Tumor microenvironment and Fe3+-triggered croconium nanoplatform for precise tumor location and combined type I photodynamic and photothermal amplified therapy

The combination of type I photodynamic therapy (PDT) and photothermal therapy (PTT) has attracted increased interest in the clinical treatment of tumors because of the suitability of oxygen-independent therapy for hypoxic tumors and the maintenance of high PTT efficacy by reactive oxygen species (ROS). Particularly, near-infrared (NIR) organic molecules have become a research hotspot because of their good reproducibility and low toxicity. However, the majority of them are still far from meeting the clinical requirements for phototherapeutic efficacy and biosafety. Herein, a croconium derivative, CR-497 , was synthesized with benzo[ e ]indole and (thiophen-2-yl)piperazine and complexed with Fe 3+ ( CR-497 -Fe 3+ ) and a tumor-targeting peptide to construct the CR-497 -Fe 3+ nanoparticle (NP) platform. At the breast tumor site, the released CR-497 exhibited pH activation for NIR fluorescence (NIRF) and photoacoustic (PA) imaging, type I PDT, and PTT. In the tumor microenvironment, where glutathione (GSH) and H 2 O 2 were overexpressed, the accumulated Fe 3+ induced ferroptosis and •OH generation. ROS from chemodynamic therapy (CDT) and PDT and lipid peroxidation from ferroptosis inhibited the expression of heat shock proteins (HSPs) and maintained the high efficacy of PTT. In a mouse model, CR-497 -Fe 3+ NPs accurately located the tumor by NIRF and PA bioimaging and exhibited the combined therapeutic effects of ferroptosis, CDT, PDT and PTT with good biosafety. This study presents an effective strategy for the design of tumor-targeted single-component croconium nanoplatforms that exhibit excellent biosafety and enhanced efficacy for type I PDT and PTT.