Cancer therapies based on reactive oxygen species (ROS) show great potential by disrupting the redox equilibrium in tumor cells through multiple pathways. In particular, approaches that combine physical and biochemical activation have gained attention due to their precise spatiotemporal control, minimal toxicity, and high treatment efficiency. In this study, we developed a nanogel complex that functions as a multilevel ROS-amplifying system by incorporating chloroperoxidase (CPO) into gold nanorod-based nanogels (ANGs) for cascade-enhanced photothermal-enzymatic tumor therapy. Upon near-infrared (NIR) laser irradiation, the AuNR nanogels induced local hyperthermia, which amplified exogenous ROS (including H2O2) via cellular stress responses. This effect enhanced the enzyme-mediated reaction of the encapsulated CPO with the abundant endogenous H2O2 in tumor cells, significantly raising intracellular ROS to levels sufficient for improved therapeutic efficacy. Both in vitro and in vivo experiments confirmed the cascade-amplified ROS-driven antitumor activity, highlighting a promising multimodal synergistic strategy for cancer treatment.
