Reversal of pancreatic desmoplasia by re-educating stellate cells with a tumour microenvironment-activated nanosystem

• DOI: 10.1038/s41467-018-05906-x
• Publication Date: 2018-08-17T12:27:05Z
• Authors: Xuexiang Han; Yiye Li; Ying Xu; Xiao Zhao; Yinlong Zhang; Xiao Yang; Yongwei Wang; Ruifang Zhao; Gregory J. Anderson; Yuliang Zhao; Guangjun Nie
• Keywords: Desmoplasia; Hepatic stellate cell

Pancreatic ductal adenocarcinoma is characterised by a dense desmoplastic stroma composed of stromal cells and extracellular matrix (ECM). This barrier severely impairs drug delivery penetration. Activated pancreatic stellate (PSCs) play key role in establishing this unique pathological obstacle, but also offer potential target for anti-tumour therapy. Here, we construct tumour microenvironment-responsive nanosystem, based on PEGylated polyethylenimine-coated gold nanoparticles, utilise it to co-deliver all-trans retinoic acid (ATRA, an inducer PSC quiescence) siRNA targeting heat shock protein 47 (HSP47, collagen-specific molecular chaperone) re-educate PSCs. The nanosystem simultaneously induces quiescence inhibits ECM hyperplasia, thereby promoting tumours significantly enhancing the efficacy chemotherapeutics. Our combination strategy restore homoeostatic function activated PSCs represents promising approach improving chemotherapy other therapeutic modalities wide range stroma-rich tumours.