A Multifunctional Enzyme Cascade Catalytic Nanoplatform for Effective Synergistic Therapy of Rheumatoid Arthritis

Abstract Insufficient oxygen supply and elevated levels of reactive oxygen species (ROS) in rheumatoid arthritis (RA) joints synergistically exacerbate inflammation and accelerate disease progression. In this study, a hybrid nanoassembly composed of superoxide dismutase (SOD) and catalase (CAT) conjugated within a single poly(ε‐caprolactone) (PCL) nanoparticle is developed for RA therapy. The synthesized nanoassembly (PSC) drives a proximity‐dependent cascade reaction that efficiently scavenges ROS and generates oxygen, thereby modulating the phenotype of inflammatory macrophages in RA synovium, significantly inhibiting the secretion of pro‐inflammatory cytokines, and consequently alleviating inflammation. Furthermore, PSC functions as a versatile drug delivery platform for hydrophobic small‐molecule drugs. Iguratimod (IGU), an anti‐rheumatic drug with bone‐protective properties, is incorporated into the PSC (PSC@IGU), which is then loaded into dissolvable microneedles (MNs) to enhance drug delivery efficiency. Finally, PSC@IGU MNs demonstrate significant therapeutic effects in RA mouse models by effectively improving joint hypoxia, alleviating synovial inflammation, and preventing bone erosion. This study highlights the potential of PSC@IGU‐loaded MNs for the treatment of RA, indicating their promising ability to bridge basic research with clinical translation.