By exploiting their biological functions, the use of biological nanoparticles such as extracellular vesicles can provide an efficient and effective approach for hepatic delivery of RNA-based therapeutics for the treatment of liver cancers such as hepatocellular cancer (HCC). Targeting liver cancer stem cells (LCSC) within HCC provide an untapped opportunity to improve outcomes by enhancing therapeutic responses. Cells with tumor-initiating capabilities such as LCSC can be identified by expression of markers such as epithelial cell adhesion molecule (EpCAM) on their cell surface. EpCAM is a target of Wnt/β-catenin signaling, a fundamental pathway in stem-cell growth. Moreover, mutations in the β-catenin gene are frequently observed in HCC and can be associated with constitutive activation of the Wnt/β-catenin pathway. However, targeting these pathways for the treatment of HCC has been challenging. Using RNA nanotechnology, we developed engineered biological nanoparticles capable of specific and effective delivery of RNA therapeutics targeting β-catenin to LCSC. Extracellular vesicles isolated from milk were loaded with small interfering RNA to β-catenin and decorated with RNA scaffolds to incorporate RNA aptamers capable of binding to EpCAM. Cellular uptake of these EpCAM-targeting therapeutic milk-derived nanovesicles resulted in loss of β-catenin expression and decreased proliferation. The uptake and therapeutic efficacy of these engineered biological nanotherapeutics was demonstrated using tumor xenograft mouse models. β-catenin can be targeted directly to control the proliferation of hepatic cancer stem cells using small interfering RNA delivered using target-specific biological nanoparticles. Application of this RNA nanotechnology-based approach to engineer biological nanotherapeutics provides a platform for developing cell-surface molecule-directed targeted therapeutics.