Biomimetic M1 macrophage Membrane–Modified liposomes Co-delivering ponatinib and ginsenoside Rg3 for inhibition of breast cancer lung metastasis

Background Breast cancer ranks among the most prevalent malignant tumors in women worldwide, with lung metastasis accounting for over 90% of fatalities. Despite this high mortality, effective targeted therapies remain insufficient. Although ponatinib (PNT) shows potential for treating breast cancer lung metastasis (BCLM), its delivery requires optimization. This study aims to construct a biomimetic nanomedicine for targeted delivery of PNT, thereby efficiently treating BCLM. Methods Ginsenoside Rg3 (Rg3) can serve as a substitute for cholesterol as a membrane support material while also acting as an adjuvant in cancer treatment. We replaced cholesterol with Rg3 to prepare PNT-Rg3-Lipo liposomes, extracted the cell membrane of M1 macrophages to coat it on the surface of PNT-Rg3-Lipo, and obtained biomimetic nano MM/PNT-Rg3-Lipo. The characterization of biomimetic nanomedicines was conducted, and the functionality of biomimetic nanomedicines was evaluated at both animal and cellular levels. Results The macrophage membrane-modified MM/PNT-Rg3-Lipo retains most proteins found on M1-type macrophages, including the characteristic proteins integrin α4 and β1. This macrophage membrane-modified MM/PNT-Rg3-Lipo reduces macrophage phagocytosis, while enhancing uptake by metastatic breast cancer cells. In vitro , macrophage membrane-modified MM/PNT-Rg3-Lipo exhibits a stronger cytotoxic effect on breast cancer cells compared to free PNT. In vivo , MM/PNT-Rg3-Lipo shows a lower hemolysis rate, demonstrating its safety. Macrophage membrane modification guides liposomes to lung metastatic sites, leading to localized drug release and consequential inhibition of breast cancer lung metastases. Conclusion The biomimetic macrophage membrane-coated liposomes, MM/PNT-Rg3-Lipo, which we have innovatively prepared, exhibit promising therapeutic effects against breast cancer lung metastases.