90K increased delivery efficiency of extracellular vesicles through mediating internalization.

Abstract

Using mass spectrometry-based high-throughput proteomics, we identified a membrane protein on extracellular vesicles (EVs), 90K, which predicts poor overall survival of patients with head and neck cancer. 90K levels in serum EVs could serve as an independent factor for poor prognosis of patients with head and neck cancer. Pre-treatment of immune competent mice with tumor-derived EVs (TDEs) elicited an immune-suppressive microenvironment for tumor cells, which was regulated by 90K. The immunosuppressive function of TDE-90K depends on the presence of myeloid derived suppressor cells (MDSCs) rather than regulatory T cells. The immune regulatory role of TDEs on MDSCs depends on miR-21 which is encapsulated in TDEs. Moreover, 90K is required for the internalization of TDE cargo though interacting with integrin-β1 and anti-siglec-9 rather than directly affecting the immune function of MDSCs. 90K modification of γδT cell-derived EVs (γδTEVs) could increase the delivery efficiency and therapeutic effect of PD-L1 siRNA by γδTEVs. We concluded that as a secreted protein modulating cell-cell and cell-matrix interactions, 90K can be carried by TDEs to mediate the internalization and delivery of TDEs cargo by recipient cells. This function of 90K could be utilized to improve the efficiency of EV-based drug delivery.