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 (O₂∙^-) generated usually exhibits a low oxidation capacity, restricting the antitumor efficacy of PDT in clinical practice. Herein, a photoactivated self-assembled nanoreactor (1-NBS@CeO₂) is designed through integration of type I PDT and cerium oxide (CeO₂) nanozymes for inducing cascade-amplified oxidative stress in hypoxic tumors. The nanoreactor is constructed though co-assembly of an amphiphilic peptide (1-NBS) and CeO₂, giving well-dispersed spherical nanoparticles with enhanced superoxide dismutase (SOD)-like and peroxidase (POD)-like activities. Following light irradiation, 1-NBS@CeO₂ undergoes type I photoreactions to generated O₂∙^-, which is further catalyzed by the nanoreactors, ultimately forming hypertoxic hydroxyl radical (∙OH) through cascade-amplified reactions. The PDT treatment using 1-NBS@CeO₂ 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@CeO₂ 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.