Abstract
Obesity is the major risk factor for metabolic diseases such as fatty liver, hyperlipidemia and insulin resistance. Beige fat has been recognized as a therapeutic target considering its great potential to burn energy. Since the evolutionary discovery of RNA interference and its utilization for gene knockdown in mammalian cells, a remarkable progress has been achieved in siRNA-based therapeutics. However, efficient delivery of siRNA into adipose tissues or differentiated adipocytes is challenging due to high lipid contents in these tissues. Here, we discovered a highly efficient fluoropolypeptide with excellent serum and lipid tolerance for this purpose from a library of amphiphlic polypeptides. The lead material F13-16 exhibited high gene knockdown efficacies in undifferentiated preadipocytes and differentiated adipocytes, as well as adipose tissues. It successfully delivered a siRNA targeting Tle3, an established suppressor gene for energy expenditure, in beige fat, and thereby ameliorated diet-induced obesity and metabolic disorders by increasing energy expenditure and thermogenic capacity. The results demonstrated that fluoropolypeptide is a useful tool for the delivery of siRNA-based therapeutics into adipocyte/adipose tissues for gene therapy.