Arming Abraxane With Cationic Spermidine Conjugate and Homologous Cell Membrane for Enhanced Triple‐Negative Breast Cancer Therapy

Triple-negative breast cancer (TNBC) poses significant therapeutic challenges due to its aggressive nature and resistance to hormone therapies and human epidermal growth factor receptor 2 (HER2)-targeted treatments. Paclitaxel is a first-line chemotherapy for TNBC. Its nanoformulation, Abraxane (Abx), has gained widespread clinical use. However, the efficacy of Abx is often limited by poor colloidal stability and a lack of active targeting capability. In this study, we aimed to address these limitations through a dual-modification strategy by complexing Abx with spermidine-conjugated dextran (spm-DEX) and coating it with homologous tumor membranes. The resulting nanoformulation, Abx/spm@4T1, displayed a core-shell structure, enhanced colloidal stability, and preserved the integrity of the membrane proteins. Additionally, Abx/spm@4T1 leveraged the homotypic targeting ability of membrane proteins and the cationic charge of spm-DEX to enhance cellular uptake and tumor accumulation. In vitro studies demonstrated superior cytotoxicity, induction of apoptosis, and inhibition of migration and invasion in tumor cells. In vivo, Abx/spm@4T1 exhibited enhanced tumor-targeting efficiency, suppressed primary tumor growth and lung metastasis, while maintaining favorable biosafety with minimal systemic toxicity. This study underscores the potential of combining biomimetic membrane coatings with modifications of cationic spermidine conjugates to overcome the limitations of conventional nanotherapeutics, providing a promising strategy for targeted therapy in TNBC.