The activity of high concentration of a specific enzyme in cancer has been utilized in a diagnosis of cancer, as well as cancer-targeted drug delivery system. NAD(P)H:quinone oxidoreductase-1 (NQO1), an over-expressed enzyme in certain cancer cells, maintains homeostasis and inhibits oxidative stress caused by elevated reactive oxygen species in cancer cells. The activity of NQO1 in lung and liver cancer cells is increased up to 50 times than that in normal cells. Interestingly, NQO1 reacts with trimethyl-locked quinone propionic acid (QPA) and produce lactone-based moiety via intramolecular cyclization. Herein, we present a novel enzyme-responsive polymeric micelle which can undergo depolymerization in response to NQO1. The enzyme-responsive polymer (PEG-b-PCL-QPA) was successfully synthesized by ring-opening polymerization of QPA-amide protected polycaprolactone (PCL) using polyethylene glycol (PEG) as a macroinitiator. These amphiphilic block copolymers self-assemble in aqueous condition into micelles that can disassemble and release encapsulated drugs through depolymerization of the polymers upon activation of NQO1. Compared to control groups, enzyme-responsive micelle showed efficient drug release and enhanced anti-cancer effects in vitro. These results indicate that the enzyme-responsive polymeric micelles present a promising potential for improving the efficacy of anti-cancer drug delivery system.