Tumor-originated pH-responsive nanovaccine mixture to treat heterogeneous tumors

Purpose: This study was aimed to develop a tumor-originated extracellular vesicle (EV)-based vaccine mixture with a pH-responsive ability to treat various tumors. Methods: The EVs vaccine mixture consisted of different EVs (MEVs extracted from MDA-MB-231 tumor cells and HEVs extracted from HepG2 tumor cells) encoded with a pH-responsive moiety (HDEA), Toll-like receptor 4 ligand (TLR4), and tumor-targeting vaccine antigen (MUC1 antigen for targeting MDA-MB-231 cells and WT1 antigen for targeting HepG2 cells) using the sonication. The physicochemical properties and in vitro/in vivo antitumor efficacy of the developed EVs mixture were characterized. Results: The EVs vaccine mixtures were efficiently internalized to dendritic cells (DCs) via hyaluronic acid (HA)-mediated CD44 receptor binding and TLR4-mediated signaling on the DCs surface. In particular, the internalized EVs vaccine mixture released MUC1 and WT1 antigens by HDEA-mediated vesicle destabilization at acidic endosomal pH, resulting in increasing the antitumor effect on both MDA-MB-231 and HepG2 tumor cells. Conclusion: We demonstrated the antitumor activity of EVs vaccine mixture in in vitro/in vivo tumor model studies. These results indicate that EVs vaccine mixture can provide an effective immunotherapy strategy for heterogeneous tumors.