Adaptive ROS Regulating Nanomedicine for Tumor Catalytic and Immunotherapy beyond Oxidative Overload

Reactive oxygen species (ROS) play critical roles in nanomedicine and cancer research, with potential to initiate catalytic and immunotherapies. Traditional ROS-based nanomedicines primarily work through oxidative overload to inhibit tumors or active immune response. However, a growing body of research has turned attention to the dual nature of ROS, proposing antitumor strategies centered on actively regulating their levels. The generation of excessive ROS for tumor killing misaligns with physiological and pathological realities; adverse therapeutic effects may even be induced by mismatched ROS levels. Thus, re-evaluation is warranted for the design principles of ROS-based nanomedicines. This review takes a distinctive approach, discussing ROS-based nanomedicines beyond traditional excessive oxidative overload strategies. The focus includes ROS-regulating nanomedicines featuring adaptive ROS generation and adaptive rectification of mismatched ROS. First, nanomedicine designs for adaptive ROS generation are summarized. This involves matching distinct kinetics and selecting appropriate external field stimulations for specific tumor pathological conditions. Second, risks of negative effects from mismatched ROS and key adaptive regulating strategies are analyzed. Particular attention is paid to emerging ROS-balancing-engineered nanomaterials for spatiotemporal ROS modulation to optimize catalytic and immunotherapies, thereby adapting ROS-modulating profiles to the specific requirements of different therapeutic stages. Finally, the most promising future directions for the development of adaptive ROS-regulating nanomedicines are outlined.