Dual-Targeting Nanoplatform to Regulate Metabolic Disorders: From Obesity to Obesity-Related Metabolic Dysfunction-Associated Steatotic Liver Disease.

Abstract

Obesity manifests as excessive fat storage within adipose tissue (AT) and is often accompanied by insulin resistance, which can initiate the development of obesity-related metabolic dysfunction-associated steatotic liver disease (MASLD). Herein, a dual-targeting drug delivery system is designed to regulate these metabolic disorders by alleviating aberrant fat accumulation and anti-inflammation. Specifically, polymetformin (P) and resveratrol (R), two therapeutic agents that show preferable antiadiposity effect, are co-loaded in macrophage-disguised and apolipoprotein A-I (apoA-I)-decorated liposome (aML/R&P). Mechanistically, P and R can upregulate uncoupling protein 1 (UCP1) expression to promote AT browning and enhance hepatocyte autophagy to ameliorate hepatic steatosis and inflammation. Meanwhile, the dual modification of macrophage membrane and apoA-I largely improves its targeting efficiency toward liver and AT. In mouse models of obesity and MASLD, aML/R&P effectively reduces body weight, restores metabolic homeostasis, enhances liver parameters, and improves insulin sensitivity, demonstrating great promise in treating obesity and obesity-associated metabolic disorders.