Reactive oxygen species-upregulating nanomedicines towards enhanced cancer therapy

Reactive oxygen species (ROS) play a crucial role in physiological and pathological processes, emerging as a therapeutic target in cancer. Owing to the high concentration of ROS in solid tumor tissues, ROS-based treatments, such as photodynamic therapy and chemodynamic therapy, and ROS-responsive drug delivery systems have been widely explored to powerfully and specifically suppress tumors. However, their anticancer efficacy is still hampered by the heterogeneous ROS levels, and thus comprehensively upregulating the ROS levels in tumor tissues can ensure an enhanced therapeutic effect, which can further sensitize and/or synergize with other therapies to inhibit tumor growth and metastasis. Herein, we review the recently emerging drug delivery strategies and technologies for increasing the H₂O₂, ˙OH, ¹O₂, and ˙O₂^- concentrations in cancer cells, including the efficient delivery of natural enzymes, nanozymes, small molecular biological molecules, and nanoscale Fenton-reagents and semiconductors and neutralization of intracellular antioxidant substances and localized input of mechanical and electromagnetic waves (such as ultrasound, near infrared light, microwaves, and X-rays). The applications of these ROS-upregulating nanosystems in enhancing and synergizing cancer therapies including chemotherapy, chemodynamic therapy, phototherapy, and immunotherapy are surveyed. In addition, we discuss the challenges of ROS-upregulating systems and the prospects for future studies.