A boronate-based modular assembly nanosystem to block the undesirable crosstalk between hepatic stellate cells and Kupffer cells
Open accessAbstract
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.
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There is cross-talk between hepatic stellate cells and macrophages, and their bidirectional regulation is conducive to efficient reversal of liver fibrosis.
“As reported in our previous work, there is cross-talk between HSCs and macrophages, and their bidirectional regulation is conducive to the efficient reversal of liver fibrosis (10).”
From Matrix mechanical remodeled carrier-free nanosystem for programmable closed-loop reversal of liver fibrosis via STING alkylation (2025) · cites this paper as [10]
Undesirable cross-talk existed between macrophages and HSCs.
“As demonstrated in our previous work (10), undesirable cross-talk existed between macrophages and HSCs.”
From Matrix mechanical remodeled carrier-free nanosystem for programmable closed-loop reversal of liver fibrosis via STING alkylation (2025) · cites this paper as [10]
Inflammation in liver fibrosis leads to continuous activation of hepatic stellate cells and subsequent collagen deposition, resulting in advanced liver fibrosis that cannot be completely cured.
“the role of inflammation in LF deterioration cannot be ignored, which leads to continuous activation of HSCs and subsequent collagen deposition,[ 9 ] resulting in advanced LF that cannot be completely cured.”
From An Autologous Macrophage‐Based Phenotypic Transformation‐Collagen Degradation System Treating Advanced Liver Fibrosis (2024) · cites this paper as [9]
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- Authors
- Jia, H., Ding, L., Yu, A., Tang, W., Tang, S., Zhang, C., & Oupický, D.
- Affiliations
- University of Nebraska Medical Center (US)
- Corresponding author
- Oupický, David
- Venue
- Bioactive Materials
- Publisher
- Elsevier BV
- Published
- 2023-07
- Volume
- 25
- Pages
- 569-579
- ISSN
- 2097-1192 (ISSN-L)
- 2452-199X
- PMC
- PMC10087950
- OpenAlex
- W4289527250
- Cited by
- 12
- References
- 34
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 2 · 2023: 3
- FWCI
- 0.90
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Bioactive Materials (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institute of General Medical Sciences (P30 GM127200)
- University of Nebraska Medical Center
- Fred and Pamela Buffett Cancer Center (- P30 CA036727)
- NIH
- National Cancer Institute
- National Institute on Alcohol Abuse and Alcoholism (R01 AA027695)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Keywords
- Kupffer cells, hepatic stellate cells, cell crosstalk, alcoholic liver disease, liver fibrosis, antifibrotic therapy, CXCR4 inhibition, miR-155, boric acid, self-assembling polymers, nanocarriers, microRNA delivery
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