A celastrol-loaded DNA nano-patroller regulates hypothalamus leptin sensitivity and adipose energy expenditure for anti-obesity therapy

Obesity is a chronic metabolic disease mainly caused by fat accumulation. Well-recognized anti-obesity therapies are lacking. Celastrol is a bioactive small-molecule drug extracted from the roots of Tripterygium Wilfordii, which has excellent anti-obesity efficacy. However, the low bioavailability and permeability of celastrol limit its clinical applications. Meanwhile, tetrahedral framework nucleic acid (tFNA) represents a nucleic acid nanomaterial with suitable biocompatibility and tissue and cell permeability. Therefore, this study aimed to use tFNA as a delivery carrier for celastrol for the first time. tFNA efficiently loaded celastrol with proper stability and in vivo bio-distribution. Celastrol-loaded tFNA simultaneously rescued leptin resistance in the hypothalamus and promoted energy expenditure in adipose tissues, acting as a systemic “nano-patroller” in search of various abnormal conditions. Compared to the celastrol monomer, celastrol-loaded tFNA exerted superior inhibitory effects on fat accumulation, obesity, inflammation, and insulin resistance. In conclusion, tFNA is a promising tool for deeper anti-obesity applications of celastrol.