# Biocatalytic Nanoregulators Restore Joint Redox‐Immune Homeostasis in Rheumatoid Arthritis

## TL;DR

A new treatment for rheumatoid arthritis uses nanomaterials to reduce inflammation and protect cartilage by regulating immune responses and reactive oxygen species.

## Contribution

A novel biocatalytic nanoregulator combining EVs and Ru@ZrMOF is developed for targeted RA therapy.

## Key findings

- Ru@ZrMOF/EVs reduce joint inflammation and pannus formation in RA.
- The treatment promotes M1 to M2 macrophage polarization and downregulates HIF-1α.
- ROS scavenging and oxygen production by the nanoregulators protect cartilage.

## Abstract

Rheumatoid arthritis (RA), a debilitating autoimmune disorder marked by progressive synovitis and osteochondral erosion, presents critical therapeutic challenges due to the limitations of existing regimens, including non‐specific biodistribution and compromised risk‐benefit profiles. In this study, a novel therapeutic approach is proposed utilizing mesenchymal stem cell‐derived extracellular vesicles (EVs) coating on ruthenium‐loaded metal‐organic frameworks (Ru@ZrMOF), which exhibit catalase mimetic activities. The EVs coating enhances the biocompatibility and targeting efficiency of the Ru@ZrMOF, while also promoting cartilage protection. Through reactive oxygen species (ROS) scavenging and oxygen production, Ru@ZrMOF/EVs significantly alleviate joint inflammation, promote cartilage protection, and inhibit pannus formation. The therapeutic mechanism involves polarization of macrophages from the M1 pro‐inflammatory phenotype to the M2 anti‐inflammatory phenotype, facilitating a shift in cytokine profiles from pro‐inflammatory to anti‐inflammatory, and downregulation of hypoxia inducible factor‐1α. These findings demonstrate that Ru@ZrMOF/EVs offer a promising strategy for RA treatment by addressing both inflammation and tissue protection through targeted ROS regulation and immune modulation.

Mesenchymal stem cell‐derived extracellular vesicles (EVs) coat ruthenium‐loaded metal‐organic frameworks (Ru@ZrMOF), creating a targeted therapeutic (Ru@ZrMOF/EVs). This platform scavenges ROS, generates oxygen, and polarizes macrophages from M1 to M2, alleviating inflammation, inhibiting pannus, promoting cartilage repair, and downregulating HIF‐1α in RA joints.