Fighting against Drug‐Resistant Tumor by the Induction of Excessive Mitophagy with Transferrin Nanomedicine

Abstract The effectiveness of chemotherapy is primarily hindered by drug resistance, and autophagy plays a crucial role in overcoming this resistance. In this project, a human transferrin nanomedicine contains quercetin (a drug to induce excessive autophagy) and doxorubicin is developed (HTf@DOX/Qu NPs). The purpose of this nanomedicine is to enhance mitophagy and combating drug‐resistant cancer. Through in vitro studies, it is demonstrated that HTf@DOX/Qu NPs can effectively downregulate cyclooxygenase‐2 (COX‐2), leading to an excessive promotion of mitophagy and subsequent mitochondrial dysfunction via the PENT‐induced putative kinase 1 (PINK1)/Parkin axis. Additionally, HTf@DOX/Qu NPs can upregulate proapoptotic proteins to induce cellular apoptosis, thereby effectively reversing drug resistance. Furthermore, in vivo results have shown that HTf@DOX/Qu NPs exhibit prolonged circulation in the bloodstream, enhanced drug accumulation in tumors, and superior therapeutic efficacy compared to individual chemotherapy in a drug‐resistant tumor model. This study presents a promising strategy for combating multidrug‐resistant cancers by exacerbating mitophagy through the use of transferrin nanoparticles.