Neutrophils are key immune cells in rheumatoid arthritis (RA) that are known for their involvement in perpetuating, but also in resolving, inflammation. One mechanism used by neutrophils to control inflammation is the production of natural vesicles (such as exosomes and microparticles), which have been shown to be joint-protective in mouse models of RA.

In a new study published in Nature Nanotechnology, researchers show how semisynthetic nanoparticles (NPs) coated in neutrophil cell membrane can also have joint-protective effects in mouse models of RA. “We collected the plasma membrane of activated neutrophil cells and then coated the membrane onto a synthetic nanoscale particle core, forming neutrophil-membrane-coated nanoparticles (neutrophil-NPs),” states corresponding author Liangfang Zhang. “The resulting neutrophil-NPs were then applied locally to inflamed joints.”

Credit: Adapted from Thomas, B.L. & Perretti, M. Neutrophil wrap. Nat. Nanotechnol. https://doi.org/10.1038/s41565-018-0260-6 (2018)

Intra-articular injection of neutrophil-NPs reduced disease severity and joint damage in two mouse models of RA (collagen-induced arthritis and a transgenic model of inflammatory arthritis) to a level comparable with mice treated with anti-TNF or anti-IL-1β antibodies. “Neutrophil-NPs were able to effectively interact with and absorb various types of inflammatory cytokines that would otherwise have interacted with real neutrophils,” says Zhang.

The researchers also investigated the ability of neutrophil-NPs to penetrate cartilage. Fluorescently labelled neutrophil-NPs could be detected to a depth of 140 μm from the cartilage surface in explants, whereas erythrocyte-membrane-coated NPs could only be detected to a depth of 30 μm. Neutrophil-NPs were also seen in close proximity to chondrocyte nuclei, indicating that the NPs might have been taken up by the chondrocytes. In explants treated with IL-1β, neutrophil-NPs reduced cartilage damage by removing IL-1β from the environment.

“The development of therapeutic approaches based on the modification of NPs with cell membrane represents an important leap forward in the field of nanomedicine since they combine the benefits of both human-made and natural materials,” explains Massimo Bottini, who was not involved in this study. “Although the authors did not assess the mechanism of interaction between neutrophil-NPs and chondrocytes, the ability of neutrophil-NPs to enter the cartilage and target the chondrocytes is an important finding,” he continues. “The next step should be to test the therapeutic efficacy of systemically administered neutrophil-NPs in mouse models of arthritis as both a therapeutic agent and a chondrocyte-specific drug delivery system.”

“We are very interested in moving this technology forward to evaluate its clinical application potential; however, a major challenge that we have to overcome is the large-scale manufacturing of the neutrophil-NPs to GMP quality,” concludes Zhang.