Despite advances, metastasis continues to be the main reason for therapeutic failure in breast cancer (BC), making it crucial to develop new strategies that target this process. BC cells responsible for tumor dissemination have an invasive and proliferative phenotype; with a characteristic overexpression of the transcriptional factor STAT3. These cells are also known to overexpress the Cluster of Differentiation 44 (CD44), a hyaluronic acid receptor that also binds many extracellular matrix components, such as Dermatan Sulfate (DS). Our research group reported nanoparticles (NPs) based on dermatan sulfate and chitosan loaded with IRW. This delivery platform selectively interacts and is internalized through the CD44 receptor, and modulates the pharmacological stress tolerance to 5-fluorouracil in colorectal cancer. Based on these results, the present work describes the study of new nanoformulations designed to deliver anti STAT3 bioactive molecules towards BC cells: (1) DS/chitosan NPs, loaded with Flubendazole (Flu-NPs), an antihelminthic recently repurposed as an anti-STAT3 antitumoral agent, and (2) NPs loaded with siRNA (siRNA-NPs). Both formulations were synthesized by ionotropic gelation and displayed a similar hydrodynamic diameter (Flu-NPs: 199±48 nm and siRNA.NPs: 202±28 nm). PEC characterization confirmed that both nanoformulations can encapsulate their loads: Flu (100 µM) and scramble siRNA (1 µM). The interaction and internalization were studied by confocal microscopy and flow cytometry, using two human BC cell lines with different CD44 expression, MDA-MB-231 and MCF-7. In both analyses, there was a positive correlation between NPs uptake and CD44 expression. Regarding its effects, wound healing assays and proliferative assays were conducted to study migration and proliferation. Flu-NPs show a significantly higher inhibition of cell viability and cell migration in MDA-MB-231 cultures, compared to the CD44-low expressing MCF-7 cells. These results support