Anti-CD19-engineered exosomes enable B cell-targeted anti-BAFF mRNA delivery to alleviate lupus progression

Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by abnormal activation of B cells. Excessive B cell activating factor (BAFF) of the tumor necrosis factor family plays an essential role in B cell hyperactivation. Blocking the binding of excessive BAFF to its receptors is becoming a promising approach for SLE treatment. Here, we constructed genetically engineered exosomes derived from HEK293 cells that were functionalized with anti-CD19 (a B cell-specific surface marker) and loaded with anti-BAFF mRNA (CD19@Anti-BAFF^mRNA Exo). The anti-CD19 modification mediated receptor-dependent targeted binding and internalization, ensuring precise delivery of anti-BAFF mRNA to B cells. This enabled B cells to produce anti-BAFF antibodies in vivo, which captured excess BAFF, thereby inhibiting abnormal B cell activation and proliferation. Notably, mice with lupus treated with CD19@Anti-BAFF^mRNA Exo exhibited alleviated kidney damage and reduced disease progression. Our B cell-targeted engineered exosomes loaded with anti-BAFF mRNA provide a novel approach to enhance antibody production and improve local antibody concentration, offering a potential therapeutic strategy for SLE.