In this study, novel smart pH-sensitive nanoparticles of PLA-mPEG(2000)/TPGS(3350)-PHis-Folate for enhanced effect of chemotherapy are developed. Polyethylene glycol (PEG) is decorated on the surface of nanocarriers in order to prolong the circulation of nanoparticles in blood; the pH-sensitive material of poly(l-histidine) is utilized in nanoparticles for the intelligent purposes: under normal physiological pH, the targeting molecule of folate can be hidden into the layer of PEG in nanoparticles, which closes the active targeting function of nanoparticles; but in weak acid of tumor tissue, poly(l-histidine) is protonated to expose folate on the surface of nanoparticles, opening the active targeting function; next, nanoparticles are internalized by cells via folate receptor-mediated endocytosis; finally, poly(l-histidine) in endosome/lysosome begins to dissociate, leading to quick intracellular drug release. The features of the nanoparticles such as morphology, particle size, drug loading content, in vitro release and in vitro cytotoxicity are further investigated. Nanoparticles designed in this work have multiple functions such as active targeting, long circulation and easy internalization by cells simultaneously, and rapid intracellular drug release, which demonstrates huge potential to apply for the efficient treatment of cancer.