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Gastric Cancer is one of the major leading causes of death by cancer worldwide, but the chemotherapeutics, one of the preferred approaches, bring about extensive side effects when systemically injected. In our work, doxorubicin-loaded pH and redox responsive hyperbranched poly(amidoamine)(h-PAMAM)-based vesicle was prepared to enhance anti-tumor efficacy of chemotherapeutic compounds. The doxorubicin (DOX) molecules were attached to PEGylated h-PAMAM by acid sensitive cis-aconityl linkage to form pH sensitive conjugate (PPCD), which self-assembled in THF into micelles. The resulted micelles were then crosslinked by disulfide bonds and transferred from THF into water to form vesicles, which could be disassembled into small-sized conjugates under the redox condition. The drug release profiles showed that the PPCD vesicle presented stimuli-triggered drug release in acidic and reducing environment, and lower DOX leakage under neutral condition. The in vitro cell assay reflected the rapid DOX release and significant tumor-cytotoxic effect of the PPCD vesicle. The in vivo anticancer activity and systematic toxicity studies showed that the PPCD vesicles had lower tissue toxicity with good antitumor effect. In brief, h-PAMAM-based PPCD vesicle provides a safe and effective drug delivery system for the therapy of gastric cancer.