Developing a smart cancer drug delivery carrier with enhanced cancer-targeting and effective drug release in tumors is critical for efficient cancer chemotherapy. Herein, we designed a pH-responsive copolymer (PEG-ELP[VH4-70]) that entraps DOX into a hydrophobic core and self-assembles into smart DOX-loaded nanoparticles. The DOX-loaded nanoparticles were stabilized by Zn2+ and disrupted as the pH drops from 7.4 to 5.6. An in vitro study demonstrated that the DOX-loaded nanoparticle system exhibited efficient internalization, triggered the release of DOX into the cytoplasm and enabled the inhibition of tumors effectively. When used to deliver chemotherapeutics to a murine cancer model, PEG-ELP[VH4-70]/DOX accomplished a 4.8-fold suppressed effect relative to the free drug after intravenous injection. This simple strategy can promote preeminent stability for targeting hydrophobic drugs to tumor tissues.