Abstract

Chemotherapy plays an irreplaceable role in the clinical treatment of malignant tumors, yet drug resistance remains a major cause of suboptimal therapeutic outcomes. Ferroptosis, a regulated cell death modality, offers a promising therapeutic strategy, as the chemotherapy-resistant tumor cells exhibit heightened sensitivity to this process. Combining chemotherapeutics with ferroptosis-inducing agents thus represents a viable approach to overcome chemotherapy resistance. The accumulation of polyunsaturated fatty acids (PUFAs) is an important factor contributing to the increase of lipid peroxides and triggering ferroptosis, and arachidonic acid (AA) is a typical type of PUFAs. Based on that, we designed an amphiphilic polymer dextran-AA (Dex-AA), and constructed an AA-functionalized micelle DA through its self-assembly, with the chemotherapeutic drug doxorubicin (DOX) encapsulated within the cores. The obtained micelle DA/DOX induced ferroptosis by promoting lipid peroxidation, which significantly enhanced the cytotoxicity of DOX against DOX-resistant tumor cells. Meanwhile, DA/DOX synergistically maintained high intracellular drug levels via an “open-source throttling” strategy by both promoting uptake via the enhanced membrane fluidity and inhibiting ATP-dependent efflux through ROS-induced mitochondrial damage/ATP depletion. In vitro studies confirmed the excellent efficacy of DA/DOX in both 4T1 and MCF-7/ADR cells. Furthermore, in the breast cancer mouse model, DA/DOX exhibited superior antitumor effects compared to the long-circulating DOX liposomes (Lip/DOX). This study presents a novel strategy based on ferroptosis to overcome chemotherapy resistance of breast cancer, which is of great significance.