NIR‐II Imaging‐Guided Self‐Enhanced Nanomedicine With Reactive Oxygen Species Amplification for Type I Photodynamic Therapy of Prostate Cancer

Abstract Prostate cancer (PCa) is widely perceived as a global health challenge among men, and the overexpression of prostate‐specific membrane antigen (PSMA) is closely associated with increased tumor malignancy and metastatic potential. Photodynamic therapy (PDT), which is highly safe and has a low resistance risk, is promising for PCa treatment. However, its efficacy is often hampered by the hypoxic microenvironment and powerful antioxidant system of tumors. Herein, a near‐infrared (NIR)‐responsive nanomedicine with reactive oxygen species (ROS) amplification is developed for near‐infrared II (NIR‐II) imaging‐guided PSMA‐targeted type I PDT of PCa. To construct a self‐enhancing nanomedicine, a pure type I photosensitizer PS‐6S‐Cl with NIR‐II fluorescence emission and the thioredoxin 1 inhibitor (Trx‐1) are coencapsulated by diselenide‐linked liposomes with surface modification of the PSMA ligand. Under NIR irradiation, the PS‐6S‐Cl in the nanomedicine generated type I ROS to activate Trx‐1 release in an NIR‐responsive manner. Through the inhibition of Trx‐1, the released Trx‐1 can efficiently block intracellular ROS depletion to further enhance the efficacy of PDT. In vitro and in vivo experiments confirmed that the NIR‐responsive nanomedicine realized NIR‐II fluorescence‐guided photodynamic immunotherapy (PIT) of PCa with good biosafety. Thus, this study develops a self‐enhancing PIT strategy for overcoming immunogenic “cold” tumors.