Integration Strategy of ROS Boosting and Antioxidation Inhibiting Initiates Ferroptosis to Enhance Phototherapic Effect on Tumor

Conventional phototherapy is often limited by hypoxia, introducing oxygen generators is the common method to relieve it, but the antioxidant path of tumor cell was inevitably initiated. Herein, by integrating oxygen generator (MnO 2 ) and inhibitor of Nrf2 (brusatol) into one nanoplatform, we strive to relieve hypoxia and inhibit the antioxidation simultaneously. Hypoxia was relieved for the triggered decomposition of MnO 2 by endogenous H 2 O 2 and it directly strengthened photodynamic therapy (PDT) through boosting reactive oxygen species (ROS) generation. Moreover, high level ROS greatly enhanced the efficacy of photothermal therapy (PTT) by attacking heat shock proteins(HSP). Antioxidant defense was prevented by brusatol through inhibiting the expression of Nrf2. Importantly, MnO 2 and brusatol collaboratively induced ferroptosis through raising oxidation, remarkably promoting tumor curative effect. Both in vitro and in vivo experiments demonstrated the strengthened therapeutic effects of synergistic PDT/PTT, highlighting the great promise of the synergistic modulation strategy with a nanomedicine to overcome the drawbacks of phototherapy.