De Novo AI‐Designed Peptide‐Functionalized Nanoparticles Modulate Lipid Metabolism to Ameliorate Metabolic Dysfunction–Associated Steatohepatitis

ABSTRACT Metabolic dysfunction–associated steatohepatitis (MASH) is characterized by the excessive accumulation of triglycerides (TG) in the liver, with long‐chain fatty acids (LCFAs) as key TG precursors. CD36, a pivotal transporter, facilitates the uptake of LCFAs into hepatocytes. Currently, there are no effective pharmacological treatments available for early‐stage MASH. To address this, we developed AILITIX, a de novo AI‐designed lipid transport inhibitor. AILITIX exhibits high binding affinity for CD36 and effectively inhibits CD36‐mediated fatty acid uptake. We then synthesized ultrasound‐responsive, liver‐targeted liposomal nanoparticles (NPs) surface‐functionalized with AILITIX and indocyanine green (ICG), and encapsulating the natural flavonoid isoquercitrin (IQ) and the FXR agonist obeticholic acid (OCA). In vitro assays demonstrated that IQ directly binds to and inhibits ACSL4 activity, thereby suppressing SREBF1‐driven de novo lipogenesis. Furthermore, the NPs inhibited the phosphorylation of mTOR, ULK1, and TFEB, activating the autophagy pathway, enhancing lipid degradation, and alleviating oxidative and mitochondrial stress. In murine models, the NPs treatment led to synergistic amelioration of steatosis, oxidative damage, and inflammation. Moreover, single‐cell transcriptomics demonstrated that the intervention suppresses fibrosis‐associated gene expression and reshapes the hepatic immune microenvironment. Collectively, our de novo AI‐designed peptide‐based nanotherapeutics presents a great potential for the precision treatment of MASH.