ROS-based dynamic therapy synergy with modulating tumor cell-microenvironment mediated by inorganic nanomedicine

Abstract Dynamic therapy (DT) by in situ ROS generation is emerging as an attractive therapeutic modality with potential to treat deep-seated tumors, avoiding side effects to healthy tissues. As one kind of DT, photodynamic therapy (PDT) has been clinically approved for cancer treatment, but restricted to superficial lesions due to the poor tissue penetration depth of excitation lights. Therefore, there is an urgent need to find out some new strategies to produce ROS under external stimulation with high penetrability or even independent of external excitation. Inorganic nanomaterials-based nanomedicine, or inorganic nanomedicine which can be designed with unique physicochemical properties, can respond to external excitations such as near-infrared (NIR) light, ultrasound (US), X-ray, and microwave (MW), or trigger internal chemical/biological reaction in tumor region to produce ROS for DT, showing great advantages for deep-seated tumor treatment with high specificity, safety, and non-invasiveness. However, most of the DT strategies are highly relied on oxygen, while the tumor microenvironment (TME), especially tumor cell-microenvironment is characterized with hypoxia and high concentration of reductive glutathione (GSH), which will impede the generation and accumulation of ROS, thus severely restricting ROS induced oxidative injury. Therefore, it is crucial to improve the efficacy of DT to enhance the anti-tumor effect. In this review, we briefly summarize the latest advances in developing types of DT related to ROS generation, including NIR-induced photo-/pyroelectric dynamic therapy, US-triggered sono-/piezo-dynamic therapy, X-ray-stimulated radio-/radiodynamic therapy, MW-triggered microdynamic therapy, alternating current-triggered electrodynamic therapy, as well as some others manners independent of external excitation such as chemodynamic therapy and self-lightened PDT. More importantly, we summarize various strategies to modulate tumor cell-microenvironment to enhance the efficacy of DT, by reliving hypoxia, augmenting hydrogen peroxide (H2O2), adjusting the pH, and depleting GSH. In addition, we also discuss the significance of nanotoxicity assessments in safely designing inorganic nanomaterials-based nanomdicine, address the challenges and limitations of DT, and further put forward the development direction of DT for future clinical translation. We hope that this timely and comprehensive review would make the value and future prospects of inorganic nanomedicine to be seen, and more in-depth studies are needed to realize the conversion of inorganic nanomedicine mediated DT strategies in clinics.