FeS embedded bioreactor collaborate with artesunate for cascade-catalytic tumor ferroptosis

Ferroptosis, a non-apoptotic programmed cell death modality, has been recognized as an emerging therapeutic target for cancer treatment, particularly with the rapid advancements in bionanotechnology. However, the insufficient intracellular Fe²⁺ ions and low reactive oxygen species (ROS) production severely restrict the efficacy of ferroptosis at tumor sites. Herein, a pH-responsive multifunctional nanoplatform (p-COF@GOx-FeS@HA/ART) was constructed to achieve efficient tumor ferroptosis through self-supplied Fe²⁺ ions and amplified ROS. In this system, the large specific surface area and mesoporous structure enabled the porphyrin-based covalent organic frameworks (p-COFs) to act as scaffolds and drug carriers for enhancing the catalytic activity of glucose oxidase-stabilized ferrous sulfide nanodots (GOx@FeS) and encapsulation of artesunate (ART). By oxidizing glucose (Glu) in tumor cells, GOx not only consumed Glu for starvation therapy but also promoted intracellular acidity and supplied hydrogen peroxide (H₂O₂) in the tumor microenvironment (TME), which facilitated the FeS-mediated chemodynamic therapy (CDT) as well as the release of hydrogen sulfide (H₂S) for accelerating the ROS generation. Moreover, the lowered acidic TME could simultaneously trigger the release of ART and Fe²⁺ ions, thus exacerbating ART-mediated ferroptosis. Due to its photothermal and photodynamic behavior, the nanoplatform under laser irradiation could generate ROS storms in tumor cells for high-performance ferroptosis therapy, which was demonstrated both in cancer cells and tumor-bearing mice. This work provides a promising strategy for the simple construction of a multifunctional nanoplatform with TME-responsive and self-triggered ferroptosis, showing great potential in cascade amplification of ferroptosis therapy.