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Theranostics 2023; 13(14):5114-5129. doi:10.7150/thno.87484 This issue Cite

Research Paper

Targeted elimination of senescent cells by engineered extracellular vesicles attenuates atherosclerosis in ApoE^-/- mice with minimal side effects

Liang Zhang^1#, Chen Wang^1#, Wei Hu^1#, Te Bu¹, Wenqi Sun¹, Tian Zhou¹, Shuo Qiu¹, Mengying Wei², Helin Xing³, Zhelong Li^1✉, Guodong Yang^2✉, Lijun Yuan^1✉

1. Department of Ultrasound Diagnostics, Tangdu Hospital, Fourth Military Medical University, Xi'an, People's Republic of China.
2. State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, People's Republic of China.
3. Department of Prosthodontics, Beijing Stomatological Hospital and School of Stomatology, Capital Medical University, Beijing, 100050, China.
^# These authors contributed equally to this article.

✉ Corresponding authors: Lijun Yuan, Department of Ultrasound Diagnostics, Tangdu Hospital, Fourth Military Medical University, Xinsi Road NO.569th, 710038, Xi'an, China, email: yuanljedu.cn; Tel: +862984777471, Fax: +862984777471; Guodong Yang, The State Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Changlexi Road NO.169th, 710032, Xi'an, email: yanggdedu.cn; Tel: +862984774516, Fax: +862984774516; Zhelong Li, Department of Ultrasound Diagnostics, Tangdu Hospital, Fourth Military Medical University, Xinsi Road NO.569th, 710038, Xi'an, China, email: lzlfmmucom; Tel: +862984777471, Fax: +862984777471. More

Abstract

Senescent cells in plaques emerge as a detrimental factor for atherosclerosis (AS), for which targeted senolysis might be a promising therapeutic strategy. The development of safe and efficient senolytics for senescent cell eradication by targeted delivery is greatly needed.

Methods: Pro-apoptotic intelligent Bax (iBax)-overexpressing plasmid was constructed by molecular cloning, in which Bax CDS was fused to miR-122 recognition sites. Extracellular vesicle-based senolytics (EV^iTx) were developed to be conjugated with magnetic nanoparticles on the surface, iBax mRNA encapsulated inside, and BAX activator BTSA1 incorporated into the membrane. EV^iTx was characterized, and in vivo distribution was tracked via fluorescence imaging. The therapeutic effects of EV^iTx on AS and its systemic side effects were analyzed in ApoE^-/- mice.

Results: Magnetic nanoparticles, iBax mRNA and BAX activator BTSA1 were efficiently loaded into/onto EV^iTx. With external magnetic field navigation, EV^iTx was delivered into atherosclerotic plaques and induced significant apoptosis in senescent cells regardless of origins. Repeated delivery of EV^iTx via tail vein injection has achieved high therapeutic efficacy in ApoE^-/- mice. Notably, EV^iTx is inevitably accumulated in liver cells, while the iBax mRNA was translationally repressed by miR-122, an endogenous miRNA highly expressed in hepatocytes, and thus the liver cells are protected from the potential toxicity of Bax mRNA.

Conclusion: Our work demonstrated that magnetic EV-based delivery of iBax mRNA and the BAX activator BTSA1, efficiently induced apoptosis in recipient senescent cells in atherosclerotic plaques. This strategy represents a promising treatment approach for AS and other age-related diseases.

Keywords: atherosclerosis, extracellular vesicles, cellular senescence, magnetic nanoparticles, BCL-2-associated X protein

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