Targeting Reprogrammed Cancer-Associated Fibroblasts with Engineered Mesenchymal Stem Cell Extracellular Vesicles for...

Area of Science:

• Extracellular vesicle engineering for targeted cancer therapy.
• Molecular mechanisms of cancer-associated fibroblast reprogramming.

Background:

• Pancreatic cancer is a lethal malignancy strongly influenced by cancer-associated fibroblasts (CAFs).
• Targeting CAFs presents a promising therapeutic strategy for pancreatic cancer.

Purpose of the Study:

• To construct engineered extracellular vesicles (EVs) targeting integrin α5 (ITGA5) and overexpressing miR-148a-3p.
• To investigate the reprogramming effect of these engineered EVs on pancreatic CAFs.

Main Methods:

• Bone marrow mesenchymal stem cells (BMSCs) were engineered to produce EVs with surface ITGA5-targeting peptide and high miR-148a-3p expression.
• Co-culture systems and dual-luciferase reporter assays were used to study EV effects and miR-148a-3p mechanism.
• Engineered EVs (ITGA5-EVs^-148a) were tested in vitro and in vivo pancreatic cancer models.

Main Results:

• Engineered ITGA5-EVs^-148a effectively suppressed pancreatic CAF proliferation and migration via the TGF-β/SMAD pathway.
• These EVs demonstrated enhanced cellular uptake and targeting ability in vitro and in vivo.
• ITGA5-EVs^-148a inactivated CAFs and reversed tumor-promoting effects in 3D and xenograft models.

Conclusions:

• Genetically engineered ITGA5-EVs^-148a represent a novel strategy for targeted CAF reprogramming.
• This approach holds significant potential as a precision therapeutic for pancreatic cancer.