Functional artemisinin derivative-engineered nanohybrids boost ferroptosis stress-driven cancer therapy

Ferroptosis has emerged as a promising anticancer target, while the clinical translation of ferroptosis inducers is greatly obstructed by the heterogeneous iron levels and inherent antioxidant defense in tumors. Given that most ferroptosis inducers alone fail to elicit cellular lipid peroxidation storm, we here design a ferroptosis booster to synergize with inducers to trigger cellular ROS eruption. Inspired by the pharmacological mechanisms of artesunate (ART), a functional ART-ferrocene (ART-Fc) conjugate is synthesized by esterification reaction. Encouragingly, ART-Fc remarkably sensitizes a variety of ferroptosis inducers through close-by iron supply and productive ROS generation, establishing it as a potential ferroptosis booster. To validate the concept, a binary nanohybrid of sorafenib (Sor) and ART-Fc is fabricated to cooperatively induce tumor ferroptosis. ART-Fc renders iron overload and raises ROS storm through close-by iron supply and intramolecular electron transfer from Fc to ART, which significantly boosts Sor-induced ferroptosis in heterotopic and orthotopic triple-negative breast cancer mouse models. This study presents a broad-spectrum synergist designed to enhance the efficacy of ferroptosis-based cancer therapies and advances an iron overload/ROS eruption/GSH depletion "triple punch" nanotherapeutics towards clinical treatment of triple-negative breast cancer.