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  3. A novel Kupffer cell-targeting nanoparticle system to Mitigate alcohol-associated liver disease

A novel Kupffer cell-targeting nanoparticle system to Mitigate alcohol-associated liver disease

  • Biomaterials. 2026 Feb:325:123623. doi: 10.1016/j.biomaterials.2025.123623.
Janitha M Unagolla 1,  Riley Flanagan 2,  Kalindu Perera 1,  Youbin Kim 1,  Curtis Soloff 3,  Emily Kaye 1,  Angela Slitt 1,  Jyothi U Menon 4
Affiliations

Affiliations

  • 1 Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, RI, 02881, USA.
  • 2 Department of Chemical Engineering, College of Engineering, University of Rhode Island, Kingston, RI, 02881, USA.
  • 3 Department of Chemical Engineering, School of Engineering, Worcester Polytechnic Institute, Worcester, MA, 01609, USA.
  • 4 Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, RI, 02881, USA; Department of Chemical Engineering, College of Engineering, University of Rhode Island, Kingston, RI, 02881, USA; Legorreta Cancer Center at Brown University, The Warren Alpert Medical School, Brown University, Providence, RI, 02912, USA; Department of Biomedical Engineering, College of Engineering, Texas A&M University, College Station, TX, 77843, USA. Electronic address: jmenon@tamu.edu.
PMID: 40795708 DOI: 10.1016/j.biomaterials.2025.123623
Abstract

Alcohol-associated liver disease (ALD) is a major cause of cirrhosis-related deaths worldwide. Due to its asymptomatic progression, early diagnosis and treatment are challenging, often resulting in severe complications. To address challenges associated with conventional treatments, including non-specificity and toxicity, we developed a poly lactic-co-glycolic acid nanoparticle (PLGA NP)-based drug delivery system that specifically targets Kupffer cells (KCs), which are major drivers of chronic liver disease progression. The PLGA NPs were loaded with the anti-inflammatory agent dexamethasone, and coated with carboxymethyl chitosan (CMC), a pH-responsive polymer that facilitates dexamethasone release in the acidic inflammatory environment. A semisynthetic bile acid, INT-777 was conjugated to the CMC-coated PLGA NPs to target G-protein coupled receptors expressed only on KCs in the liver. The NP formulation containing 1 % (w/v) CMC demonstrated significantly higher dexamethasone release at pH 6.0 and were cytocompatible. Cellular uptake studies with differentiated THP1 monocytes (modeling KCs) and HepG2 cells indicated a preferential uptake by THP1 cells, confirming INT-777 specificity. In an ALD mouse model developed through ad libitum ethanol feeding (5 % (v/v) for 10 days), biodistribution studies showed significant NP accumulation in the liver at 24 and 72h following administration. Treatment with CMC-coated PLGA NPs containing dexamethasone and INT-777 led to significantly decreased serum aspartate aminotransferase, alanine aminotransferase, and pro-inflammatory cytokines levels, and reduced liver inflammation as confirmed by Hematoxylin and Eosin, and Oil red O staining. These findings demonstrate that CMC-coated PLGA NPs hold significant potential as a treatment option for ALD-associated inflammation.

Keywords

ALD; Biodistribution; Inflammation; Kupffer cells; Nanoparticles.

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