Oral Celastrol Micelles Forming High-Density Lipoprotein Corona Targeting Hepatocytes for MASLD Treatment.

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a multifactorial hepatic manifestation of metabolic syndrome, such as aberrant lipid accumulation. Celastrol (CEL), a potent leptin sensitizer, has been studied for the treatment of MASLD; however, its clinical application is hindered by its low oral bioavailabilities and high toxicities. Herein, CEL is encapsulated into the micelles of poly[2-(N-oxide-N,N-diethylamino)ethyl methacrylate]-block-poly(ε-caprolactone) (OPDEA-PCL), whose shell is capable of fast penetrating mucus due to its protein-non-fouling and rapid transcytosis induction as a result of phospholipid-binding characteristic. After oral administration, OPDEA-PCL/CEL micelles sequentially permeated through the gastrointestinal barriers into the blood. Notably, it is found that OPDEA-PCL/CEL specifically captured high-density lipoproteins (HDL) in plasma, forming an HDL corona actively targeting the hepatocytes, delivering a high concentration of CEL. In the MASLD mouse model, oral administration of OPDEA-PCL/CEL effectively alleviated hepatic lipid accumulation, lessened hepatic inflammation, and mitigated the toxicities of CEL with therapeutic efficacy superior to free CEL and PEG-PCL/CEL and even the current clinical simvastatin. Therefore, the OPDEA-PCL may be a promising oral CEL delivery system for treating MASLD.