Engineering a macromolecular JAK inhibitor for treating acute inflammation and endotoxaemia

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.