In this work, we have investigated the potential benefits of combining biodegradable pH sensitive core-shell PCL NPs loaded with IM and enzyme sensitive polyelectrolyte complexes (PECs) loaded with doxorubicin (DOX). Our in vitro studies confirmed the excellent antileukemic activity of dual drug loaded nanoparticles on CML cells. As compared with a drug alone, co-treatment with IM and DOX loaded in nanoparticles allowed a sustained downregulation of BCR-ABL and significant CML stem cell death. This furthermore showed that couple formulation of nanoparticles enhanced the drugs' kinetics and efficacy, combined with the pH sensibility of core-shell PCL NPs loaded with IM and enzyme sensitive polyelectrolyte complexes (PECs) loaded with DOX. Our study demonstrates that dual drug loaded nanoparticles work in a synergistic manner, lowering the dose and confirming that both drugs reach the target cell specifically, maximizing the cytotoxicity while minimizing the chances of cell resistance to any one drug.