Wei Xu,1,2 Keren Wang,2 Ke Wang,3 Ye Zhao,4 Zhaoying Yang,2 Xiuying Li1 

1Scientific Research Center, China-Japan Union Hospital of Jilin University, Changchun, Jilin, People’s Republic of China; 2Department of Breast Surgery, China-Japan Union Hospital of Jilin University, Changchun, Jilin, People’s Republic of China; 3Gynecology and Obstetrics Department, China-Japan Union Hospital of Jilin University, Changchun, Jilin, People’s Republic of China; 4Dermatological Department, China-Japan Union Hospital of Jilin University, Changchun, Jilin, People’s Republic of China

Correspondence: Xiuying Li; Zhaoying Yang, Email lixiuying@jlu.edu.cn; zyyang@jlu.edu.cn

Introduction: Exosomes (Exos) are promising drug delivery systems due to their low immunogenicity, minimal toxicity, high biocompatibility, and effective delivery capabilities. However, addressing the cardiotoxicity and other toxic side effects associated with anthracyclines has proven challenging.
Methods: In this study, we loaded doxorubicin (Dox) into Exos derived from human placental mesenchymal stem cells (MSCs) and modified them with carboxylated Fe3O4 nanoparticles (NPs) to create an Exo-Dox-NP delivery system. Using an external magnetic force (MF), we regulated the distribution of Exos for targeted Dox delivery in breast cancer treatment. We characterized and determined the drug-loading efficiency of Exo-Dox-NPs, their uptake by tumor cells, and the modulation of drug release. The therapeutic efficacy of Exo-Dox-NPs was evaluated through both in vitro and in vivo anti-tumor experiments.
Results: Our results indicated that Exo-Dox-NPs remain stable in the bloodstream while releasing the drug in the acidic environment of tumor cells and their lysosomes. As a drug delivery system, Exo-Dox-NPs enhanced Dox absorption by tumor cells, demonstrating high targeting specificity. Moreover, Exo-Dox-NPs inhibited the migration of breast cancer cells, as confirmed by scratch migration and Transwell Matrigel invasion assays. In vivo experiments confirmed the effective targeting and delivery of Dox to malignant tumors using Exo-Dox-NPs/MFs, with the Exo-Dox-NP/MF formulation exhibiting the most potent anti-tumor activity.
Conclusion: The utilization of Exos as carriers for Dox showed promising efficacy in breast cancer management. Carboxylated Fe3O4 NPs demonstrated to be suitable targeting agents, potentially advancing the development of natural nanocarriers for combination cancer therapy.

Keywords: breast cancer, doxorubicin, exosomes, carboxylated Fe3O4 nanoparticles, magnetic targeting