Hepatocellular carcinoma-derived protein encapsulated iron oxide/black phosphorus nanosheets for targeted photothermal-chemotherapy

Abstract In cancer treatment, single modalities such as chemotherapy or photothermal therapy (PTT) often face significant limitations, leading to suboptimal therapeutic outcomes. In recent years, the combination of chemotherapy and PTT has garnered significant attention as a promising approach for enhancing cancer treatment efficacy. In this study, we designed a nanodrug delivery system based on black phosphorus nanosheets (BPNS) and Fe 3 O 4 composites, incorporating molecular and magnetic targeting strategies. The system loaded the small-molecule anticancer drug RSL3 and was encapsulated with hepatocellular carcinoma cell membrane proteins to form the Pro@Fe 3 O 4 /BPNS-RSL3 composite nanosystem. The goal was to enhance targeted chemo-photothermal combination therapy. The physical and chemical properties, photothermal performance and stability, drug release kinetics, in vitro cellular uptake, cell compatibility, and synergistic therapeutic effects were all evaluated. The results demonstrated that the composite nanosystem exhibited excellent photothermal performance and stability. After 72 h at pH 5.5, the cumulative release of RSL3 reached 69.93%, indicating a faster and higher drug release profile under acidic conditions. In vitro cell uptake experiments showed significantly higher uptake by liver cancer cells (Huh7) compared to normal cells (LO2), suggesting that the system effectively targets liver cancer cells. Additionally, in vitro synergistic therapeutic results revealed that the composite nanosystem reduced the survival rate of liver cancer cells to less than 15%. Western blot analysis further confirmed that the system downregulated the expression of FACL4, Ferritin, and GPX4, thereby promoting the ferroptosis of cancer cells. Overall, the findings highlight that this nanosystem exhibits remarkable cancer cell-killing effects and offers a promising novel strategy for tumor therapy. Its potential for application in cancer treatment is significant, providing a new avenue for more effective and targeted therapies.