Two Birds with One Stone: Guanidyl Carbon Dots with Enhanced Antioxidative and Lipolytic Functions in Metabolic Associated Fatty Liver

Abstract Metabolic‐associated fatty liver disease (MAFLD) has become one of the most widespread metabolic diseases nowadays, while no definitive agent is approved for practical treatment. Given excessive lipid deposition and cellular oxidative stress are two main inducers of MAFLD, developing synergistic therapeutic agents that enhance lipid metabolism and antioxidative ability are effective routes for MAFLD therapy. Herein, a novel kind of bio‐functional carbon dots (MTCDs) derived from metformin and tea polyphenols based on a fused pharmacophore strategy is developed. The surface of MTCDs retains abundant phenolic hydroxyl and guanidine groups, which are designed to reduce both lipid deposition and oxidative stress in the liver. Moreover, by finely controlling the surface charge, MTCDs exhibit excellent lysosome targeting functionality with favorable biocompatibility and low biotoxicity. Mechanistical studies further reveal that MTCDs treatment protects lysosomes from oxidative stress damage and activates hepatocyte AMP‐activated protein kinase signaling, which initiates lipophagy progress to accelerate lipolysis and lipid consumption. Collectively, these studies propose an effective “two birds with one stone” tool for MAFLD synergistic therapy and suggest a viable strategy for multi‐pharmacophore agent development.