Abstract
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.
Original language | English (US) |
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Pages (from-to) | 569-579 |
Number of pages | 11 |
Journal | Bioactive Materials |
Volume | 25 |
DOIs | |
State | Published - Jul 2023 |
Keywords
- CXCR4
- Liver fibrosis
- Modular assembly
- Nanoparticles
- Undesirable crosstalk
- miRNA
ASJC Scopus subject areas
- Biotechnology
- Biomaterials
- Biomedical Engineering