Exosome-mediated delivery of inflammation-responsive <i>Il-10</i> mRNA for controlled atherosclerosis treatment

Abstract

<b>Rationale:</b> 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 <i>Il-10</i> mRNA preferentially into macrophages for tailored inflammation control. <b>Methods:</b><i>Il-10</i> 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 <i>Il-10</i> mRNA was passively encapsulated into exosomes by forced expression in donor cells. Therapeutic effects on atherosclerosis and the systemic leaky expression effects <i>in vivo</i> of the functionalized exosomes were analyzed in ApoE^-/- (Apolipoprotein E-deficient) mice. <b>Results:</b> The engineered IRES-<i>Il-10</i> 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-<i>Il-10</i> 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 <i>Il-10</i> mRNA was functionally translated into protein, with relatively low leaky in other tissues/organs without obvious inflammation. Consistent with the robust <i>Il-10</i> induction in the plaque, exosome-based delivery of the engineered <i>Il-10</i> could alleviate the atherosclerosis in ApoE^-/- mice. <b>Conclusion:</b> Our study established a potent platform for controlled inflammation control via exosome-based systemic and repeated delivery of engineered <i>Il-10</i> mRNA, which could be a promising strategy for atherosclerosis treatment.