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Doxorubicin (DOX) has been extensively used to treat a wide range of cancers in free and nanotized form. Nanotization of DOX has alleviated its toxicity and efflux-mediated resistance. However, frequent upregulation of anti-apoptotic pathways, chemotherapy-enhanced inflammation, and epithelial-mesenchymal transition (EMT), present additional aspects of cellular DOX résistance. Nanoparticle-mediated combination therapy of DOX with additional anticancer agents is expected to offer greater therapeutic benefit by alleviating the overall drug résistance. We synthesized CD44-targeted DOX loaded nanoparticles (PSHA-DOXNPs) and evaluated their anticancer efficacy in combination with curcumin loaded selenium nanoparticles (Se-Cur NPs), previously developed by our group (Kumari et al., 2017). Combination of these nanoparticles (NPs) increased ROS level, decreased mitochondrial membrane potential, induced cell cycle arrest and apoptosis in HCT116 cells. This combination decreased the expressions of NFκB, Phospho-NFκB, EMT-metastasis-associated proteins (Snail, Vimentin, N-cadherin, CD44, MMP-2 and MMP-9), autophagy-associated proteins (Beclin-1 and LC-3BII), as well as anti-apoptotic protein Bcl-2, increased the expression of pro-apoptotic protein Bax, and increased cyt c release, which indicated decrease in inflammation, metastasis, and autophagy with increase in apoptosis. Moreover, the combination of NPs decreased tumor burden and increased survival of Ehrlich’s ascites carcinoma (EAC)-bearing mice.