We report on a novel pH and reduction dual-sensitive drug delivery system crosslinked by quaternary ammonium salt.The fabrication of the pH and reduction-sensitive polymeric drug carrier with the accelerated cellular internalization function was achieved via two-step synthesis.Firstly,monomethoxyl poly(ethylene glycol)-block-poly-(N,N-diethylaminoethyl methacrylate) (MPEG-b-PDEA) was prepared by atom transfer radical polymerization, using MPEG-based macroinitiator.Then, polymeric nanoparticles crosslinked by N,N-bis(bromoacetyl) cystamine were fabricated via quaternization of the nitrogen from DEA and bromine from crosslinker.These novel dual-bioresponsive nanoparticles functionalized with quaternary ammonium salts can efficiently accelerated cellular internalization.Also, they are likely destabilized in the endo/lysosomal compartments as a result of the solubilizing PDEA block as well as in the cytoplasms owing to cleavage of the intervening disulfide bonds, resulting in efficient intracellular delivery of anticancer drugs.Doxorubicin (DOX), an anthracycline anticancer drug, was used as model drug in this study.DOX released faster from NPs in a weakly acidic environment (pH 6.8) than at pH 7.4 (in the presence of 0 or 10 mM glutathione).The release is more effective under acidic and reductive conditions (pH 6.8 and 10 mM glutathione).In vitro cytotoxicity studies demonstrated that the DOX-loaded pH and reduction-sensitive polymeric nanoparticles can effectively enhance the intracellular drug delivery, resulting in a higher cytotoxicity than free DOX.Utilizing confocal fluorescence microscopy and fluorescence flow cytometry, we demonstrate that DOX-loaded NPs can deliver DOX into the cytoplasm and nucleus of cells, with efficiency better than that of free DOX.This increased cellular internalization is more significant under acidic and reductive conditions, which is analogous to pH and reduction conditions in the endosomes.These dual-bioresponsive nanoparticles with quaternary ammonium salt group have appeared to be highly promising for further development of drug transporters for intracellular delivery.