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Background &amp; aims <p>Treatment of metabolic dysfunction-associated steatohepatitis (MASH) is constrained by the challenge of delivering highly hydrophobic drugs, whose poor water solubility severely hinders clinical application.</p> Methods <p>A prodrug-based self-assembly strategy was employed. <b>PEGylated 3d</b> was synthesized via covalent conjugation of Elafibranor derivative <b>3d</b> with Polyethylene glycol (PEG), and the amphiphilic conjugate spontaneously self-assembled into nanoparticles in aqueous solution without requiring exogenous polymers/lipids. The nanoparticles were characterized for size, morphology, and colloidal stability. In vitro lipid-lowering activity was assessed in an Free fatty acids (FFAs) -induced HepG2 model. In vivo efficacy was evaluated in a high-fat diet (HFD)-induced MASH mouse model following oral administration of <b>PEGylated 3d</b> nanoparticles (30&#xa0;mg/kg, <b>3d</b>-equivalent) compared to free <b>3d</b>.</p> Results <p><b>PEGylated 3d</b> self-assembled into stable spherical nanoparticles with a mean diameter of 255.3 ± 24.79&#xa0;nm. In the MASH mouse model, <b>PEGylated 3d</b> (30&#xa0;mg/kg) demonstrated significantly superior efficacy compared to free 3d: serum total cholesterol (TC) decreased by 34.3%, liver superoxide dismutase (SOD) activity increased by 35.6%, non-alcoholic fatty liver disease (NAFLD) activity score (NAS) score decreased by 62.3%, and liver lipid droplets reduced by 90.2%.</p> Conclusion <p>The structure-guided PEGylated prodrug nanoassembly effectively overcomes the solubility limitation of hydrophobic MASH therapeutics and exhibits enhanced anti-steatotic and antioxidant effects through improved drug delivery. This work establishes a promising nanocarrier-free drug self-delivery paradigm for MASH treatment.</p>

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Self-assembled PEGylated nanoparticles based on Elafibranor derivative 3d for the treatment of metabolic dysfunction-associated steatohepatitis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月7日

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  • Jiajia Yu,
  • Jiawen Wang,
  • Shuhan Li,
  • Sule Bai,
  • Xi Wang,
  • Yuxuan Ban,
  • Shouqing Zhang,
  • Yue Yu,
  • Jiang Liu,
  • Zhen Liu,
  • Herve Galons,
  • Yongmin Zhang,
  • Peng Yu,
  • Cen Xiang,
  • Yuou Teng

摘要

Background & aims

Treatment of metabolic dysfunction-associated steatohepatitis (MASH) is constrained by the challenge of delivering highly hydrophobic drugs, whose poor water solubility severely hinders clinical application.

Methods

A prodrug-based self-assembly strategy was employed. PEGylated 3d was synthesized via covalent conjugation of Elafibranor derivative 3d with Polyethylene glycol (PEG), and the amphiphilic conjugate spontaneously self-assembled into nanoparticles in aqueous solution without requiring exogenous polymers/lipids. The nanoparticles were characterized for size, morphology, and colloidal stability. In vitro lipid-lowering activity was assessed in an Free fatty acids (FFAs) -induced HepG2 model. In vivo efficacy was evaluated in a high-fat diet (HFD)-induced MASH mouse model following oral administration of PEGylated 3d nanoparticles (30 mg/kg, 3d-equivalent) compared to free 3d.

Results

PEGylated 3d self-assembled into stable spherical nanoparticles with a mean diameter of 255.3 ± 24.79 nm. In the MASH mouse model, PEGylated 3d (30 mg/kg) demonstrated significantly superior efficacy compared to free 3d: serum total cholesterol (TC) decreased by 34.3%, liver superoxide dismutase (SOD) activity increased by 35.6%, non-alcoholic fatty liver disease (NAFLD) activity score (NAS) score decreased by 62.3%, and liver lipid droplets reduced by 90.2%.

Conclusion

The structure-guided PEGylated prodrug nanoassembly effectively overcomes the solubility limitation of hydrophobic MASH therapeutics and exhibits enhanced anti-steatotic and antioxidant effects through improved drug delivery. This work establishes a promising nanocarrier-free drug self-delivery paradigm for MASH treatment.