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

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. • INT-777 conjugated nanoparticles (NPs, 219 nm) targets liver macrophages. • The NPs showed higher drug release in acidic pH of inflammatory environments. • The DEX-encapsulated NPs with INT reduced the inflammatory cytokines in vitro. • The NPs reduced AST, ALT and cytokines (IL-6, IL-1β, and TNFα) in ALD mouse models. • Anti-Inflammatory effects of NPs were confirmed via H&E and Oil red O staining.