Triglyceride-Targeted Molecularly Imprinted Polymers Activate Lipophagy via Cargo Exchange for Nonalcoholic Fatty Liver Disease Treatment

Lipid accumulation is a prominent pathologic feature of nonalcoholic fatty liver disease (NAFLD), which is due to imbalances in triglycerides metabolism. However, none of the available therapeutic strategies have been able to achieve the effective removal of triglycerides from the lesion site. Herein, MIP@QUE, a mimetic transporter with a high affinity for triglycerides, was synthesized using molecular imprinting. The physicochemical features of MIP@QUE are such that it binds to triglycerides and releases the drug in an affinity-driven reaction. In vivo and in vitro experiments showed that the metabolism of triglycerides was promoted by dual activation of the autophagy-lysosomal pathway through the size effect of the molecularly imprinted polymer (MIP) and the pharmacological action of quercetin (QUE). Moreover, MIP@QUE not only reduced triglyceride accumulation to reverse hepatic steatosis but also effectively lowered the level of oxidative stress to reduce hepatocellular damage. Targeting the key causative factors of NAFLD, MIP@QUE offers an effective therapeutic strategy to control the disease process by promoting the lysosomal transport and metabolism of triglycerides in hepatocytes; it also serves as a platform for the treatment of triglyceride-related metabolic syndrome.