Biomimetic Bimetallic‐Polyphenol Network as a Novel siRNA Carrier for the Treatment of Rheumatoid Arthritis via Macrophage Repolarization

Abstract Rheumatoid arthritis (RA) is an auto‐immune disease characterized by inflammatory episodes and joint degradation. Activated macrophages produce large amounts of reactive oxygen species (ROS) and pro‐inflammatory cytokines, which damage chondrocytes and destroy the cartilage matrix. Therefore, a promising therapeutic strategy for the treatment of RA is to inhibit the secretion of pro‐inflammatory cytokines and ROS to promote macrophage polarization and facilitate cartilage repair. In this paper, an active targeting nanomedicine based on metal‐phenolic networks (MPNs) is constructed to re‐polarize activated macrophages for RA therapy. Sr ²⁺ and Cu ²⁺ are first coordinated with tannic acid (TA) to prepare TSC, and TNF‐α siRNA is loaded into TSC via simple ultrasonic treatment to obtain TSSC. Finally, TSSC is coated with M1 macrophage membrane (termed as TSSC@M1) to enhance its inflammatory targeting ability. TSSC@M1 can actively target macrophages by releasing TA, Cu ²⁺ , and TNF‐α siRNA to synergistically scavenge ROS and inhibit the expression of TNF‐α to induce macrophage polarization, while Sr ²⁺ can further protect cartilage. In the collagen‐induced arthritis (CIA) mouse model, TSSC@M1 can accumulate at inflamed joints and alleviate RA symptoms by modulating macrophage phenotype and repairing cartilage. Overall, TSSC@M1 NPs offer a promising and safe approach to treat RA.