds appointments in the Department of Biomedical Engineering and the UW School of Medicine and Public Health’s Department of Ophthalmology and Visual Sciences.
Gong, along with Mingzhou Ye and Yi Zhao, two postdoctoral fellows in the Gong group, conducted the interdisciplinary project. A professor in the Department of Medical Microbiology and Immunology, John-Demian Sauer, also contributed to the experiment.
Sepsis has two stages, each of which can be fatal. First, an infection starts in the body. The immune system reacts by inducing severe inflammation, which reduces blood flow and causes blood clots, which can lead to tissue death and a cascade of events leading to organ failure. Following that, the body overcorrects by weakening the immune system, increasing infection susceptibility. Controlling inflammation-related consequences is critical in sepsis treatment.
The Gong lab’s lipid-coated calcium phosphate or metal-organic framework nanoparticles can distribute NAD(H) and antibiotics simultaneously. The NAD(H)-loaded nanoparticles were examined in a variety of mice models, such as endotoxemia, multidrug-resistant pathogen-induced polymicrobial bacteremia, and a puncture-induced sepsis model with secondary infection by P. aeruginosa, a prevalent illness-causing bacteria.
The nanoparticle therapy performed significantly better than using NAD(H) alone. In an endotoxemia mouse model, mice that were not given any treatment or were given free NAD(H) died within two days. Mice treated with NAD(H)-loaded nanoparticles, on the other hand, all survived. The NAD(H) nanoparticles were shown to assist in maintaining a healthy immune system, promote blood vessel function, and stop multiorgan harm in these animal investigations.
This technology could open the way for the creation of a new sepsis therapeutic treatment that could also be used in other inflammation-related settings, such as the treatment of COVID-19. Another advantage of this treatment is that it allows illness to be treated with fewer antibiotics, reducing antibiotic misuse. Before clinical trials in humans can begin, more research in larger animal models is required.
The NAD(H) nanoparticles have the potential to treat many other diseases because NAD(H) is involved with so many biological pathways. There is strong evidence for the use of NAD(H) as an intervention or aid in critical illnesses.
Shaoqin “Sarah” Gong, Professor, Madison’s Institute for Discovery, University of Wisconsin
Journal Reference:
Ye, M., et al. (2022) NAD(H)-loaded nanoparticles for efficient sepsis therapy via modulating immune and vascular homeostasis. Nature Nanotechnology. doi.org/10.1038/s41565-022-01137-w.