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

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∙) 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) is designed through integration of type I PDT and cerium oxide (CeO) 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, giving well-dispersed spherical nanoparticles with enhanced superoxide dismutase (SOD)-like and peroxidase (POD)-like activities. Following light irradiation, 1-NBS@CeO undergoes type I photoreactions to generated O∙, which is further catalyzed by the nanoreactors, ultimately forming hypertoxic hydroxyl radical (∙OH) through cascade-amplified reactions. The PDT treatment using 1-NBS@CeO 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 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.