Biomimetic Nanoplatform for Targeted Rheumatoid Arthritis Therapy: Modulating Macrophage Niches Through Self‐Sustaining Positive Feedback‐Driven Drug Release Mechanisms

Abstract The core strategies in treating rheumatoid arthritis (RA) now focus on ameliorating the inflammatory microenvironment and reversing macrophage phenotypes within the joint cavity. This study introduces a co‐delivery system of integrating nanoenzymes and gene therapeutics sequentially modified with guanidinium‐based polymers and macrophage membranes to achieve synergistic therapeutic effects. This co‐delivery system is named MACP siTNF‐α nanoparticles (NPs). MACP siTNF‐α nanoparticles are designed for targeted delivery to the inflamed joint site, where they are preferentially internalized by M1‐type macrophages and efficiently evade lysosomal degradation. Subsequently, the co‐delivery system operates efficiently via a self‐sustaining positive feedback drug release mechanism. The biomimetic nanoplatform reduces reactive oxygen species (ROS) levels and prevents glutathione (GSH) depletion. GSH degrades the polymers to release small interfering RNA (siRNA) and expose the Prussian blue (PB) nanoenzymes, which effectively scavenge ROS and restore GSH levels. This feedback loop significantly enhances the gene silencing capability and ROS scavenging efficiency of the co‐delivery system. In summary, MACP siTNF‐α NPs can reverse macrophage ecological niche in inflammatory soils through the dual mechanism of efficiently inhibiting the expression of tumor necrosis factor‐alpha (TNF‐α) the upstream pathway of the inflammatory response, and eliminating ROS, thus realizing efficient treatment of RA.