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Replacement therapy with tumor suppressive microRNA (TS-miRNA) might be the next-generation oligonucleotide therapy; however, a novel drug delivery system (DDS) is required. Recently, we developed the cell-penetrating peptide, model amphipathic peptide with α-aminoisobutyric acid (MAP­(Aib)), as a carrier for oligonucleotide delivery to cells. In this study, we examined whether a modified MAP­(Aib) analogue, MAP­(Aib)-cRGD, could be a DDS for TS-miRNA replacement therapy. MIR145-5p, a representative TS-miRNA especially in colorectal cancer, was selected. The MAP­(Aib)-cRGD dose was adjusted for MIR145-5p delivery to cells using peripheral blood mononuclear cells and degradation analysis. AlexaFluor488-labeled MIR145-5p incorporation into cells and negative regulation of MIR145-5p-targeting genes demonstrated MAP­(Aib)-cRGD’s functionality as a miRNA DDS. Treating MIR145-5p with MAP­(Aib)-cRGD also revealed various anticancer effects, such as cell viability, invasion inhibition, and apoptosis induction in WiDr cells. Altogether, these findings suggest that MAP­(Aib)-cRGD could be a DDS for TS-miRNA replacement therapy, but in vivo investigations are required.

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