Nanosponges Offer New Approach to Treatment of Rheumatoid Arthritis

Transmission electron microscopy of neutrophil nanosponges. [Qiangzhe Zhang/Nature Nanotechnology]

University of California (UC), San Diego scientists say they have developed neutrophil nanosponges that can safely absorb and neutralize a variety of proteins that play a role in the progression of rheumatoid arthritis. Injections of these nanosponges effectively treated severe rheumatoid arthritis in two mouse models. Administering the nanosponges early on also prevented the disease from developing.

The study (“Neutrophil membrane-coated nanoparticles inhibit synovial inflammation and alleviate joint damage in inflammatory arthritis”) is published In Nature Nanotechnology.

“Rheumatoid arthritis is a common chronic inflammatory disorder and a major cause of disability. Despite the progress made with recent clinical use of anti-cytokine biologics, the response rate of rheumatoid arthritis treatment remains unsatisfactory, owing largely to the complexity of cytokine interactions and the multiplicity of cytokine targets. Here, we show a nanoparticle-based broad-spectrum anti-inflammatory strategy for rheumatoid arthritis management,” write the investigators.

“By fusing neutrophil membrane onto polymeric cores, we prepare neutrophil membrane-coated nanoparticles that inherit the antigenic exterior and associated membrane functions of the source cells, which makes them ideal decoys of neutrophil-targeted biological molecules. It is shown that these nanoparticles can neutralize proinflammatory cytokines, suppress synovial inflammation, target deep into the cartilage matrix, and provide strong chondroprotection against joint damage. In a mouse model of collagen-induced arthritis and a human transgenic mouse model of arthritis, the neutrophil membrane-coated nanoparticles show significant therapeutic efficacy by ameliorating joint damage and suppressing overall arthritis severity.”

“Nanosponges are a new paradigm of treatment to block pathological molecules from triggering disease in the body,” says senior author Liangfang Zhang, Ph.D., a nanoengineering professor at the UC San Diego Jacobs School of Engineering. “Rather than creating treatments to block a few specific types of pathological molecules, we are developing a platform that can block a broad spectrum of them, and this way we can treat and prevent disease more effectively and efficiently.”

When rheumatoid arthritis develops, cells in the joints produce inflammatory cytokines which signal neutrophils to enter the joints. Once there, cytokines bind to receptors on the neutrophil surfaces, activating them to release more cytokines, which in turn draws more neutrophils to the joints and so on.

The nanosponges essentially nip this inflammatory cascade in the bud. By acting as tiny neutrophil decoys, they intercept cytokines and stop them from signaling even more neutrophils to the joints, reducing inflammation and joint damage.

These nanosponges offer a promising alternative to current treatments for rheumatoid arthritis, according to the researchers. Some monoclonal antibody drugs, for example, have helped patients manage symptoms of the disease, but they work by neutralizing only specific types of cytokines. This is not sufficient to treat the disease, says Dr. Zhang, because there are so many different types of cytokines and pathological molecules involved.

“Neutralizing just one or two types might not be as effective. So our approach is to take neutrophil cell membranes, which naturally have receptors to bind all these different types of cytokines, and use them to manage an entire population of inflammatory molecules,” explains Dr. Zhang.

“This strategy removes the need to identify specific cytokines or inflammatory signals in the process. Using entire neutrophil cell membranes, we're cutting off all these inflammatory signals at once,” adds first author Qiangzhe Zhang, a Ph.D. student in Dr. Liangfang Zhang's research group at UC San Diego.

To make the neutrophil nanosponges, the researchers first developed a method to separate neutrophils from whole blood. They then processed the cells in a solution that causes them to swell and burst, leaving the membranes behind. The membranes were then broken up into much smaller pieces. Mixing them with ball-shaped nanoparticles made of biodegradable polymer fused the neutrophil cell membranes onto the nanoparticle surfaces.

“One of the major challenges of this work was streamlining this entire process, from isolating neutrophils from blood to removing the membranes, and making this process repeatable. We spent a lot of time figuring this out and eventually created a consistent neutrophil nanosponge production line,” says Qiangzhe Zhang.

In mouse models of severe rheumatoid arthritis, injecting nanosponges in inflamed joints led to reduced swelling and protected cartilage from further damage. The nanosponges performed just as well as treatments in which mice were administered a high dose of monoclonal antibodies.

The nanosponges also worked as a preventive treatment when administered prior to inducing the disease in another group of mice.

Dr. Zhang cautions that the nanosponge treatment does not eliminate the disease. “We are basically able to manage the disease. It's not completely gone. But swelling is greatly reduced and cartilage damage is minimized,” he says.