Development of Liver-Targeting α_Vβ₅⁺ Exosomes as Anti-TGF-β Nanocarriers for the Treatment of the Pre-Metastatic Niche

Abstract

Liver metastases frequently occur in pancreatic and colorectal cancer. Their development is promoted by tumor-derived exosomes with the integrin αVβ5 on their membrane. This integrin directs exosomes to the liver, where they promote a TGF-β-dependent pre-metastatic niche. We proposed the development of αVβ5+ exosomes to deliver anti-TGF-β therapy to the liver. This study demonstrates that the overexpression of αVβ5 in 293T cells allows its transfer to the secreted exosomes. αVβ5 overexpression increases exosome delivery to the liver, and αVβ5+ exosomes accumulate more in the liver compared to the lungs, kidneys, and brain in mice. We then sought 293T cells to directly produce and load an anti-TGF-β agent in their exosomes. First, we transduced 293T cells to express shRNAs against Tgfb1; however, the exosomes isolated from these cells did not knock down Tgfb1 in treated macrophages in vitro. However, when 293T expressed an mRNA coding a soluble form of betaglycan (sBG), a TGF-β inhibitor, this mRNA was detected in the isolated exosomes and the protein in the conditioned media of macrophages treated in vitro. In turn, this conditioned media decreased the TGF-β-induced phosphorylation of SMAD2/3 in hepatic cells in vitro. Our findings suggest that αVβ5+ exosomes could serve as nanocarriers for liver-targeted anti-TGF-β therapies.

Keywords

• exosome
• drug delivery
• targeted therapy
• integrin
• TGF-β
• cancer