The matrix protein (MP) is the core structure of the oncolytic vesicular stomatitis virus (VSV) and it played a vital role during the process of VSV infection and corresponding cytopathic effects in cancer treatment. In this study, a novel delivery synthesized by PEG-PCL-PEG and DOTAP (PPPD) was applied to encapsulate MP plasmids to derive the advantage and overcome the drawback of VSV platform in the treatment of colon cancer. The MP/DPPP micelles were stable in physiological solution, with an average diameter of 102 nm and zeta potential of 5.4 mV. This delivery system has a high encapsulation rate of 96% and transfection efficiency of 36%. A prominent anti-cancer activity of MP/DPPP was found both in Ct26 cells and animal models. The mechanisms of antitumor were further explored in this research. Our results indicated that MP/DPPP micelles were promising agents for future clinical application in the treatment of colon cancer.