While the underlying biological mechanisms of TNBC has been unraveled to a large extent over the last decade, effective strategies to deliver therapeutics to cancer cells in vivo has remained a great challenge. We have constructed a new generation of drugs composed purely of RNA that is capable of targeting and treating cancers utilizing the phi29 pRNA three-way junction (3WJ) motif. Here, we have applied our innovative non-toxic and non-immunogenic RNA constructs with specific TNBC targeting capability to deliver high doses of therapeutic payloads to the cancer cells, while hoping to exhibit little or no collateral damage to healthy tissues. During this reporting period, we have successfully constructed RNA nanoparticles (NP) with ligands proven to bind and internalize into Human breast cancer stem cells as confirmed by flow cytometry and confocal microscopy. The targeted nanoparticles were able to significantly silence marker gene or oncogenic miRNA in vitro using Human breast cancer stem cells. Furthermore, utilizing 3D culture models to closer reflect in vivo conditions, RNA nanoparticles were delivered to TNBC cultures showing successful therapeutic effect by studying cell proliferation, migration, and invasion. We showed that RNA nanoparticles we constructed did not show side effects as demonstrated by immunogenicity assay. These studies establish a baseline of future in vivo studies as the final stage of this contract, in which we expect RNA nanoparticles to specifically treat TNBC tumor models in mice, with no side effects.