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Theranostics 2021; 11(20):9988-10000. doi:10.7150/thno.64229 This issue Cite

Research Paper

Exosome-mediated delivery of inflammation-responsive Il-10 mRNA for controlled atherosclerosis treatment

Te Bu1#, Zhelong Li1#, Ying Hou1#, Wenqi Sun1, Rongxin Zhang2, Lianbi Zhao1, Mengying Wei2, Guodong Yang2, Lijun Yuan1✉

1. Department of Ultrasound Diagnostics, Tangdu Hospital, Fourth Military Medical University, Xi'an, People's Republic of China.
2. The State Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology, Fourth Military Medical University, Xi'an, People's Republic of China.
#These authors contributed equally to this article.

✉ Corresponding author: Lijun Yuan, Department of Ultrasound Diagnostics, Tangdu Hospital, Fourth Military Medical University, Xinsi Road NO. 569th, 710038, Xi'an, China. E-mail: yuanljedu.cn; Tel: +862984777471; Fax: +862984777471.

Citation:
Bu T, Li Z, Hou Y, Sun W, Zhang R, Zhao L, Wei M, Yang G, Yuan L. Exosome-mediated delivery of inflammation-responsive Il-10 mRNA for controlled atherosclerosis treatment. Theranostics 2021; 11(20):9988-10000. doi:10.7150/thno.64229. https://www.thno.org/v11p9988.htm
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Abstract

Graphic abstract

Rationale: Tailored inflammation control is badly needed for the treatment of kinds of inflammatory diseases, such as atherosclerosis. IL-10 is a potent anti-inflammatory cytokine, while systemic and repeated delivery could cause detrimental side-effects due to immune repression. In this study, we have developed a nano-system to deliver inflammation-responsive Il-10 mRNA preferentially into macrophages for tailored inflammation control.

Methods: Il-10 was engineered to harbor a modified HCV-IRES (hepatitis C virus internal ribosome entry site), in which the two miR-122 recognition sites were replaced by two miR-155 recognition sites. The translational responsiveness of the engineered mRNA to miR-155 was tested by Western blot or ELISA. Moreover, the engineered Il-10 mRNA was passively encapsulated into exosomes by forced expression in donor cells. Therapeutic effects on atherosclerosis and the systemic leaky expression effects in vivo of the functionalized exosomes were analyzed in ApoE-/- (Apolipoprotein E-deficient) mice.

Results: The engineered IRES-Il-10 mRNA could be translationally activated in cells when miR-155 was forced expressed or in M1 polarized macrophages with endogenous miR-155 induced. In addition, the engineered IRES-Il-10 mRNA, when encapsulated into the exosomes, could be efficiently delivered into macrophages and some other cell types in the plaque in ApoE-/- mice. In the recipient cells of the plaque, the encapsulated Il-10 mRNA was functionally translated into protein, with relatively low leaky in other tissues/organs without obvious inflammation. Consistent with the robust Il-10 induction in the plaque, exosome-based delivery of the engineered Il-10 could alleviate the atherosclerosis in ApoE-/- mice.

Conclusion: Our study established a potent platform for controlled inflammation control via exosome-based systemic and repeated delivery of engineered Il-10 mRNA, which could be a promising strategy for atherosclerosis treatment.

Keywords: Atherosclerosis, exosomes, interleukin-10, inflammation-responsive, internal ribosome entry site

Citation styles

APA
Bu, T., Li, Z., Hou, Y., Sun, W., Zhang, R., Zhao, L., Wei, M., Yang, G., Yuan, L. (2021). Exosome-mediated delivery of inflammation-responsive Il-10 mRNA for controlled atherosclerosis treatment. Theranostics, 11(20), 9988-10000. https://doi.org/10.7150/thno.64229.

ACS
Bu, T.; Li, Z.; Hou, Y.; Sun, W.; Zhang, R.; Zhao, L.; Wei, M.; Yang, G.; Yuan, L. Exosome-mediated delivery of inflammation-responsive Il-10 mRNA for controlled atherosclerosis treatment. Theranostics 2021, 11 (20), 9988-10000. DOI: 10.7150/thno.64229.

NLM
Bu T, Li Z, Hou Y, Sun W, Zhang R, Zhao L, Wei M, Yang G, Yuan L. Exosome-mediated delivery of inflammation-responsive Il-10 mRNA for controlled atherosclerosis treatment. Theranostics 2021; 11(20):9988-10000. doi:10.7150/thno.64229. https://www.thno.org/v11p9988.htm

CSE
Bu T, Li Z, Hou Y, Sun W, Zhang R, Zhao L, Wei M, Yang G, Yuan L. 2021. Exosome-mediated delivery of inflammation-responsive Il-10 mRNA for controlled atherosclerosis treatment. Theranostics. 11(20):9988-10000.

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