Synergistic rheumatoid arthritis therapy by interrupting the detrimental feedback loop to orchestrate hypoxia M1 macrophage polarization using an enzyme-catalyzed nanoplatform

A detrimental feedback loop between hypoxia and oxidative stress consistently drives macrophage polarization toward a pro-inflammatory M1 phenotype, thus persistently aggravating rheumatoid arthritis (RA) progression. Herein, an enzyme-catalyzed nanoplatform with synergistic hypoxia-relieving and reactive oxygen species (ROS)-scavenging properties was developed using bovine serum albumin-bilirubin-platinum nanoparticles (BSABR-Pt NPs). Bilirubin was employed to eliminate ROS, while platinum exhibited a synergistic effect in scavenging ROS and simultaneously generated oxygen. In mice RA model, BSA-BR-Pt NPs treatment exhibited superior effects, resulting in significant improvements in joint inflammation, cartilage damage, and bone erosion, compared to methotrexate, the most widely used antirheumatic drug. Mechanistically, RNA-sequencing data and experimental results elucidated that BSA-BR-Pt NPs induced a re-polarization of hypoxic M1 macrophages to M2 macrophages via switching glycolysis to oxidative phosphorylation through the inhibition of HIF-1 alpha pathway. Collectively, this research for the first time elaborated the underlying mechanism of enzyme-catalyzed nanoplatform in orchestrating macrophage polarization, and identified a novel therapeutic strategy for RA and other inflammatory disorders.