HSC-targeted delivery of shRNA-TGFβ1 by vitamin A-functionalized polyaminoglycoside for hepatic fibrosis therapy

Abstract

Liver fibrosis is a scar repair response to liver injury and is a key aspect of liver disease. Transforming growth factor (TGFβ1), one of the most potent pro-fibrotic cytokines known, is involved in almost all critical dimensions of liver fibrosis development. Currently, attenuating the pro-fibrotic effect of TGFβ1 is a promising treatment for liver fibrosis. However, the key to applying this approach is to find a more reliable and effective targeting regulation. In this work, a targeting degradable nucleic acid delivery carrier (SS-HPVA) was constructed based on branched polyaminoglycoside (SS-HPT) modified by hepatic stellate cells (HSCs) targeting molecule vitamin A (VA) for the delivery of the TGFβ1 gene silencing plasmid pshRNA-TGFβ1. The reductive responsiveness and VA modification conferred SS-HPVA with high gene transfection ability and specific targeting properties to HSCs. Multispectral photoacoustic tomography and in vivo fluorescence imaging verified that the SS-HPVA/pshRNA-TGFβ1 system showed superior liver targeting ability, especially in the hepatic fibrosis model.On this basis, it was demonstrated that this system could exhibit good therapeutic effects on liver fibrosis by down-regulating TGFβ1 expression through non-invasive assays and histopathological analysis. Therefore, this gene silencing targeting delivery nanosystem is expected to provide a new strategy for the clinical treatment of liver fibrosis.