Long-circulating ROS-responsive micelles for targeted eradication of cancer stem cells to inhibit tumor metastasis and recurrence.

Ovarian cancer mortality is driven largely by therapy-resistant ovarian cancer stem cells (OCSCs), which mediate tumor metastasis, post-treatment recurrence, and chemoresistance that conventional therapies fail to address. Here, we developed reactive oxygen species (ROS)-responsive "stealth-to-sticky" micelles (TK-NMs) for co-delivery of paclitaxel (PTX) and curcumol (CC). The TK-NMs were constructed with a thioketal (TK)-linked PEG5000 shell, which shields the follicle-stimulating hormone β (FSHβ) targeting ligand during systemic circulation. Tumor microenvironmental ROS triggers site-specific PEG shedding and FSHβ exposure, enabling FSH receptor (FSHR)-mediated selective uptake by OCSCs and efficient intracellular drug enrichment, bypassing ATP-binding cassette (ABC) transporter-mediated drug efflux. The system establishes a positive feedback loop between ROS-responsive carrier disassembly and drug-amplified ROS accumulation to enhance apoptosis, while the combined PTX and CC synergistically block hyperactivation of the Wnt/β-catenin stemness pathway to reverse chemoresistance and suppress OCSC malignant phenotypes. In ovarian cancer mouse models, TK-NMs showed preferential tumor accumulation, robust anti-tumor efficacy, reduced lung metastasis, and delayed post-surgical recurrence, with no systemic toxicity. This study provides a modular OCSC-targeted nanotherapeutic platform to overcome key limitations of current ovarian cancer treatment.