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Introduction: Multi-drug nanosystem has been employed in several therapeutic models due to the synergistic effect of the drugs and/or bioactive compounds, which help in tumor targeting and limit the usual side effects of chemotherapy. Methods: In this research, we developed the amphiphilic Heparin-poloxamer P403 (HSP) nanogel that could load curcumin (CUR) and Paclitaxel (PTX) through the hydrophobic core of Poloxamer P403. The features of HSP nanogel were assessed through Fourier-transform infrared spectroscopy (FT-IR), transmission electron microscopy (TEM), differential light scattering (DLS), and critical micelle concentration (CMC). Nanogel and its dual drug-loaded platform showed high stability and spherical morphology. Results: The drug release profile indicated fast release at pH 5.5, suggesting effective drug distribution at the tumor site. In vitro research confirms lower cytotoxicity of HSP@ CUR@PTX compared to free PTX and higher inhibition effect with MCF-7 than HSP@PTX. These results support the synergism between PTX and CUR. Conclusion: HSP@CUR@PTX suggests a prominent strategy for achieving the synergistic effect of PTX and CUR to circumvent undesirable effects in breast cancer treatment.