Macrophage-Derived CuET Vesicles Synergistically Enhance Paclitaxel Efficacy by Inhibiting Tumor Growth and Boosting Immunity in Breast Cancer

Xiaoling Guo,1,* Lina Zhou,2,3,* Anya Buerliesi,1,* Jiahui Ye,1 Yinhua Lv,1,3 Wenqian Wei,1,3 Jinlan Jiao,1 Weihong Ge,2– 4 Yun Zhu,2– 4 Weijie Zhang1,3 1Division of Breast Surgery, Department of General Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, People’s Republic of China; 2Department of Pharmacy, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, 210008, People’s Republic of China; 3Department of Pharmacy, Nanjing Drum Tower Hospital, Drum Tower Clinical Medical College of Nanjing Medical University, Nanjing, 210000, People’s Republic of China; 4Nanjing Medical Center for Clinical Pharmacy, Nanjing, 210008, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yun Zhu, Email [email protected] Weijie Zhang, Email [email protected]: Paclitaxel is a cornerstone of breast cancer treatment, but its efficacy is often limited by low response rates and drug resistance. To address this, we developed MEVs@CuET, a novel therapeutic approach combining cuproptosis-inducing copper(II) complex (CuET) with macrophage-derived extracellular vesicles (MEVs), aiming to enhance paclitaxel’s antitumor effects.Methods: The tumor-targeting capability of MEVs@CuET was evaluated through cellular uptake and in vivo distribution studies. In vitro synergy was assessed using the ZIP model, while transcriptome sequencing analyzed gene expression changes. In vivo antitumor activity and immune modulation were examined in breast cancer models, with tumor growth inhibition, apoptosis, and Th17 lymphocyte levels measured.Results: MEVs@CuET demonstrated efficient tumor targeting and synergistic antiproliferative effects with paclitaxel in vitro (synergy score: 29.37). Transcriptomic analysis revealed significant alterations in immune-related pathways, particularly upregulation of the IL-17 signaling pathway. In vivo, the combination therapy markedly inhibited tumor growth, increased apoptosis, and elevated Th17 cell levels, aligning with the transcriptomic findings.Conclusion: MEVs@CuET significantly enhances paclitaxel’s efficacy by inducing cuproptosis and modulating antitumor immunity, offering a promising strategy to overcome resistance in breast cancer treatment.Keywords: breast cancer, Paclitaxel, macrophage-derived extracellular vesicles, cuproptosis, combination therapy