Polyphotosensitizer‐Based Nanoparticles with Michael Addition Acceptors Inhibiting GST Activity and Cisplatin Deactivation for Enhanced Chemotherapy and Photodynamic Immunotherapy

Glutathione S‐transferase (GST), which is a key enzyme in the conjugation reaction of glutathione (GSH), is overexpressed in cancer cells, leading to cisplatin deactivation and ultimately drug resistance. In addition, many tumors are immune “cold tumors,” limiting the application of immune checkpoint inhibitors. Herein, a reactive oxygen species (ROS)‐responsive polyphotosensitizer‐based nanoparticle (NP2) with Michael addition acceptors inhibiting GST activity and cisplatin deactivation is designed. Under the 808 nm light irradiation, on the one hand, the Michael addition acceptor in NP2 can react with GST and inhibit its activity, thereby decreasing the GSH conjugation and reducing the GSH‐mediated deactivation of cisplatin and improving its chemotherapeutic effect. On the other hand, NP2+L induces more ROS production in prostate tumor cells, which can further induce type II immunogenic cell death (ICD) and stimulate a stronger antitumor immune response. It is found that NP2 under the 808 nm light irradiation (NP2+L) can increase PD‐L1 expression on the surface of prostate cancer cells. Subsequently, NP2+L combined with PD‐L1 treatment is found to simultaneously enhance the efficacies of chemotherapy and photodynamic immunotherapy in prostate tumors, providing a new paradigm for the clinical multimodal treatment of tumors.