Nanoparticle-inhibited neutrophil elastase prevents neutrophil extracellular trap and alleviates rheumatoid arthritis in C57BL/6 mice

Rheumatoid arthritis (RA) is characterized by inflammation outbreak and joint destruction. As the main culprit of RA, neutrophils firstly migrated to inflamed joints and aggravate inflammatory reaction by release excess neutrophil extracellular traps (NETs). However, it remains unsatisfactory efficiency to prevent NETs formation. Emerging evidence indicated that inhibition of neutrophil elastase (NE) could prevent NETs production. Here, we established a method in which sivelestat (ST, a low molecular specific inhibitor of NE)-conjugated bovine serum albumin nanoparticles (BTST NPs) could specifically target inflamed neutrophils for delivery of ST, which could selectively inhibit NE and prevent NETs production. Moreover, BTST NPs were also loaded with dexamethasone palmitate (DP), a classic glucocorticoid drug for RA, to deliver DP to the inflammatory site to achieve synergistically treatment of RA. It was identified that activated neutrophil could selectively internalize DP/BTST NPs. The release of ST and DP were depending on ROS environments in neutrophils at inflamed joints, subsequently could hinder NETs generation. In collageninduced arthritis (CIA) models, DP/BTST NPs significantly improved targeting effect, alleviated RA symptoms, and enhanced prominent biological safety. We pioneer proved that this novel ST-conjugated BSA NPs holds a promising approach to improve treatment of RA and various NET-mediated inflammatory diseases.(c) 2023 Published by Elsevier Ltd.