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

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.