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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\u2010(N\u2010oxide\u2010N,N\u2010diethylamino)ethyl methacrylate]\u2010block\u2010poly(\u03b5\u2010caprolactone) (OPDEA\u2010PCL), whose shell is capable of fast penetrating mucus due to its protein\u2010non\u2010fouling and rapid transcytosis induction as a result of phospholipid\u2010binding characteristic. After oral administration, OPDEA\u2010PCL\/CEL micelles sequentially permeated through the gastrointestinal barriers into the blood. Notably, it is found that OPDEA\u2010PCL\/CEL specifically captured high\u2010density 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\u2010PCL\/CEL effectively alleviated hepatic lipid accumulation, lessened hepatic inflammation, and mitigated the toxicities of CEL with therapeutic efficacy superior to free CEL and PEG\u2010PCL\/CEL and even the current clinical simvastatin. Therefore, the OPDEA\u2010PCL may be a promising oral CEL delivery system for treating MASLD.<\/jats:p>","DOI":"10.1002\/advs.202500854","type":"journal-article","created":{"date-parts":[[2025,9,23]],"date-time":"2025-09-23T10:14:55Z","timestamp":1758622495000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Oral Celastrol Micelles Forming High\u2010Density Lipoprotein Corona Targeting Hepatocytes for MASLD Treatment"],"prefix":"10.1002","volume":"12","author":[{"given":"Chang","family":"Xu","sequence":"first","affiliation":[{"name":"Hangzhou First People\u2019s Hospital Zhejiang University School of Medicine  Hangzhou 310058 China"},{"name":"Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province Affiliated Hangzhou First People's Hospital School of Medicine Westlake University  Hangzhou 310006 China"},{"name":"Zhejiang University School of Medicine  Hangzhou 310058 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