Engineered Apoptotic Extracellular Vesicles for Programmable Regulation of Neutrophil‐Macrophage‐ROS Pathogenic Axis to Reconstruct Rheumatoid Arthritis Microenvironment

Abstract Rheumatoid arthritis microenvironment (RAM) contains complex pathogenic mediators that interact dynamically to drive the progression of rheumatoid arthritis (RA). However, most current RA treatments are single‐target interventions, exerting limited impact on RAM. Herein, apoptotic extracellular vesicles (ApoEV) are constructed for programmable regulation of the neutrophil‐macrophage‐ROS pathogenic axis, aiming to reconstruct RAM and improve RA therapy. Mesenchymal stem cells (MSCs) are pretreated with dexamethasone (Dex) and induced apoptosis to produce Dex‐loaded and FasL‐overexpressing ApoEV (D@ApoEV FasL ), which is further modified with low‐molecular‐weight heparin (LMWH) through a ROS‐responsive cleavage linker to form D@ApoEV FasL ∩L. After intravenous injection into RA mice, D@ApoEV FasL ∩L targeted the inflamed joints based on their MSC‐derived feature and blocked neutrophil recruitment through binding to P‐selectin on vascular endothelial cells. In response to high ROS, D@ApoEV FasL ∩L shed LMWH and exposed FasL, inducing neutrophil apoptosis through the Fas/FasL signaling pathway. Subsequently, the apoptotic neutrophils triggered macrophage reprogramming from M1 to M2 phenotype, and the released Dex significantly reduced the oxidative damage. Various in vitro and in vivo assessments have confirmed that D@ApoEV FasL ∩L can effectively regulate neutrophils, macrophages, and ROS, trigger an immune cascade, and restore intra‐articular immune homeostasis, exhibiting an effective RAM reconstruction ability and a promising therapeutic effect for RA.