Design of prodrugs with reactive oxygen species as activators and their application in tumor therapy

Major challenges lie in the precise management (encompassing diagnosis and treatment) of malignant neoplasms. Traditional chemotherapy faces restrictions in clinical use because of its ineffective targeting and significant toxicity, along with side effects. Notably, the ROS levels are observably elevated in cancer cells compared to healthy tissues, which presents a distinct opportunity for the creation of prodrugs that respond to ROS. This article systematically reviewed the research progress on ROS-responsive small molecule prodrugs and nanodelivery systems (including polymer/inorganic nanoparticles and hydrogels) over the past five years and elaborated in detail on the design principles based on seven key activation mechanisms. By combining ROS responsiveness with TME specificity, these systems have achieved precise controlled drug release, significantly reduced toxic and side effects, and demonstrated multiple synergistic effects of chemotherapy, immunotherapy, and photodynamic therapy. Additionally, some systems integrate theranostic and imaging functions, allowing real-time observation of the drug release. Subsequently, the latest progress in the field from molecular design to preclinical research was summarized, and the promise of ROS-responsive systems for clinical applications was emphasized. It directs the creation of prodrugs that are highly specific and supports the advancement of multi-responsive theranostic platforms, thereby paving the way for improved precision in the diagnosis and treatment of tumors.