Grapefruit-derived nanovectors deliver miR-18a for treatment of liver metastasis of colon cancer by induction of M1 macrophages

Liver metastasis accounts for many of the cancer deaths in patients. Effective treatment for metastatic liver tumors is not available. Here, we provide evidence for the role of miR-18a in the induction of liver M1 (F4/80(+) interferon gamma (IFN gamma)(+) IL-12(+)) macrophages. We found that miR-18a encapsulated in grapefruit-derived nanovector (GNV) mediated inhibition of liver metastasis that is dependent upon the induction of M1 (F4/80(+) IFN gamma(+) IL-12(+)) macrophages; depletion of macrophages eliminated its anti-metastasis effect. Furthermore, the miR-18a mediated induction of macrophage IFN gamma by targeting IRF2 is required for subsequent induction of IL-12. IL-12 then activates natural killer (NK) and natural killer T (NKT) cells for inhibition of liver metastasis of colon cancer. This conclusion is supported by the fact that knockout of IFN gamma eliminates miR-18a mediated induction of IL-12, miR-18a treatment has an antimetastatic effects in T cell deficient mice but there is no anti-metastatic effect on NK and NKT deficient mice. Co-delivery of miR-18a and siRNA IL-12 to macrophages did not result in activation of co-cultured NK and NKT cells. Taken together our results indicate that miR-18a can act as an inhibitor for liver metastasis through induction of M1 macrophages.