Bone-targeting exosome nanoparticles activate Keap1 / Nrf2 / GPX4 signaling pathway to induce ferroptosis in osteosarcoma cells
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Published:2023-09-30
Issue:1
Volume:21
Page:
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ISSN:1477-3155
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Container-title:Journal of Nanobiotechnology
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language:en
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Short-container-title:J Nanobiotechnol
Author:
Chen Wenkai,Li Zongguang,Yu Naichun,Zhang Linlin,Li Hongyu,Chen Yongjie,Gong Fengqing,Lin Wenping,He Xu,Wang Siyuan,Wu Yue,Ji Guangrong
Abstract
Abstract
Background
In recent years, the development of BMSCs-derived exosomes (EXO) for the treatment of osteosarcoma (OS) is a safe and promising modality for OS treatment, which can effectively deliver drugs to tumor cells in vivo. However, the differences in the drugs carried, and the binding of EXOs to other organs limit their therapeutic efficacy. Therefore, improving the OS-targeting ability of BMSCs EXOs and developing new drugs is crucial for the clinical application of targeted therapy for OS.
Results
In this study, we constructed a potential therapeutic nano platform by modifying BMSCs EXOs using the bone-targeting peptide SDSSD and encapsulated capreomycin (CAP) within a shell. These constructed nanoparticles (NPs) showed the ability of homologous targeting and bone-targeting exosomes (BT-EXO) significantly promotes cellular endocytosis in vitro and tumor accumulation in vivo. Furthermore, our results revealed that the constructed NPs induced ferroptosis in OS cells by prompting excessive accumulation of reactive oxygen species (ROS), Fe2+ aggregation, and lipid peroxidation and further identified the potential anticancer molecular mechanism of ferroptosis as transduced by the Keap1/Nrf2/GPX4 signaling pathway. Also, these constructed NP-directed ferroptosis showed significant inhibition of tumor growth in vivo with no significant side effects.
Conclusion
These results suggest that these constructed NPs have superior anticancer activity in mouse models of OS in vitro and in vivo, providing a new and promising strategy for combining ferroptosis-based chemotherapy with targeted therapy for OS.
Funder
Program of the National Natural Science Foundation of China
Guangdong Basic and Applied Basic Research Foundation
Science and Technology Planning Project of Shenzhen Municipality
Scientific Research Foundation for Advanced Talents, Xiang’an hospital of Xiamen university
Natural Science Foundation of Fujian Province of China
Fujian provincial health technology project
Publisher
Springer Science and Business Media LLC
Subject
Pharmaceutical Science,Applied Microbiology and Biotechnology,Biomedical Engineering,Molecular Medicine,Medicine (miscellaneous),Bioengineering
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