Tumor Cell Membrane-Camouflaged Nanoparticles Co-delivering Docetaxel and Metformin for Enhanced Synergistic Therapy of HER2-positive Breast Cancer

The clinical efficacy of docetaxel (DTX) in treating HER2-positive breast cancer is hampered by poor solubility and systemic toxicity, while metformin (Met) shows anti-cancer potential by targeting tumor metabolism. We hypothesized that a biomimetic nanoplatform co-delivering DTX and Met could achieve synergistic anti-tumor effects with enhanced safety. This study developed tumor cell membrane-camouflaged mesoporous silica nanoparticles co-loaded with DTX and Met (mem(DTX&Met@MSNs)). The nanoparticles were characterized for particle size, stability, drug loading, and membrane coating. <i>In vitro</i> assays were conducted to assess cellular uptake, cytotoxicity, and synergistic effects. <i>In vivo</i> studies were performed in HER2-positive breast cancer-bearing mice to evaluate biodistribution, anti-tumor efficacy, toxicity, and histopathology. The mem(DTX&Met@MSNs) nanoparticles showed a core-shell structure and pH-responsive release, with over 80% drug release at pH 6.5 versus less than 40% at pH 7.4. Biomimetic coating enabled homologous targeting, enhancing cellular uptake and synergistic cytotoxicity in SK-BR-3 cells (7.89% apoptosis). <i>In vivo</i>, the system prolonged the circulation half-life to nearly 6 hours, effectively suppressed tumor growth, and demonstrated excellent biocompatibility with no significant toxicity or body weight loss. In conclusion, mem(DTX&Met@MSNs) integrates homologous targeting with dual-drug synergism, offering a safe and effective strategy for the treatment of HER2-positive breast cancer.