Chitosan Nanoparticles for Natural Antioxidant Delivery in Metabolic Dysfunction-Associated Steatohepatitis Liver Disease (MASLD)

Abstract: Metabolic Dysfunction-Associated Steatohepatitis Liver Disease (MASLD) is a global clinical challenge, with oxidative stress and inflammation as drivers of disease progression. Numerous natural antioxidants exhibit hepatoprotective activity, but their application is often limited by poor solubility, gastrointestinal instability, presystemic metabolism, and limited oral bioavailability. These conditions demand the development of advanced drug delivery systems (DDS). Chitosan polymer, due to its unique combination of physicochemical and biological properties, including cationicity, biocompatibility, and biodegradability, emerges as a highly promising polymeric platform for nanocarrier engineering. This narrative-critical review summarises the primarily preclinical evidence regarding chitosan-based nanosystems for MASLD/the legacy term Non-alcoholic fatty liver disease (NAFLD), assessing reported pharmacokinetic (PK) exposures and pharmacodynamic outcomes. In general, chitosan-based formulations are often associated with improved pharmacodynamic (PD) outcomes, particularly reductions in Alanine Aminotransferase (ALT)/Aspartate Aminotransferase (AST) and indicators of oxidative stress, while quantitative PK evidence and measurable biodistribution are available in a subset of studies and indicate variability influenced by chitosan attributes (molecular weight, degree of deacetylation, charge density), formulation design, and disease model. Thus, claims of liver “targeting” should be framed as hepatic enrichment unless supported by consistent quantitative tissue data and PK–PD associations, and accompanied by repeated dose safety evaluation. Keywords: metabolic dysfunction-associated steatohepatitis liver disease, chitosan nanoparticles, oral drug delivery, oxidative stress, asialoglycoprotein receptor