Hepatic Stellate Cells Targeted Nucleic Acid Drug Delivery For Liver Fibrosis Therapy Based On Nanoparticle Protein-corona Manipulation

Nanoparticles have emerged as important players in drug delivery. It was reported that once a nanosized particle enters the circulation, proteins in the blood plasma rapidly form a layer of’corona’ on its surface, which endows the drug carrier with new ’biological identity’ in the body. The type and amount of the corona proteins would dictate the transportation routes and final destination of the vehicle. As such, harnessing the power of the corona proteins holds a crucial position.Hepatic fibrosis is a liver disease characterized by the excessive type I collagen deposition, which is mainly produced by activated hepatic stellate cells (HSCs); there is no available treatment currently. A promising therapeutic strategy is the HSCs-targeted silence of the collagen I expression by antisence oligodeoxynucleotide (ASO). Circulating albumin is a powerful natural carrier in the body for physiological material transport, and it has the unique capability of going through the filtration system in the body without being phagocytized. In our present study, we designed a strategy to harness the naturally existing albumin in host circulation as a relay in the HSC-targeting route. We designed a vehicle for ASO delivery by conjugating small molecular weight polyetherimine (PEI) to retinol via an N, N’-carbonyldiimidazole (CDI)-activation method..As RBP is the sole transporter for retinol in the circulation, HSCs can efficiently take RBP-bound retinol from the blood. This delivery vehicle was designed based on the hypothesis that our delivery vehicle could associate with albumin in blood circulation and then harness the natural transporting capacity of albumin to protect the vehicle from being quickly eliminated by the filtration system; following the specific interaction of retinol/retinol-binding protein (RBP) with the receptors on HSCs, this delivery vehicle could further achieve active targeting at the cellular level. And in carbon tetrachloride (CCl4)-induced murine liver fibrosis model, the Retinol-c-PEI/ASO complex was preferentially accumulated in HSCs during liver fibrosis. Moreover, the type I collagen expression was much more sufficiently suppressed in comparison with the naked ASO.