Up to now, though remarkable progress has been achieved in tumor chemotherapy, there are still some issues to be concerned, such as severe side effects on the normal tissues and low efficiency against multi-drug resistant cancer cells.Various intelligent drug delivery systems, e.g., those responsive to intracellular microenvironmental stimuli (pH and redox), have exhibited great potential in solving these problems.In this work, a disulfide-bonded linkage was first introduced between doxorubicin (DOX) and the amino-terminal of positively charged dendrimer PAMAM to produce the conjugated complex PAMAM-SS-DOX.The complex exhibited an accelerated drug release profile in the presence of GSH and also an enhanced tumor cellular proliferation inhibition in vitro.Then a pH-dependent amphiphilic chitosan derivative with pI of 7.0 (ATC) was constructed to modify the surface of complex, and eventually a tumor-targeting supermolecule ATC(PAMAM-SS-DOX) was prepared.Under physiological conditions, the ATC shell could reduce the hemolytic toxicity of PAMAM, and effectively blocked the binding of opsonin in the blood, avoiding the RES phagocytosis.At low pH environment in the tumor environment, ATC shell would separate from the supermolecule because of charge reversal, while PAMAM-SS-DOX was released rapidly and entered the cell through endocytosis mechanism.Therefore, the novel pH and redox dual responsive supermolecular drug delivery system is highly promising for targeted intracellular delivery of anticancer drugs.