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

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.