An Anthracenyl‐Functionalized Boron Dipyrromethene Based Glutathione‐Responsive Nanoplatform for Efficient Photodynamic Therapy Enhanced by Perfluorooctanoic Acid

ABSTRACT Photodynamic therapy (PDT) relies on light‐activated photosensitizers to generate cytotoxic reactive oxygen species (ROS) for cancer treatment. However, its efficacy is severely limited by tumor microenvironment (TME) features such as hypoxia and elevated antioxidant levels (e.g., glutathione, GSH). To address these challenges, a GSH‐responsive nanoplatform (enBDP‐F NPs) was developed by integrating a heavy‐atom‐free photosensitizer (enBDP) with perfluorooctanoic acid (PFOA). The donor–acceptor‐structured enBDP, featuring an anthracene‐modified BODIPY core, enables efficient ROS generation via a spin–orbit charge transfer intersystem crossing (SOCT‐ISC) mechanism. In the TME, enBDP‐F NPs undergo GSH‐triggered disassembly, releasing PFOA to alleviate hypoxia while simultaneously depleting intracellular GSH through disulfide bond cleavage, thereby disrupting redox homeostasis and suppressing ROS scavenging. This dual‐responsive mechanism synergistically enhances oxidative stress and promotes tumor cell death. Both in vitro and in vivo studies demonstrate that enBDP‐F NPs exhibit minimal dark toxicity but potent phototoxicity, significantly suppress tumor growth, reduce 4T1 cell viability to below 20% under irradiation, and display an oxygen‐carrying capacity approximately threefold higher than PBS. This work provides a promising strategy for synergistic TME modulation to enhance PDT efficacy in cancer therapy.