Smart Type I Squaraine Nano-Photosensitizer Combined with MnO for Tumor-Targeted and Ferroptosis-Induced Immunogenic Photodynamic Therapy.

Most photosensitizers face enormous challenges in tumor hypoxia, the redox microenvironment, and low immune efficacies for reactive oxygen species (ROS). Herein, dye SQ-580 was constructed by coupling the electron-donating indole and thiophenazine-thiophene with the electron-withdrawing dicyanovinyl squaraine. It exhibited a high generation of OH and O by decreasing Δ and acted as an excellent type I photosensitizer for conquering tumor hypoxia. The nanoplatform involving SQ-580, MnO, and a targeting peptide CREKA was constructed and targeted breast tumor. In the tumor microenvironment, MnO reacted with high-expressed GSH and produced Mn, which catalyzed HO to decompose into OH and induced chemodynamic therapy (CDT). The reduction of GSH inhibited the consumption of SQ-580 and maintained its high photodynamic therapy (PDT) efficacy. GSH depletion and ROS resulted in cell ferroptosis. Under the synergy of ferroptosis and ROS, Mn amplified immunogenic cell death (ICD). In the mouse models, SQ-580@MnO NPs showed NIRF/MR imaging-guided tumor targeting, effectively inhibited the growth of the primary and distant tumors, and amplified PDT and immune efficacies in the synergy of PDT, CDT, ferroptosis, and ICD. This study provides an effective strategy to design excellent type I photosensitizers and amplify the PDT and ICD efficacies utilizing valence metals and the tumor microenvironment.