Dual-Targeting Nanoplatform to Regulate Metabolic Disorders: From Obesity to Obesity-Related Metabolic Dysfunction-Associated Steatotic Liver Disease
Qiaqia Xiao, Chuying Wang, H. J. Yang, Xueyu Gao, Zhaoan Chen, Zheming Niu, Yi Hou, Cong Fu, Ziwei Yan, Guangda Zhu, Hening Liu, Yue Yin, Jing Shang, Wei Wang, Lu Tang
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.