When infections rage, few players have more “skin in the game” than immune cells. And now, thanks to a new drug delivery technology, the immune cells known as neutrophils may soon have even more of their skin in the infection-fighting game. Neutrophils may literally contribute their skin—their membranes—to drug-carrying nanovesicles.
The idea is being explored by scientists at Washington State University (WSU). They’ve already demonstrated that human neutrophil–membrane derived nanovesicles can carry drugs to a specified target. The drugs—an anti-inflammatory called resolvin-1 (RvD1) and an antibiotic called ceftazidime—were delivered to lung tissues infected by Pseudomonas aeruginosa, which has been implicated in hospital-acquired infections such as ventilator-associated pneumonia and various sepsis syndromes.
In mouse models, this treatment approach alleviated both inflammation and bacterial growth. Additional details appeared recently in Communications Biology, in an article titled, “Co-delivery of resolvin D1 and antibiotics with nanovesicles to lungs resolves inflammation and clears bacteria in mice.”
“Using the nitrogen cavitation method, we generated liposome-like nanovesicles from human neutrophil membrane,” the article’s authors wrote. “The results showed that nanovesicles loaded with RvD1 decreased cytokine levels and neutrophil lung infiltration, thus shortening the resolution intervals of lung inflammation. When RvD1 and ceftazidime were co-loaded in nanovesicles, they alleviated both inflammation and bacterial growth in the mouse lung.”
The WSU scientists stated that their work reveals a new strategy to treat infectious diseases by designing nanoparticles to simultaneously target host inflammatory pathways and pathogens. The scientists also suggested that their drug-carrying neutrophil-derived nanovesicles could be used to treat various infectious diseases, including COVID-19.
“If a doctor simply gives two drugs to a patient, they don’t go directly to the lungs. They circulate in the whole body, so potentially there’s a lot of toxicity,” said Zhenjia Wang, PhD, the study’s corresponding author and an associate professor in WSU’s College of Pharmacy and Pharmaceutical Sciences. “Instead, we can load the two types of drugs into these vesicles that specifically target the lung inflammation.”
Wang and his research team have developed a method to essentially peel the membrane from neutrophils, the most common type of white blood cells that lead the body’s immune system response. Once emptied, these membranes can be used as nanovesicles, tiny empty sacks only 100 to 200 nanometers wide, which scientists can then fill with medicine.
These nanovesicles retain some of the properties of the original white blood cells, so when they are injected into a patient, they travel directly to the inflamed area just as the cells would normally, but these nanovesicles carry the medicines that the scientists implanted to attack the infection.
“During the inflammation response, lung endothelium is activated and highly express intercellular adhesion molecule-1 (ICAM-1) that binds to integrin β2 on neutrophils (most abundant white blood cells) in response to bacterial invasion,” the article’s authors explained. “Inspired by intercellular interactions between neutrophils and endothelium during lung infections, we have established an approach to generate liposome-like nanovesicles from human neutrophil membrane [so that] nanovesicles may home to inflamed lung endothelium, as nanovesicles possess cell adhesion proteins of their parent cells.”
RvD1 can bind to G protein–coupled receptors, decreasing the expression of adhesion molecules on endothelium, promoting the neutrophil apoptosis, and enhancing the phagocytosis. Simultaneously, ceftazidime can block bacterial proliferation in the lungs.
In the current study, first author Jin Gao, PhD, a WSU research associate, loaded the nanovesicles with ceftazidime and RvD1, which is derived from Omega 3 fatty acids. Two drugs were used because lung infections often create two problems, the infection itself and inflammation created by a strong immune system response.
Toxicity studies and clinical trials would have to be conducted before this method could be used in human patients, but this study provides evidence that the innovation works for lung inflammation. If the method is ultimately proven safe and effective for humans, the nanovesicles could, Wang said, be loaded with any type of drug to treat a range of infectious diseases, including COVID-19.
“I think it’s possible to translate this technology to help treat COVID-19,” asserted Wang. “COVID-19 is a virus, not a bacterial pathogen, but it also causes an inflammation response in the lung, so we could load an antiviral drug like remdesivir into the nanovesicle, and it would target that inflammation.”