Artesunate-loaded bovine serum albumin nanoplatform with metal–polyphenol network coating for ferroptosis-driven breast cancer therapy

Ferroptosis, an iron-dependent programmed cell death process driven by reactive oxygen species (ROS) accumulation, represents a promising therapeutic strategy for breast cancer. However, the efficacy of ferroptosis therapy in breast cancer is often compromised by insufficient intracellular levels of hydrogen peroxide (H 2 O 2 ) and iron ions. To address these problems, we developed pH-responsive nanoparticles comprising a metal–phenolic network (MPN) shell and a bovine serum albumin (BSA) core for the delivery of artesunate (ART) (designated as BAM NPs). The designed BAM NPs aim to amplify oxidative stress and enhance ferroptosis-based therapy for breast cancer. Upon endocytosis by tumor cells, BAM NPs underwent degradation under acidic conditions to release ART and Fe 3+ . Subsequently, the reduction of Fe 3+ to Fe 2+ by glutathione (GSH) initiated the Fenton reaction, which led to aberrant accumulation of ROS. Meanwhile, the endoperoxide bridge of ART could be cleaved by Fe 2+ to further generate carbon-centered radicals (·C). Furthermore, BAM NPs effectively deplete GSH via Fe 3+ /Fe 2+ conversion to inactivate glutathione peroxidase 4 (GPX4), thereby disrupting redox homeostasis and increasing intracellular LPO levels. Both in vitro and in vivo experiments showed that BAM NPs significantly inhibited tumor cell proliferation by inducing robust ferroptosis in tumor cells, leading to a tumor inhibition rate of 83.11%. In summary, the constructed BAM NPs served as a promising tailored nanoplatform for augmenting ferroptosis therapy in breast cancer.