Red Blood Cell-derived Extracellular Vesicles enable Cisplatin and Cetuximab Synergistic Therapy against Triple-Negative Breast Cancer

Triple-negative breast cancer is an aggressive breast cancer subtype characterized by the absence of human epidermal growth factor receptor 2, estrogen and progesterone receptors, limiting targeted therapy options. Cisplatin, a chemotherapeutic agent, induces DNA damage and exhibits some efficacy against triple-negative breast cancer, but its effectiveness is often reduced by chemoresistance and systemic toxicity.

A very promising strategy to augment cisplatin treatment can be based on combining it with the biologic Cetuximab, an epidermal growth factor receptor inhibitor, which boosts cisplatin efficacy by inducing ferroptosis.

To optimize this synergy in a biocompatible and precise manner, we developed a nanoplatform based on red blood cell-derived extracellular vesicles for the synergistic delivery of Cetuximab and cisplatin. This formulation increases cisplatin uptake, as demonstrated in vitro and in patient-derived organoids, effectively reduces chemoresistance by downregulating hypoxia-related genes and upregulating ferroptosis-associated genes, and enhances cisplatin cytotoxicity while mitigating hemotoxicity compared to free cisplatin administration.