Recent advances on endogenous/exogenous stimuli-triggered nanoplatforms for enhanced chemodynamic therapy

In view of certain unique internalization features of the tumor microenvironment (TME) (mainly including hypoxia, acidity and higher concentrations of H2O2 and GSH), advanced nanotechnology has been introduced to increase intracellular reactive oxygen species (ROS), mainly involving the Fenton and Fenton-like reactions of transition metals, metal-catalyzed reactions and peroxidase-catalyzed reactions for chemodynamic therapy (CDT) of tumors. However, there are many inevitable problems, such as the harsh conditions and low reaction efficiency for the Fenton reaction of iron-based materials, limited endogenous H2O2, neutralization of ROS produced by the antioxidant system, and unsatisfactory results of a single CDT mode of treatment, which seriously limit the application of CDT in the field of anticancer, while this has facilitated the generation and development of enhanced CDT nanoplatforms with better therapeutic effects in turn. The objective of this review article is to present representative and latest research progress of improving CDT antitumor effects, involving the amplification strategy of oxidative stress triggered by endogenous/exogenous stimuli. Endogenous stimuli mainly come from inside the TME or cancer cells (such as acidic pH, glucose, glutathione (GSH), some specific enzymes, etc.), and exogenous stimuli include light, heat, and US, etc. Here enhanced CDT nanomaterials are classified into three major categories based on the sources of these stimulations, namely endogenous stimulus-responsive nanomaterials, exogenous stimulus-responsive nanomaterials, and endogenous/exogenous co-stimuli-responsive nanomaterials. Representative examples in each type are dissected and discussed in terms of rational design and preparation of materials, mechanism of action and potential medical applications. Finally, the difficulties and bottlenecks encountered in the current development of CDT are summarized, and preliminary directions for the future development of the field are pointed out in an effort to maximize the potential power of scheduling and coordination of biology and chemistry.