Augmented the sensitivity of photothermal-ferroptosis therapy in triple-negative breast cancer through mitochondria-targeted nanoreactor

Abstract

Ferroptosis primarily relies on reactive oxygen (ROS) production and lipid peroxide (LPO) accumulation, which opens up new opportunities for tumor therapy. However, a standalone ferroptosis process is insufficient in inhibiting tumor progression. Unlike previously reported Fe-based nanomaterials, we have engineered a novel nanoreactor named IR780/Ce@EGCG/APT, which uses metal-polyphenols network (Ce@EGCG) based on rare-earth cerium and epigallocatechin gallate (EGCG) to encapsulate IR780 and modified with the aptamer (AS1411). The intricately designed nanoreactor is specifically taken up by tumor cells, releasing Ce3+, EGCG, and IR780. On the one hand, Ce3+ triggers ROS production via a Fenton-like reaction, inducing ferroptosis in tumor cells. On the other hand, IR780 accumulates in mitochondria and disrupts mitochondrial function upon laser irradiation, leading to tumor cell apoptosis. EGCG serves as a sensitizer, simultaneously enhancing the sensitivity of tumor cells to ferroptosis and photothermal therapy. After a single dose and three times of 808 nm laser irradiation for treatment, it has been observed that the nanoreactor induces dendritic cells (DCs) maturation, facilitates cytotoxic T lymphocyte infiltration, improves immunosuppressive microenvironment, activates the systemic immune system, and generates long-term immune memory.