Engineering of dendritic cell bispecific extracellular vesicles for tumor-targeting immunotherapy

Advances in the development of therapeutic extracellular vesicles (EVs) for cancer immunotherapy have allowed them to emerge as an alternative to cell therapy. In this proof-of-concept work, we develop bispecific EVs (BsEVs) by genetically engineering EV-producing dendritic cells (DCs) with aCD19 scFv and PD1 for targeting tumor antigens and blocking immune checkpoint proteins simultaneously. We find that these bispecific EVs (EVs-PD1-aCD19) have an impressive ability to accumulate in huCD19-expressing solid tumors following intravenous injection. In addition, EVs-PD1-aCD19 can remarkably reverse the immune landscape of the solid tumor by blocking PD-L1. Furthermore, EVs-PD1-aCD19 can also target tumor-derived EVs in circulation, which prevents the formation of a premetastatic niche in other tissues. Our technology is a demonstration of bispecific EV-based cancer immunotherapy, which may inspire treatments against various types of tumors with different surface antigens and even a patient-tailored therapy. [Display omitted] •Bispecific EVs expressing aCD19 and PD1 are developed by genetic engineering•Bispecific EVs target tumor antigen huCD19 and bind PD-L1 within solid tumors•Bispecific EVs also target tumor-derived EVs to prevent the formation of premetastatic niche Xu et al. develop therapeutic dendritic cell-derived bispecific EVs with aCD19 scFv and PD1 expression for targeting tumor antigens and binding immune checkpoint proteins simultaneously. The bispecific EVs accumulate in solid tumor and rebuild the immunosuppressive microenvironment, showing significant primary tumor regression and metastasis inhibition in a mouse model.