Combined delivery of drug and gene has emerged as an exciting method of treating cancer which possesses a synergistic effect of increasing drug efficacy or enhancing gene transfection efficiency, thereby increasing the efficiency of cancer treatment and prolong the survival time of cancer patients.However, endow the co-delivery systems with efficient intracellular (tumor cell)delivery and tumor sensitive drug release remains a big challenge.In this study, the multifunctional dual pH-sensitive nanocarrier was designed and prepared for the co-delivery of doxorubicin (DOX) and tumor necrosis factor-related apoptosis-inducing ligand encoding plasmid gene (pTRAIL).Firstly, Poly(ethyleneimine) flED-polyethylene glycol (PEG)-cell penetrating peptide (TAT) conjugates (PEI-PEG-TAT, PPT, enhance cellular internalization) and DOX-PEI (DP, linked with hydrazone bonds, pH-seusitive drug release) were successfully synthesized.Then, PPT and DP were mixed and used to condense pTRAIL to form the DOX and pTRAIL co-loaded PPT/DP/pTRAIL nanocarriers (PDT).Another pH sensitive material O-carboxymethyl-chitosan-PEG-NGR (CMCS-PEG-NGR) was coated to PDT to form the dual pH-sensitive nanocarrier CPDT.CPDT exhibited spherical structures with the particle size distribution of 137.4±2.7 nm.The cellular uptake results showed that CPDT could be efficiently co-delivery DOX and gen to the same cell.The gene transfection results showed that CDPD could successfully transfect HepG2 cells at acid pH conditions.Western Blot assay results showed that the CDPD could significantly enhance the pTRAIL protein expression after transfection compared with free pTRAIL.There results demonstrated that dual-pH sensitive CDPD was a promising carrier for drug and gene co-delivery.