MicroRNAs (miRNAs) play critical roles in modulating the oncogenic driver pathways involved in the acquisition of resistance to cancer treatments. MiR-542-3p serves as a potent tumor suppressor molecule by targeting tumor suppressor p53 and apoptosis inhibitor survivin. A hyaluronic acid (HA)-decorated polyethylenimine-poly(d,. l-lactide-co-glycolide) (PEI-PLGA) nanoparticle system was developed in this study for targeted co-delivery of doxorubicin (DOX) and miR-542-3p for triple negative breast cancer (TNBC) therapy. This system showed an average size at 131.7 nm and high drug encapsulation efficiency, and prevented miR-542-3p degradation in the serum. HA/PEI-PLGA nanoparticles increased both drug uptake and cytotoxicity in MDA-MB-231 cells compared to MCF-7 cells, which express lower CD44 levels. Intracellular restoration of miR-542-3p further promoted TNBC cell apoptosis via activating p53 and inhibiting survivin expression. These results indicate that HA/PEI-PLGA nanoparticles have the potential to co-deliver chemotherapeutic agents and tumor suppressive miRNAs in combinatorial TNBC therapy. From the Clinical Editor: Breast cancer is a leading cause of mortality in women worldwide. The so-called triple negative tumors for estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) usually signifies poor prognosis. In this article, the authors developed a hyaluronic acid (HA)-decorated polyethylenimine-poly(D,L-lactide-co-glycolide) (PEI-PLGA) nanoparticle system for the delivery of both doxorubicin (DOX) and miR-542-3p against this tumor sub-type. This may represent a promising new therapy to treat breast cancer patients in the near future. © 2015 Elsevier Inc.