NIR-responsive Cu2 − xSe@Fc nanoparticles for photothermal- ferroptosis combination therapy in esophageal cancer

Esophageal cancer (EC) represents a highly recurrent and aggressive malignancy within the digestive system. However, conventional therapeutic strategies exhibit notable limitations in their clinical applications. Photothermal therapy (PTT), combined with ferroptosis, has attracted considerable attentions, emerging as a promising novel strategy for EC treatment. Therefore, there is a critical need to develop a drug delivery system capable of effectively integrating these two therapeutic approaches. In this work, we report a novel drug delivery system based on ferrocene (Fc), which is mixed with lauric acid (a phase-change material with a melting point around 44 ^oC) and then coated on the surface of Cu_{2 - x}Se nanoparticles. The photothermal properties of Cu_{2 - x}Se triggers the melting of lauric acid under near-infrared (NIR) laser irradiation, facilitating controlled release of Fc. Following internalization by tumor cells via endocytosis, the synergistic effect of PTT and ferroptosis, triggered by Cu_{2 - x}Se@Fc, induced immunogenic cell death, which promoted dendritic cell maturation and cytotoxic T lymphocytes recruitment while decreasing the proportion of regulatory T cells, thereby strengthening the antitumor immune surveillance and improving the therapeutic efficacy of Anti-PD-1 blockade. These findings propose that the NIR-responsive Cu_{2 - x}Se@Fc formulation represents a promising and effective strategy with prospecting application for cancer treatment.