To develop a robust drug-delivery system using multi-arm amphiphilic block copolymers for enhanced efficacy in cancer therapy. Two series of amphiphilic polymer micelles, PEG-b-PCL and PEG-b-PCL/TPGS, were synthesized. Doxorubicin (DOX) loading into the micelles was achieved via solvent dialysis. The micelles displayed excellent biocompatibility, narrow size distribution, and uniform morphology. DOX-loaded micelles exhibited enhanced antitumor efficacy and increased drug accumulation at tumor sites compared with free DOX. Additionally, 4A-PEG-b-PCL/TPGS micelles effectively suppressed drug-resistant MCF-7/ADR cells. This study introduces a novel micelle formulation with exceptional serum stability and efficacy against drug resistance, promising for cancer therapy. It highlights innovative strategies for refining clinical translation and ensuring sustained efficacy and safety .