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

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.