Eliciting ferroptosis with a visual magnetic nanogel to sensitize triple negative breast cancer to taxol by blocking extracellular vesicle-mediated iron efflux.

Although ferroptosis demonstrates significant potential in combating drug-resistant cancers, the efficacy of iron-based nanomaterials is often limited by insufficient iron accumulation within tumors, a problem further exacerbated by extracellular vesicle (EV)-mediated iron efflux. To address this challenge, we developed an acid-responsive magnetic nanogel (MNG) via Schiff base crosslinking for the co-delivery of Prominin2 small interfering RNA (siProminin2) and ultrasmall iron oxide nanozymes. In paclitaxel-resistant triple-negative breast cancer (MDA-MB-231/TaxR) cells, siProminin2@MNG promotes ferroptosis through dual mechanisms: direct delivery of iron oxide nanozymes that exhibit peroxidase-like activity to catalyze the Fenton reaction, thereby intensifying reactive oxygen species (ROS) production, and simultaneous suppression of EV-mediated iron export via Prominin2 knockdown. Ferroptosis induction was confirmed by deferoxamine (DFO) rescue assays, along with elevated levels of ROS, lipid peroxidation (LPO), malondialdehyde (MDA), and decreased GPX4 protein expression. Furthermore, nanoparticle tracking analysis (NTA) and downregulated TSG101 expression validated the inhibition of extracellular vesicle secretion following Prominin2 knockdown. The degradation of MNG within acidic lysosomes not only facilitates cargo release but also enhances T1-weighted MRI contrast due to changes in the aggregation state of the nanozymes, enabling non-invasive monitoring of siRNA release. In a tumor-bearing mouse model, siProminin2@MNG effectively sensitized MDA-MB-231/TaxR tumors to paclitaxel, leading to significant tumor growth inhibition. Mechanistic studies confirmed that this synergistic therapeutic outcome was mediated through the ferroptosis pathway. This rationally designed platform provides a powerful theranostic strategy for synergistic ferroptosis therapy.