Development of Liver-Targeting αVβ5+ Exosomes as Anti-TGF-β Nanocarriers for the Treatment of the Pre-Metastatic Niche
by
, , , , and
Paloma Acosta Montaño
1,2
,
Eréndira Olvera Félix
1,2,
Veronica Castro Flores
1,2,
Arturo Hernández García
1,2,
Ruben D. Cadena-Nava
3,
Octavio Galindo Hernández
4
,
Patricia Juárez
2 and
Pierrick G. J. Fournier
2,*
1
Posgrado en Ciencias de la Vida, Centro de Investigación Científica y de Educación Superior de Ensenada (CICESE), Ensenada 22860, BC, Mexico
2
Departamento de Innovación Biomédica, Centro de Investigación Científica y de Educación Superior de Ensenada (CICESE), Ensenada 22860, BC, Mexico
3
Centro de Nanociencias y Nanotecnología, Universidad Nacional Autónoma de México (UNAM), Ensenada 22860, BC, Mexico
4
Laboratorio Multidisciplinario de Estudios Metabólicos y Cáncer, Facultad de Medicina Mexicali, Universidad Autónoma de Baja California (UABC), Mexicali 21000, BC, Mexico
*
Author to whom correspondence should be addressed.
Biology 2024, 13(12), 1066; https://doi.org/10.3390/biology13121066
Submission received: 11 November 2024
/
Revised: 8 December 2024
/
Accepted: 16 December 2024
/
Published: 19 December 2024
(This article belongs to the Special Issue The Role of Extracellular Vesicles in Cancer Metastasis)
Simple Summary
Exosomes are small vesicles released by our cells to communicate. Tumor cells also release exosomes that can go to the liver when they have the integrin αVβ5, an adhesion receptor, on their surface. These exosomes reach the liver first, where their content establishes a pre-metastatic niche that increases the chances of the upcoming metastatic cells surviving and forming a liver metastasis, a frequent complication in pancreatic and colorectal cancer. To prevent this pre-metastatic niche in the liver, we were inspired by cancer cells and modified some non-cancerous cells to produce more integrin αVβ5. Consequently, this integrin was transferred to its exosomes, and the exosomes we collected accumulated more efficiently and specifically in the liver of mice. Since the protein TGF-β initiates the pre-metastatic niche, we further modified our cells to produce the mRNA of a TGF-β inhibitor. Cells that internalized the exosomes containing these mRNA produced the TGF-β inhibitor and inhibited TGF-β signaling. These functionalized exosomes could then be a nanocarrier to bring TGF-β inhibitors specifically to the liver to limit their side effects and prevent 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; pre-metastatic niche
