摘要
Crosstalk between Kupffer cells(KCs)and hepatic stellate cells(HSCs)plays an important role in multiple liver disease conditions,including the formation of liver fibrosis in alcohol-associated liver disease(AALD).Therapeutic targeting of the KC-HSC crosstalk is a prime target for therapeutic interventions.Herein,a novel modular nanosystem was designed and prepared through the self-assembly utilizing boric acid and catechol interactions to prepare polymers modified with a CXCR4-inhibiting moieties.The polymers were used to encapsulate anti-miR-155 and to block the undesirable crosstalk between HSCs and KCs by downregulating miR-155 expression in KCs with the parallel inhibition of CXCR4 signaling in activated HSCs.The combined inhibition of miR-155 and CXCR4 at two different liver cell types achieved improved antifibrosis effects in a mouse model of AALD fibrosis.Our finding highlights the key role that blocking the undesirable crosstalk between HSCs and KCs plays in reversing AALD fibrosis as well as demonstrates a proof-of-concept approach for designing and constructing multifunctional delivery nanosystems using orthogonal functional modules based on the understanding of disease mechanisms.
基金
This work was supported by a grant from the National Institute on Alcohol Abuse and Alcoholism(R01 AA027695)
The Small Animal Ultrasound Core at UNMC is supported in part by funding from the Nebraska Center for Nanomedicine COBRE grant from the National Institute for General Medical Science(NIGMS)P30 GM127200.The UNMC Advanced Microscopy Core Facility receives partial support from the NIGMS INBRE-P20 GM103427 and COBRE-P30 GM106397 grants,as well as support from the National Cancer Institute(NCI)for The Fred&Pamela Buffett Cancer Center Support Grant-P30 CA036727
the Nebraska Research Initiative.
