Genetically engineered extracellular vesicles expressing decoy protein TACI provide a therapeutic effect in systemic lupus erythematosus mouse model.

The suppression of B-cell activation and autoantibody production through immunotherapy has garnered substantial interest in advancing systemic lupus erythematosus (SLE) treatments. Although SLE patients do benefit from current therapies, no efficient therapeutic approaches are available to a substantial number of patients. In this study, we developed extracellular vesicles to express a fusion protein of the transmembrane activator and cyclophilin ligand interaction molecule (TACI). We performed a comprehensive functional evaluation, including in vitro binding assays and therapeutic efficacy assessments in a murine SLE model. Our findings demonstrate that the engineered extracellular vesicles stably express the TACI receptor, effectively bind the cytokine BLyS and inhibit the BCMA-NF-κB signaling pathway in vitro. In vivo, TACI-engineered small extracellular vesicles significantly attenuated SLE severity and reduced inflammatory kidney damage in SLE mice by blocking BLyS/APRIL signaling. Collectively, these findings highlight the therapeutic potential of TACI-engineered small extracellular vesicles as a novel approach to suppress autoimmunity, prolong survival, and ameliorate lupus nephritis in MRL/lpr mice.