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, we have developed a human transferrin nanomedicine known as HTf@DOX/Qu NPs, which contains quercetin (a drug to induces excessive autophagy) and doxorubicin. The purpose of this nanomedicine is to enhance mitophagy and combating drug-resistant cancer. Through in vitro studies, we have 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 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. This article is protected by copyright. All rights reserved.