ABSTRACT Chronic and unresolved liver inflammation due to persistent liver injury from alcohol abuse can lead to fibrosis, cirrhosis and eventually hepatocellular carcinoma (HCC) – which is the fasted growing cause of cancer-related mortality in the world. Nearly 4.5 million adults in the United States are living with chronic liver disease. Effective and safe treatment strategies against hepatic inflammation remains an unmet clinical need due to the poor pharmacokinetics, toxicity and lack of specificity of current therapies. Nanoparticle (NP)-mediated targeted drug delivery can achieve high hepatic concentrations and low systemic concentrations of the drug. We have demonstrated that NPs can be targeted towards G-protein coupled bile acid receptor1 (Gpbar1) expressed by Kupffer cells, to regulate the hepatic inflammatory response. Coating the NPs with pH-responsive polymers offers further control over the drug release kinetics by facilitating release of the encapsulated drugs into the acidic inflammatory microenvironment. Therefore, the overarching goal of this R21 project is to develop a Kupffer cell-targeting dual-functional NP formulation that can be used for targeted stimulation of Gpbar1 and simultaneous pH-responsive release of anti-inflammatory therapeutics. We hypothesize that the combined action of Gpbar1 stimulation and anti-inflammatory therapy will have an additive effect in mitigating chronic liver inflammation associated with alcoholic liver disease. Our proposed aims are: Aim 1: To evaluate the in vivo targeting capabilities and biodistribution of the Gpbar1-targeted NPs. We will study and optimize the targeting capabilities and biodistribution of our biodegradable polymeric NPs surface decorated with INT-777- a potent Gpbar1 agonist, using a widely used chronic-plus-binge animal model of alcoholic liver disease. Aim 2: To investigate the therapeutic efficacy of the designed NPs in vitro and in vivo. Based on the optimized properties in Aim 1, the NPs will be further modified to incorporate the anti-inflammatory drug dexamethasone, and tested against alcohol-treated liver-chip models and the chronic-plus-binge animal models to determine their pharmacokinetic and pharmacodynamic (PK/PD) properties. We will use histology, biomarker analysis, collagen assays and cytokine ELISA to study whether our dual-functional NPs can significantly mitigate chronic hepatic inflammation compared to free drugs or NPs without INT-777. Our results will lead to a paradigm shift in the development and testing of new therapeutic strategies for chronic liver inflammation, where there is an urgent need for the development and safe and consistently effective therapies.