Liver fibrosis affects millions of people worldwide and is rising vastly over the past decades. With no viable
therapies available,
liver transplantation is the only curative treatment for advanced diseased patients. Excessive accumulation of aberrant extracellular matrix (ECM)
proteins, mostly
collagens, produced by activated hepatic stellate cells (HSCs), is a hallmark of
liver fibrosis. Several studies have suggested an inverse correlation between
collagen-I degrading
matrix metalloproteinase-1 (MMP-1) serum levels and
liver fibrosis progression highlighting reduced MMP-1 levels are associated with poor disease prognosis in patients with
liver fibrosis. We hypothesized that delivery of MMP-1 might potentiate
collagen degradation and attenuate
fibrosis development. In this study, we report a novel approach for the delivery of MMP-1 using MMP-1 decorated polymersomes (MMPsomes), as a surface-active vesicle-based ECM therapeutic, for the treatment of
liver fibrosis. The storage-stable and enzymatically active MMPsomes were fabricated by a post-loading of Psomes with MMP-1. MMPsomes were extensively characterized for the physicochemical properties, MMP-1 surface localization, stability, enzymatic activity, and biological effects. Dose-dependent effects of MMP-1, and effects of MMPsomes versus MMP-1, empty polymersomes (Psomes) and
MMP-1 + Psomes on gene and
protein expression of
collagen-I,
MMP-1/TIMP-1 ratio, migration and cell viability were examined in TGFβ-activated human HSCs. Finally, the
therapeutic effects of MMPsomes, compared to MMP-1, were evaluated in vivo in
carbon-tetrachloride (CCl4)-induced early
liver fibrosis mouse model. MMPsomes exhibited favorable physicochemical properties, MMP-1 surface localization and improved therapeutic efficacy in TGFβ-activated human HSCs in vitro. In CCl4-induced early
liver fibrosis mouse model, MMPsomes inhibited intra-hepatic
collagen-I (ECM marker, indicating early
liver fibrosis) and F4/80 (marker for macrophages, indicating liver
inflammation) expression. In conclusion, our results demonstrate an innovative approach of MMP-1 delivery, using surface-decorated MMPsomes, for alleviating
liver fibrosis.