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

Overview

Journal Biomater Res

Specialty Biomedical Engineering

Date 2024 Aug 5

PMID 39099892

Authors

Pengcheng Zhou

Xianguang Ding

Xuanlong Du

Lianhui Wang

Yewei Zhang

Affiliations

Soon will be listed here.

Abstract

As one of the most aggressive and lethal cancers, pancreatic cancer is highly associated with cancer-associated fibroblasts (CAFs) that influence the development and progression of cancer. Targeted reprogramming of CAFs may be a promising strategy for pancreatic cancer. This study aims to construct engineered extracellular vesicles (EVs) with surface modification of integrin α5 (ITGA5)-targeting peptide and high internal expression of miR-148a-3p by endogenous modification for targeted reprogramming of pancreatic CAFs. Bone marrow mesenchymal stem cells (BMSCs) and pancreatic CAFs were cocultured to examine the effect of BMSC-derived EVs on the expression levels of CAF markers. miR-148a-3p was identified as a functional molecule. The mechanism of miR-148a-3p was elucidated using the dual-luciferase reporter assay. BMSCs were infected with TERT-encoding and miR-148a-3p-encoding lentiviruses. Subsequently, BMSCs were modified with ITGA5-specific targeting peptide. The supernatant was ultracentrifuged to obtain the engineered EVs (ITGA5-EVs), which were used to reprogram CAFs. BMSCs modulated CAF marker expressions through EVs. miR-148a-3p was up-regulated in BMSCs. The expression of miR-148a-3p in pancreatic CAFs was down-regulated when compared with that in normal fibroblasts (NFs). Mechanistically, ITGA5-EVs effectively suppressed the proliferation and migration of pancreatic CAFs by targeting ITGA5 through the TGF-β/SMAD pathway. ITGA5-EVs was associated with enhanced cellular uptake and exhibited enhanced in vitro and in vivo targeting ability. Moreover, ITGA5-EVs exerted strong reconfiguration effects in inactivating CAFs and reversing tumor-promoting effects in 3D heterospheroid and xenograft pancreatic cancer models. This targeted CAF reprogramming strategy with genetically engineered ITGA5-EVs holds great promise as a precision therapeutics in clinical settings.

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