Biomimetic hybrid membrane-coated nanoparticles loaded with rhein-iron complex enhance ferroptosis and immunotherapy for triple-negative breast cancer

Triple-negative breast cancer (TNBC), recognized as the most aggressive subtype of breast cancer, presents significant challenges in clinical management owing to the absence of effective therapeutic targets and the limitations of single-modal treatment strategies. It has been verified that rhein possesses diverse pharmacological activities, including anti-tumor and antibacterial properties, and can exert anti-cancer effects by inducing cellular ferroptosis. Meanwhile, ferroptosis of tumor cells can enhance the anti-tumor immune effect. However, the insufficient water solubility and high cytotoxicity of rhein limit its application in clinical practice. To address this challenge, we designed a rhein-iron (RH-Fe) complex and encapsulated it in a hybrid membrane (HM) derived from platelets membrane and M2 macrophages membrane to construct Rhein-Fe@HM (RF@HM) nanoparticles. The nanoparticles have appropriate particle size and good biocompatibility, which can accurately target tumor tissues. In vivo and in vitro experimental findings demonstrated that RF@HM could induce ferroptosis by regulating TP53 in tumor cells and activate the immune response of body, thereby significantly suppressing the growth of TNBC. Therefore, RF@HM-mediated ferroptosis with immunotherapy are expected to provide great potential in the clinical treatment of TNBC.