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

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. Sr²⁺ and Cu²⁺ 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, Cu²⁺, and TNF-α siRNA to synergistically scavenge ROS and inhibit the expression of TNF-α to induce macrophage polarization, while Sr²⁺ 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.