A novel extracellular vesicle-engineered immunotherapy drug for Her2+ breast cancer.

Trastuzumab profoundly improves outcomes of Her2+ breast cancer (BC) patients, but eventual drug resistance is inevitable. Therefore, new treatment options are urgently needed. Here, we modify extracellular vesicles (EVs) with a Her2 single-chain variable fragment of trastuzumab (EVs/Her2-scFv) to target Her2+ BC and found that EVs/Her2-scFv inhibit human Her2+ orthotopic BC comparable to trastuzumab and also uniquely suppress brain metastasies. Moreover, EVs/Her2-scFv loaded with rabeprazole (EVs/Her2-scFv/Rabe) effectively improve tumor immunosuppressive microenvironment and abnormal vasculature of Her2+ BC by reducing tumor EVs. When further anchored with CD8+ T cell chemotactic CXCL9, CXCL9-loaded EVs/Her2-scFv/Rabe (EVs/Her2-scFv/CXCL9/Rabe) facilitate CD8+ T cell recruitment and subsequent activation, thereby exhibiting immunotherapeutic effects on mouse Her2+ BC. In BC patient-derived tumor organoids (PDOs) and peripheral blood mononuclear cell coculture systems, EVs/Her2-scFv/CXCL9/Rabe limit PDO growth by blocking Her2 signaling and activating CD8+ T cells. Besides, EVs/Her2-scFv/CXCL9/Rabe are low-immunogenic with biosafety. Altogether, EVs/Her2-scFv/CXCL9/Rabe hold high potential in Her2+ BC therapy.