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<p>Uncontrolled and sustained inflammation is inextricably associated with the pathogenesis of numerous diseases. However, there is still demand for effective and safe anti-inflammatory therapies. Here we report a potent anti-inflammatory macromolecular therapy named HPL, created by conjugating polyethylene glycol and luminol onto a multivalent and hydrolysable cyclic structure. Leveraging its amphiphilic nature, HPL can spontaneously self-assemble into micelles capable of targeting inflamed tissues and localizing in inflammatory cells. In mice with acute lung, kidney and liver injuries, as well as endotoxaemia, HPL shows anti-inflammatory effects that rivals or surpasses those of two commonly used anti-inflammatory drugs. HPL micelles can act as bioactive and inflammation-responsive carriers for site-specific delivery to release anti-inflammatory drugs. Mechanistically, HPL exerts its anti-inflammatory activity mainly by inhibiting the IL-6/JAK2/STAT3 signalling pathway. HPL shows favourable safety profiles in mice at doses at least 5-fold higher than those used in therapeutic studies. These findings suggest that HPL holds great promise as a highly potent, cost-effective and safe JAK2 inhibitor for treating various diseases associated with inflammation.</p>

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Engineering a macromolecular JAK inhibitor for treating acute inflammation and endotoxaemia

  • 期刊论文

  • 发表日期：

    2025年10月17日

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  • Min Zhou,
  • Yan Wang,
  • Bin Yang,
  • Yang Zhang,
  • Ling Zhong,
  • Kaiyao Hu,
  • Wendan Pu,
  • Gaoxing Luo,
  • Jianxiang Zhang

摘要

Uncontrolled and sustained inflammation is inextricably associated with the pathogenesis of numerous diseases. However, there is still demand for effective and safe anti-inflammatory therapies. Here we report a potent anti-inflammatory macromolecular therapy named HPL, created by conjugating polyethylene glycol and luminol onto a multivalent and hydrolysable cyclic structure. Leveraging its amphiphilic nature, HPL can spontaneously self-assemble into micelles capable of targeting inflamed tissues and localizing in inflammatory cells. In mice with acute lung, kidney and liver injuries, as well as endotoxaemia, HPL shows anti-inflammatory effects that rivals or surpasses those of two commonly used anti-inflammatory drugs. HPL micelles can act as bioactive and inflammation-responsive carriers for site-specific delivery to release anti-inflammatory drugs. Mechanistically, HPL exerts its anti-inflammatory activity mainly by inhibiting the IL-6/JAK2/STAT3 signalling pathway. HPL shows favourable safety profiles in mice at doses at least 5-fold higher than those used in therapeutic studies. These findings suggest that HPL holds great promise as a highly potent, cost-effective and safe JAK2 inhibitor for treating various diseases associated with inflammation.