A superoxide anion-responsive supramolecular polymer from peptide-H₂S donor conjugates for preventing liver...

Liver transplantation is the ultimate therapeutic intervention for patients with end-stage liver diseases. However, hepatic ischemia-reperfusion injury (HIRI) could occur and influence the success of transplantation and postoperative patient survival rates. Although there are several treatments available alleviating the pathology, the efficacy is suboptimal because only the oxidative stress or inflammation involved in HIRI is singly addressed. Given that these two causes are mutually entangled with each other in HIRI, we report a superoxide anion-responsive supramolecular polymer from peptide-H₂S donor conjugates (designated as HMS) to simultaneously address the challenge, thereby augmenting the efficacy. Upon superoxide anion stimulation, HMS controllably releases persulfides/H₂S, which then acts synergistically with methionine residues to exert a potent antioxidant effect, ultimately blocking the initiation of the oxidative stress-inflammation vicious cycle. Besides, the anti-inflammatory sequence SESSE in the conjugate could induce macrophage M2 polarization by modulating the energy metabolism and boost the mitigation of HIRI in vitro. In vivo assessment further shows that HMS could protect mice from HIRI effectively. Owing to its favorable biocompatibility and outstanding therapeutic efficacy, the strategy presented here may inspire new preventive or therapeutic approaches for ischemic diseases.