Sun, Y.; Tang, Z.; Guo, M.; Zhai, Z.; Wu, Z.; Wang, X.; Li, F.; An, W.; Dou, X.

Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disease driven by aberrant B cell activation and autoantibody production. Here, we engineered NK-92 cell-derived extracellular vesicles displaying a CD19 single-chain variable fragment (V-CD19-Exo) to target pathogenic B cells. V-CD19-Exo retained the cytotoxicity of parental NK-92 cells while selectively targeting CD19 B cells. In MRL/lpr lupus mice, intraperitoneal administration of V-CD19-Exo reduced splenic CD19CD20 B cells from 10.53% to 1.51%, attenuated proteinuria and lupus nephritis, reversed splenomegaly, downregulated pro-inflammatory cytokines and autoantibodies, and improved survival to ~80% versus ~25% in controls. This cell-free strategy bypasses limitations of CAR-T/CAR-NK therapies-including cytokine release syndrome, lymphodepletion requirements, and high cost-while offering scalable production and a modular targeting platform for B cell-mediated autoimmune diseases.