Chemotherapy is considered a foundation in the management of many types of cancer.However, its effectiveness in the cure of cancer is partly hampered by inherent or acquired multidrug resistance (MDR).There is great need to develop new strategy to overcome MDR tumors.Over-expression of P-glycoprotein (P-gp) plays a major role in MDR.Recently, it is indicated that nanoparticles have the ability to accumulate in cells without being recognized by P-gp.In this study, we prepared a lipid-polymer hybrid nanoparticle (HNP), consisting of a hydrophobic polymeric core and an amphiphilic shell.1,2-Distearoyl-sn-glycero-3-phosphoethanolamine-poly (ethylene glycol)-folic acid and cholesterol-arginine-histidine methyl ester as lipid layer, PLGA as polymeric core.Doxorubicin (DOX) was entrapped in the HNP to form DOX-HNP.Uniform and spherical nanoparticles were obtained at an average size of 170±13 nm.The FA receptor was successfully loaded in the surface of DOX-HNP.The DOX-HNP showed high entrapment efficiency and drug loading, and the drug release was faster in an acidic environment than in a neutral environment (pH=7.4).Compared with A549 cells, more DOX-HNP were taken up in KB cells, and DOX-HNP induced more apoptosis in KB cells and MDA-MB-231/ADR cells.Moreover, DOX-HNP can get into the nuclear of MDA-MB-231/ADR cells.Compared with free DOX, DOX-HNP delivered more DOX to the nuclear of KB cells, MDA-MB-231 cells and MDA-MB-231/ADR cells.DOX-HNP showed higher cytotoxicity on KB cells, MDA-MB-231 cells and MDA-MB-231/ADR cells as compared to the free DOX.The results of in vivo experiments indicated that DOX-MNP showed higher antitumor activity as compared to the same dose of free DOX.We believe that HNP present a promising strategy in overcoming MDR and improving the therapeutic index of chemotherapeutics by enhancing therapeutic efficacy and reducing side effects.