A Photoactivated Self‐Assembled Nanoreactor for Inducing Cascade‐Amplified Oxidative Stress toward Type I Photodynamic Therapy in Hypoxic Tumors

Abstract Type I photodynamic therapy (PDT) generates reactive oxygen species (ROS) through oxygen‐independent photoreactions, making it a promising method for treating hypoxic tumors. However, the superoxide anion (O 2 ∙ – ) generated usually exhibits a low oxidation capacity, restricting the antitumor efficacy of PDT in clinical practice. Herein, a photoactivated self‐assembled nanoreactor ( 1 ‐NBS@CeO 2 ) is designed through integration of type I PDT and cerium oxide (CeO 2 ) nanozymes for inducing cascade‐amplified oxidative stress in hypoxic tumors. The nanoreactor is constructed though co‐assembly of an amphiphilic peptide ( 1 ‐NBS) and CeO 2 , giving well‐dispersed spherical nanoparticles with enhanced superoxide dismutase (SOD)‐like and peroxidase (POD)‐like activities. Following light irradiation, 1 ‐NBS@CeO 2 undergoes type I photoreactions to generated O 2 ∙ – , which is further catalyzed by the nanoreactors, ultimately forming hypertoxic hydroxyl radical (∙OH) through cascade‐amplified reactions. The PDT treatment using 1 ‐NBS@CeO 2 results in elevation of intracellular ROS and depletion of GSH content in A375 cells, thereby inducing mitochondrial dysfunction and triggering apoptosis and ferroptosis of tumor cells. Importantly, intravenous administration of 1 ‐NBS@CeO 2 alongside light irradiation showcases enhances antitumor efficacy and satisfactory biocompatibility in vivo. Together, the self‐assembled nanoreactor facilitates cascade‐amplified photoreactions for achieving efficacious type I PDT, which holds great promise in developing therapeutic modules towards hypoxic tumors.