Three‐Level Nanoparticle Rocket Strategy for Colorectal Cancer Therapeutics in Photothermal Therapy, Inflammation Modulation, and Cuproptosis Induction

Abstract Disturbances in intracellular copper (Cu) homeostasis can trigger cuproptosis, a new form of cell death, which, when combined with photothermal therapy (PTT), offers a promising solution to the persistent challenges in colorectal cancer (CRC) treatment. In this study, a “three‐level nanoparticle rocket” strategy is developed by engineering Cu5.4O, a multifunctional Cu‐based nanoenzyme that is photothermal and has electron transfer properties and antioxidant efficiency. Cu5.4O effectively remodels the inflammatory environment by scavenging reactive oxygen species, thereby overcoming the traditional limitations of PTT. Concurrently, Cu5.4O releases substantial amounts of Cu+ into malignant cells, disrupting Cu homeostasis, inducing cuproptosis, and ultimately inhibiting tumor progression. In vivo and in vitro experiments demonstrate that Cu5.4O operates through multiple successive and interlocking stages to significantly eradicate tumors, prevent relapse, and prolong survival. This study provides profound insights into the synergistic effects of PTT, inflammatory regulation, and cuproptosis within the complex tumor microenvironment, presenting innovative approaches for future CRC therapy.