Modulating intracellular oxidative stress via engineered nanotherapeutics

Elevated oxidative stress is a representative hallmark of tumor cells. The development of redox-responsive nanovectors capable of being selectively activated in cancer cells has emerged as a popular approach to fabricate anticancer agents. However, despite tremendous achievements of redox-responsive nanotherapeutics, many of them suffer from limited therapeutic efficacy due to the unsatisfactory selectivity of pathological tissues over normal ones. On the one hand, although cytosolic glutathione (GSH) is much higher than that in plasma, the cytosolic GSH concentrations of cancer cells and healthy cells is not significantly different. On the other hand, elevated ROS levels are not sufficient to selectively activate the therapeutic agents in cancer cells. To this end, amplification of intracellular ROS levels to enhance the selective responsiveness of redox-responsive nanotherapeutics in cancer cells is of increasing interest. In this Minireview, redox-responsive nanovectors responding to intracellular endogenous redox species is first briefly introduced. Subsequently, the strategies to engineer cancer cells as intelligent nanoreactors aiming at amplification of intracellular oxidative stress by either boosting ROS generation and/or suppressing antioxidation systems are discussed. These ROS-generating platforms can be either directly used for chemodynamic therapy (CDT) or be coupled with conventional redox-responsive nanotherapeutics, representing a novel and promising methodology to improve therapeutic efficacy.