Cancer cell membrane and iRGD peptide co-modified cantharidin liposomes for targeted therapy and immunotherapy of triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is a subtype of breast cancer that poses a great threat to women's health. Herein, we report that cantharidin (CTD), a main ingredient of Mylabris, can effectively inhibit the proliferation of TNBC cells, making it a potential therapeutic agent for this kind of tumor. However, the poor water solubility, short half-life, and systemic toxicity of CTD greatly limit its clinical application. To address these issues, we developed a cancer cell membrane and iRGD peptide co-modified CTD liposomes (CTD@LipsMR). The results of in vitro and in vivo experiments showed that CTD@LipsMR precisely released CTD in the tumor tissue. This nanomedicine significantly increased intracellular Fe2+ levels, inhibited the solute carrier family 7 member 11/glutathione/glutathione peroxidase 4 (SLC7A11/GSH/GPX4) antioxidant axis, and remarkably promoted the production of reactive oxygen species (ROS) in tumor cells, thereby inducing ferroptosis. Additionally, CTD@LipsMR could decrease the mitochondrial membrane potential of TNBC cells, down-regulate the expression level of Bcl-2 protein, and promote cell apoptosis. Through inducing ferroptosis, CTD@LipsMR also triggered immunogenic cell death (ICD) characterized by the release of damage-associated molecular patterns (DAMPs). DAMPs activated anti-tumor immunity by promoting the maturation of dendritic cells (DCs) and the proliferation of cytotoxic T lymphocytes (CD8+ T cells). Overall, CTD@LipsMR exhibited excellent biocompatibility and safety, and could effectively inhibit tumor growth and lung metastasis. This study demonstrated that CTD@LipsMR can be used for targeted therapy and immunotherapy of TNBC, and revealed new mechanisms of CTD in TNBC treatment, including the ferroptosis and ICD of cells, providing a promising strategy for the treatment of TNBC.