Dual-targeting by rotating magnetic field-driven superparamagnetic bionic nanorobots for enhanced triple-negative breast cancer therapy

Abstract Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer with limited treatment options and poor prognosis due to the absence of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2). Doxorubicin (DOX)-based chemotherapy remains the standard of care, yet dose-limiting cardiotoxicity and rapid chemoresistance compromise efficacy. To overcome these hurdles, we engineered rotating magnetic field-driven nanorobots (MFDNs) comprising DOX-loaded hollow mesoporous iron oxide nanoparticles cloaked with 4T1 cancer cell membranes. Under a rotating magnetic field (RMF; 5 Hz, 100 mT), MFDNs self-assemble into dynamic chains, evading the aggregation that plagues static magnetic field approaches and enabling deep intratumoral penetration. This dual-targeting mechanism, passive homing via membrane recognition and active navigation via RMF, delivers a three-fold higher intracellular DOX concentration than uncoated carriers. Mechanistically, MFDNs depleted intracellular glutathione by 70%, suppressed glutathione peroxidase-4 (GPX4), and elevated Fe 2+ , reactive oxygen species (ROS), and lipid peroxidation, thereby triggering robust ferroptosis. In 4T1 tumor-bearing mice, intravenous MFDNs plus RMF shrank tumors by 90% compared with 45% for free DOX, without systemic toxicity or weight loss. Histopathology confirmed extensive necrosis, abundant ferroptosis markers, and negligible off-target accumulation. Collectively, the seamless integration of dynamic RMF guidance with biomimetic membrane cloaking positions MFDNs as a clinically translatable nanoplatform that overcomes chemoresistance and markedly improves therapeutic outcomes for TNBC.