Enhancing inter-system crossing efficiency of NIR-II emitting type-I photosensitizers for tumor ferroptosis induction

Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation (LPO), represents a compelling avenue for cancer therapy. Photodynamic therapy (PDT), which relies on the production of LPO-reactive oxygen species (ROS), has emerged as a potent therapeutic strategy. However, the clinical efficacy of conventional photosensitizers (PSs) is frequently constrained by tumor hypoxia, which intensifies local oxygen deficiency and diminishes PDT performance. In contrast, Type I PDT facilitates the generation of cytotoxic ROS, such as superoxide (O₂^-•) through electron transfer mechanisms, offering enhanced oxygen independence and improved therapeutic efficacy. In this study, we introduce a near-infrared (NIR)- activated Type I PS, TPP-TPA, designed via a receptor-engineering strategy. TPP-TPA exhibits robust NIR absorption and NIR-II fluorescence emission, enabling efficient Type I ROS production that induces ferroptosis in 4T1 breast cancer cells. This work establishes a promising approach for cancer therapy and imaging, addressing key limitations of traditional PDT while offering significant potential for clinical translation. STATEMENT OF SIGNIFICANCE: This study presents a near-infrared (NIR)-activated Type I photosensitizer (PS), TPP-TPA, designed via a receptor-engineering strategy to overcome the limitations of conventional photodynamic therapy (PDT). By efficiently generating Type I reactive oxygen species (ROS) under NIR activation, TPP-TPA NPs induce ferroptosis in breast cancer cells, offering enhanced oxygen independence and improved therapeutic efficacy. This work advances cancer therapy and imaging by addressing the challenges of tumor hypoxia in PDT, highlighting its potential for clinical translation.