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.