Smart exosomes with lymph node homing and immune-amplifying capacities for enhanced immunotherapy of metastatic breast cancer

Tumor-draining lymph nodes (TDLNs) are the primary sites to initiate immune responses against cancer, as well as the origin of metastasis for most breast cancer cases. Reverting the immunosuppression microenvironment in TDLNs is critical to improving the outcome of the malignancy, though still a big technical challenge. In this study, a type of smart exosomes was developed in which the exosome surface was functionally engineered with CD62L (L-selectin, a gene for lymphocyte homing to lymph nodes) and OX40L (CD134L, a gene for effector T cell expansion and regulatory T cell [Treg] inhibition) by forced expression of the genes in the donor cells. Compared with control exosomes, the smart exosomes displayed strong TDLN homing capacity in the 4T1 syngeneic mouse model. Moreover, injection of the smart exosomes activated effector T cells and inhibited Treg induction, thereby amplifying the antitumor immune response and inhibiting tumor development. Together, the engineered smart exosomes provide a novel nanoplatform for TDLN-targeted delivery and cancer immunotherapy.