Background <p>Metastatic melanoma exhibits poor response to conventional chemotherapy due to resistance, immune evasion, and tumor heterogeneity. Strategies that increase melanoma cell sensitivity to apoptosis and reduce metastatic behavior can improve therapeutic outcomes. Interferon‑α (IFN-α) is a cytokine which has well‑documented direct antiproliferative and pro‑apoptotic effects on tumor cells in vitro, and its combination with chemotherapeutic agents can further potentiate these intrinsic cytotoxic mechanisms. When delivered through nanocarrier-based systems, such combinations may improve intracellular drug accumulation and reduce off‑target toxicity.</p> Purpose <p>This study evaluated the feasibility of amphiphilic dextran-stearic acid (Dex-SA) nanoparticles (NPs) for co-delivery of temozolomide (TMZ) and IFN-α in B16-F10 melanoma cells.</p> Methods <p>Dex-SA conjugates were synthesized and self-assembled into NPs through a sonication method. Physicochemical properties of NPs, including particle size, surface charge, morphology, and drug encapsulation efficiency (EE) were characterized. In vitro assays, including MTT, apoptosis analysis, wound healing, and western blotting were carried out to assess the anti-tumor efficacy of TMZ + IFN-α NPs.</p> Results <p>The Dex-SA NPs displayed uniform spherical morphology with an average diameter of 217.70 nm and high EE for both agents. The NPs demonstrated enhanced cellular uptake and low cytotoxicity. Moreover, TMZ + IFN-α NPs significantly increased apoptosis rates and inhibited cancer cell migration compared to free drugs as single agents or in combination. </p> Conclusion <p>The prepared Dex‑SA construct delivers both agents efficiently and demonstrates a promising in vitro approach for enhancing chemotherapeutic efficacy through improved intracellular co-delivery. These findings support the rationale for further preclinical evaluation of combined chemo-immunotherapeutic strategies in melanoma.</p> Graphical Abstract <p></p>