A Scalable COF-Based Sequestrant for Synergistic Bile Acid Modulation in Fatty Liver Disease.

Metabolic dysfunction-associated fatty liver disease (MAFLD), closely linked to abnormal cholesterol metabolism and bile acid imbalance, has become a rapidly increasing clinical challenge. Herein, we develop a synergistic anion-exchange/pore-adsorption strategy for treating MAFLD using a highly stable, bio/industrial-compatible olefin-linked covalent organic framework (COF) platform as an oral bile acid (BA) adsorbent. This synergistic approach enables the COFs to efficiently and selectively adsorb both deprotonated and protonated BAs while avoiding nutrient adsorption. The adsorbent performance significantly surpasses that of the clinical drug cholestyramine, which targets only deprotonated BAs and often leads to nutrient loss, as validated by in vitro and in vivo experiments. Notably, in a high-fat-diet-induced MAFLD mouse model, a 10-week COF treatment markedly reduced serum levels of total cholesterol and low-density lipoprotein cholesterol as well as liver injury markers, thereby alleviating hepatic steatosis, inflammation, and overall liver damage. This study not only establishes COFs as a promising class of next-generation oral adsorbents but also offers a mechanistic blueprint for targeting metabolic disorders through molecularly engineered materials.