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Drug-resistance and drastic side effects are two major issues of traditional chemotherapy which may result in trail failure even death. Nanoparticle-mediated multidrug combination treatment has been proven to be a feasible strategy to overcome these challenges. In the present study, amphipathic block polymer of methoxyl poly(ethylene glycol)-poly(aspartyl(dibutylethylenediamine)-co-phenylalanine) (mPEG-P(Asp(DBA)-co-Phe)) was synthesized and self-assembled into pH-responsive polymeric vesicle. The vesicle was utilized to co-deliver cancer-associated epidermal growth factor (EGFR) inhibitor of afatinib and DNA-damaging chemotherapeutic doxorubicin hydrochloride (DOX) for enhanced non-small-cell lung cancer (NSCLC) therapy. As evaluated in vitro, the pH-responsive design of nanovesicle resulted in a rapid release of encapsulated drugs into tumor cells and caused enhanced cell apoptosis. In addition, in vivo therapeutic studies were conducted and the results evidenced that the co-delevery of DOX and afatinib using pH-sensitive nanovector was a promising strategy for NSCLC treatment. [ABSTRACT FROM AUTHOR]