Engineered extracellular vesicles for targeted reprogramming of cancer-associated fibroblasts to potentiate therapy of pancreatic cancer  

作　　者：Pengcheng Zhou Xuanlong Du Weilu Jia Kun Feng Yewei Zhang 

机构地区：[1]Department of General Surgery,Affiliated Hospital of Nantong University,Nantong,China [2]School of Medicine,Southeast University,Nanjing,China [3]Nanjing Medical University,Nanjing,China [4]Hepatobiliary and Pancreatic Center,The Second Affiliated Hospital of Nanjing Medical University,Nanjing,China

出　　处：《Signal Transduction and Targeted Therapy》2024年第7期3077-3096,共20页信号转导与靶向治疗（英文）

基　　金：supported by National Major Scientific Research Instrument Development Project:62227803;the Key Program of the National Natural Science Foundation of China:62331016;National Natural Science Foundation of China:62141109;the Leading-edge Technology Programme of Jiangsu Natural Science Foundation:BK20212012;Key Research and Development Plan Project of Jiangsu Province:BE2022812.

摘　　要：Pancreatic cancer is one of the deadly malignancies with a significant mortality rate and there are currently few therapeutic options for it.The tumor microenvironment(TME)in pancreatic cancer,distinguished by fibrosis and the existence of cancer-associated fibroblasts(CAFs),exerts a pivotal influence on both tumor advancement and resistance to therapy.Recent advancements in the field of engineered extracellular vesicles(EVs)offer novel avenues for targeted therapy in pancreatic cancer.This study aimed to develop engineered EVs for the targeted reprogramming of CAFs and modulating the TME in pancreatic cancer.EVs obtained from bone marrow mesenchymal stem cells(BMSCs)were loaded with miR-138-5p and the anti-fibrotic agent pirfenidone(PFD)and subjected to surface modification with integrinα5-targeting peptides(named IEVs-PFD/138)to reprogram CAFs and suppress their pro-tumorigenic effects.Integrinα5-targeting peptide modification enhanced the CAF-targeting ability of EVs.miR-138-5p directly inhibited the formation of the FERMT2-TGFBR1 complex,inhibiting TGF-βsignaling pathway activation.In addition,miR-138-5p inhibited proline-mediated collagen synthesis by directly targeting the FERMT2-PYCR1 complex.The combination of miR-138-5p and PFD in EVs synergistically promoted CAF reprogramming and suppressed the pro-cancer effects of CAFs.Preclinical experiments using the orthotopic stroma-rich and patient-derived xenograft mouse models yielded promising results.In particular,IEVs-PFD/138 effectively reprogrammed CAFs and remodeled TME,which resulted in decreased tumor pressure,enhanced gemcitabine perfusion,tumor hypoxia amelioration,and greater sensitivity of cancer cells to chemotherapy.Thus,the strategy developed in this study can improve chemotherapy outcomes.Utilizing IEVs-PFD/138 as a targeted therapeutic agent to modulate CAFs and the TME represents a promising therapeutic approach for pancreatic cancer.

关 键 词：inhibited TARGETED CHEMOTHERAPY 

分 类 号：R735.9[医药卫生—肿瘤]