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

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.