Self‐Assembled Acid‐Responsive Nanosystem for Synergistic Anti‐Angiogenic/Photothermal/Ferroptosis Therapy against Esophageal Cancer

Abstract Esophageal cancer (EC) treatment via anti‐angiogenic therapy faces challenges due to non‐cytotoxicity and non‐specific biodistribution of the anti‐angiogenic agents. Hence, the quest for a synergistic treatment modality and a targeted delivery approach to effectively address EC has become imperative. In this study, an acid‐responsive release nanosystem (Bev‐IR820@Fe III TA) that involves the conjugation of bevacizumab, an anti‐angiogenic monoclonal antibody, with TA and Fe 3+ to form a metal‐phenolic network, followed by loading with the near‐infrared photothermal agent (IR820) to achieve combinational therapy, is designed. The construction of Bev‐IR820@Fe III TA can be realized through a facile self‐assembly process. The Bev‐IR820@Fe III TA exhibits tumor‐targeting capabilities and synergistic therapeutic effects, encompassing anti‐angiogenic therapy, photothermal therapy (PTT), and ferroptosis therapy (FT). Bev‐IR820@Fe III TA exhibits remarkable proficiency in delivering drugs to EC tissue through its pH‐responsive release properties. Consequently, bevacizumab exerts its therapeutic effects by obstructing tumor angiogenesis, thereby impeding tumor growth. Meanwhile, PTT facilitates localized thermal ablation at the tumor site, directly eradicating EC cells. FT synergistically collaborates with PTT, giving rise to the formation of a reactive oxygen species (ROS) storm, subsequently culminating in the demise of EC cells. In summary, this amalgamated treatment modality carries substantial promise for synergistically impeding EC progression and showcases auspicious prospects for future EC treatment.