Tumor‐Specific Chemotherapy by Nanomedicine‐Enabled Differential Stress Sensitization

Abstract Most of current nanomedicines are administrated intravenously to favour tumor accumulation through enhanced permeability and retention (EPR) effect, which, however, suffers from several drawbacks such as low drug bioavailability and severe side effect. In this work, we have constructed a doxorubicin(Dox)‐based liposomal nanosystem for tumor‐specific chemotherapy, by enabling differential stress sensitization between cancer and normal cells for restricting the chemodrug toxicity exclusively in tumor regions. 2‐Deoxy‐D‐glucose (2DG) was loaded in the nanoliposome to inhibit glycolysis of cancer cells, which works in synergy with the co‐loaded chemodrug Dox to promote mitochondrial depolarization and subsequent apoptosis. In addition, the starvation effect of 2DG can counteract the toxicity of Dox in normal cells and thus mitigates the harmful side effect of chemotherapy. It is expected that such a differential stress sensitization strategy may greatly benefit future nanomedicine design.