Biocompatible Quaternized Chitosan‐Whey Protein Nanofibrous Porous Microspheres for Multi‐Functional Synergistic Regulation of the Gut‐Liver Axis in the Treatment of Metabolic Dysfunction‐Associated Steatotic Liver Disease

Abstract

ABSTRACT Metabolic dysfunction‐associated steatotic liver disease (MASLD) has emerged as a major global health burden, yet effective pharmacological interventions remain limited. Dysregulation of the gut microbiota‐bile acid axis plays a pivotal role in MASLD pathogenesis; however, developing targeted therapies that address this complex interplay remains challenging. Here, we present a safe oral delivery system (QW) comprising in situ self‐assembled nanofibrous porous microspheres derived from whey protein and quaternized chitosan, which integrates physical adsorption with bio‐regulatory functions. In a murine MASLD model, oral QW administration reduced serum ALT (258.6 to 50.3 U/L) and AST (204.4 to 86.7 U/L) levels, and decreased hepatic triglyceride (0.54 to 0.18 mmol/g) and cholesterol (0.12 to 0.05 mmol/g) content. The NAS score decreased significantly, accompanied by marked histopathological improvements. Multi‐omics analysis revealed that QW reshaped gut microbial composition, doubled the relative abundance of Bacteroidetes, modulated bile acid metabolism, and preserved intestinal barrier integrity through reactivation of the hepatic FXR‐SHP signaling pathway. This biocompatible, multi‐functional oral system offers a promising therapeutic strategy for MASLD and advances the paradigm of gut‐liver axis‐based interventions for metabolic liver diseases.