Bioactive molecule-derived covalent organic frameworks as biocompatible scaffolds for targeted AKR1B10 inhibition in alcoholic liver disease.

Alcoholic liver disease (ALD) incidence is rising globally, yet effective targeted therapies remain elusive. In recent years, bioactive molecules have gained prominence in liver disease research. However, no natural inhibitors targeting key drivers of ALD have yet to be reported. Herein, we first identified AKR1B10 as a key pathogenic driver through transcriptomic analysis of 33 ALD patients and 23 healthy controls. Through virtual screening, we discovered four inhibitors targeting this enzyme, including ellagic acid, vitamin B8, hematoxylin, and porphyrin. Inspired by these findings, we developed four bioactive molecule-derived covalent organic frameworks (COFs) by polymerizing these inhibitors with a spinach-derived tetraboryl-modified porphyrin. Following zinc coordination and hyaluronic acid (HA) modification, the resulting HA-grafted, zinc-coordinated COF composites exhibited significant therapeutic efficacy in acute alcohol-intoxicated mice. Notably, the ellagic acid-based COF system loaded with miRNA-223 ameliorated hepatocyte apoptosis, oxidative stress, lipid accumulation, and macrophage polarization in ALD mice. Furthermore, serum untargeted metabolomics confirmed its role in regulating bile acid metabolism and restoring metabolic homeostasis. This work not only presents the first bioactive molecule-derived COFs and expands the diversity of COF-based therapeutics but also offers a highly promising multifunctional nanoplatform for targeted ALD therapy.