Abstract
Paclitaxel (PTX) resistance in triple-negative breast cancer (TNBC) is closely associated with ATP-binding cassette (ABC) transporters-medicated drug efflux and hypoxia-driven upregulation of hypoxia-inducible factor-1α (HIF-1α), which together promote tumor progression and metastasis. Although blood transfusion or hyperbaric oxygen therapy can partially alleviate systemic hypoxia, neither approach effectively relieves chemoresistance driven by intratumoral hypoxia. To address this challenge, we have developed a biomimetic hybrid delivery system (red blood cell hitchhiking-liposomes encapsulate hemoglobin and paclitaxel, RBC-LEHP) that utilizes red blood cell-hitchhiking technology along with pH-responsive liposomes, to co-deliver hemoglobin (Hb) and PTX to overcome hypoxia-associated chemoresistance. This system achieves dual-stage targeting: passive sequestration in pulmonary metastatic lesions through erythrocyte hitchhiking and active tumor internalization mediated by pH-sensitive DOPE phospholipids. Our study revealed that RBC-LEHP effectively alleviated the hypoxia microenvironment through Hb-mediated oxygenation upon tumor cellular internalization and downregulated HIF-1α and glutathione peroxidase 4 (GPX4), while simultaneously enhancing reactive oxygen species (ROS)-mediated lipid peroxidation to induce ferroptosis. This amplified oxidative stress further triggered mitochondrial dysfunction, suppressed P-glycoprotein (P-gp)-mediated PTX efflux, reversed PTX resistance, and promoted apoptotic cell death. In vivo results confirmed that RBC-LEHP-mediated therapeutic cascade of “lung targeted delivery → hypoxia alleviation → ferroptosis/chemotherapy → tumor suppression” significantly enhanced antitumor efficacy against TNBC. This biomimetic platform provides a promising strategy for overcoming physiological barriers and chemoresistance in metastatic TNBC therapy.