<p>A d-α-Tocopheryl Polyethylene Glycol-1000 Succinate (TPGS)-functionalized nanoparticle formulation was developed for the co-delivery of Paclitaxel (PTX) and Gefitinib (GEF) to achieve synergistic therapeutic efficacy against triple-negative breast cancer (TNBC). To determine the optimal drug ratio, multiple PTX: GEF combinations were evaluated in MDA-MB-231 TNBC cells. Among the tested ratios, 0.72:0.25 (w/w) demonstrated the most pronounced cytotoxic response, with a combination index (CI) of 0.547, confirming a strong synergistic interaction between PTX and GEF. Co-loaded nanoparticles were prepared using the single emulsion solvent evaporation method and surface-functionalized with TPGS to enhance cellular uptake, stability, and therapeutic performance. The TPGS-functionalized co-loaded nanoparticles exhibited a mean particle size of 246.7 ± 4.5&#xa0;nm, a PDI of 0.28 ± 0.03, and a zeta potential of − 21.6 ± 2.8 mV, with high entrapment efficiencies of 87.3 ± 3.4% for PTX and 80.5 ± 2.9% for GEF. In cellular uptake studies, TPGS-functionalized co-loaded nanoparticles achieved 2.87-fold higher internalization in MDA-MB-231 cells compared to free drugs, resulting in the lowest IC₅₀ (0.87 ± 0.38&#xa0;µg/mL) among all formulations. Furthermore, 3-D spheroid experiments demonstrated enhanced penetration and therapeutic efficiency, yielding a 2.8-fold reduction in spheroid volume from Day 0 to Day 8 (147.38 ± 12.33 mm³ to 50.09 ± 3.87 mm³). Overall, these findings indicate that the optimized PTX: GEF ratio, delivered via TPGS-functionalized nanoparticles, facilitates enhanced cellular uptake, potent cytotoxicity, and improved tumor penetration, representing a promising strategy for synergistic and targeted therapy in aggressive TNBC.</p> Graphical Abstract <p></p>