Anti-cancer effect of hUC-MSC-derived exosome-mediated delivery of PMO-miR-146b-5p in colorectal cancer

Background: Antisense oligonucleotide (ASO) is a novel therapeutic platform for targeted cancer therapy. Colorectal cancer (CRC) is the third leading cause of cancer mortality and the prognosis of CRC is poor when hepatic metastasis occurs. We have demonstrated that miR-146b-5p plays an important role in CRC progression. Knocking down miR-146b-5p by an ASO is expected to slow down the progression. However, a safe and effective strategy for delivery of an ASO to its targeted RNA remains as a major hurdle in translational advances. Results: Human umbilical cord mesenchymal cell (hUC-MSC)-derived exosomes were used as vehicles to deliver an anti-miR-146b-5p ASO (PMO-146b) to CRC cells. PMO-146b was assembled onto the surface of exosomes(e) through a covalently conjugated anchor peptide CP05(P) that recognized an exosomal surface marker, CD63, forming a complex named ePPMO-146b. The conjugate (ePPMO-146b) was taken up by SW620 cells and effectively inhibited cellular proliferation and epithelial-to-mesenchymal transition. It also exerted antitumor efficacy in a xenograft mouse model of colon cancer by systematic administration, where PPMO-146b was enriched in tumor tissue. Of particular importance was selective distribution of ePPMO-146b in liver compared to native exosomes through in vivo imaging, indicating its therapeutic potential to inhibit hepatic metastasis of CRC. Conclusion: Our study highlights the potential of hUC-MSC-derived exosomes anchored with PPMO-146b as a novel safe and effective approach for ASO delivery.