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

Liver metastases frequently occur in pancreatic and colorectal cancer. Their development is promoted by tumor-derived exosomes with the integrin αβ 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 αβ exosomes to deliver anti-TGF-β therapy to the liver. This study demonstrates that the overexpression of αβ in 293T cells allows its transfer to the secreted exosomes. αβ overexpression increases exosome delivery to the liver, and αβ 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 ; however, the exosomes isolated from these cells did not knock down 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 αβ exosomes could serve as nanocarriers for liver-targeted anti-TGF-β therapies.