Messenger Nanozyme for Reprogramming the Microenvironment of Rheumatoid Arthritis

Dysregulation of superoxide anion (O₂^-) and hydrogen peroxide (H₂O₂) metabolism in the microenvironment of rheumatoid arthritis (RA) drives the feedback loops of TNF-α and IL-1β thereby inducing an inflammatory storm between immune cells and joint tissue cells. Here, we combine nanoscale manganese dioxide (MnO₂) with microvesicles derived from macrophage (MMV). The former possesses superoxide dismutase (SOD) and catalase (CAT)-like activities that can modulate this imbalance, and we amplify the enzyme-like activities by using the amorphous hollow mesoporous structure and surface modification. The latter is a natural endogenous component with the parent cell-like inflammatory homing ability and a unique function of transmitting information to surrounding and distant cells (″messenger function″), which helps amorphous hollow MnO₂ (H-MnO₂) nanozymes to cloak in the blood and reach the site of inflammation, where they can not only accumulate in activated macrophages but also pretend to be ″messengers″ that are utilized by fibroblast-like synoviocytes (FLS) and chondrocytes. In addition, we also load dexamethasone sodium phosphate (DSP) for helping the nanozymes work. Messenger nanozyme (MMV-MnO₂@DSP) inherits the natural properties of MMV and mimics the enzymatic activity of SOD and CAT. It accumulates in activated macrophages to restore the metabolism of O₂^- and H₂O₂ while promoting repolarization and inhibits the feedback loops of TNF-α and IL-1β among macrophages, fibroblast-like synoviocytes, and chondrocytes, leading to anti-rheumatoid arthritis effects in vitro and in vivo.