Paclitaxel-erianin prodrug self-assembled nanoparticles mediate a positive feedback loop of ferroptosis and immunity in breast cancer.

Abstract

Breast cancer chemotherapy is hindered by multiple therapeutic challenges, including tumor immune evasion and ferroptosis resistance. Herein, we design and synthesize carrier-free prodrug self-assembled nanoparticles (PSSE NPs) with an ultrahigh drug-loading capacity. In response to the high intracellular glutathione (GSH) abundance in tumor cells, the disulfide bonds embedded in PSSE NPs are cleaved, enabling the simultaneous release of paclitaxel (PTX) and erianin (ERI). Specifically, PTX exerts potent chemotherapeutic efficacy against breast cancer cells, whereas ERI initiates tumor ferroptosis and facilitates immunogenic cell death (ICD). The subsequently activated CD8⁺ T cells secrete interferon-γ (IFN-γ), which downregulates SLC7A11 expression, suppresses GSH biosynthesis, and further sensitizes tumor cells to ferroptosis. In vitro experimental results confirm that PSSE NPs trigger robust ferroptosis by elevating intracellular reactive oxygen species (ROS) levels and promoting excessive lipid peroxidation (LPO) accumulation. In three distinct breast cancer animal models (subcutaneous xenograft, bilateral tumor, and lung metastasis models), PSSE NPs significantly inhibit tumor proliferation and metastasis while eliciting systemic antitumor immune responses. This study constructs a positive feedback loop of ferroptosis-immunity synergism via a prodrug nanoplatform strategy, realizing the synergistic integration of chemotherapy, ferroptosis induction, and tumor immunotherapy. This work thereby provides a feasible and high-efficiency prodrug nanotherapeutic strategy for improving breast cancer chemotherapy outcomes.