Oxidation-responsive PEG-poly(α-lipoic acid) nanoparticles for coenzyme Q10 delivery attenuate hepatic ischemia-reperfusion injury via ROS scavenging and ferroptosis inhibition.

Hepatic ischemia-reperfusion injury (IRI) is characterized by an acute surge of reactive oxygen species (ROS) upon reperfusion, leading to oxidative damage and cell death. Ferroptosis, a form of iron-dependent lipid peroxidation-driven cell death, has recently been implicated in hepatic IRI, compounding the injury. Here, we present an oxidation-responsive nanoparticle system designed to mitigate liver IRI by scavenging ROS and inhibiting ferroptosis. We synthesized a PEGylated poly(α-lipoic acid) (PEG-PαLA) copolymer that self-assembles into nanoparticles encapsulating the lipophilic antioxidant coenzyme Q10 (CoQ10). The PEG-PαLA/CoQ10 nanoparticles have an average diameter of ∼100 nm and release CoQ10 preferentially under oxidative conditions. In vitro, the nanoparticles efficiently neutralized free radicals and protected hepatocytes from oxidative injury. In a mouse model of partial hepatic IRI, treatment with PEG-PαLA/CoQ10 nanoparticles significantly reduced liver injury markers, preserved liver histology, and abrogated lipid peroxidation, indicating suppression of ferroptosis. Our results demonstrated that the PEG-PαLA/CoQ10 nanoparticle is a novel antioxidant nanomedicine that synergistically attenuates ROS-mediated damage and ferroptotic cell death in hepatic IRI. These findings highlight a promising strategy for protecting organs from ischemia-reperfusion damage by targeting oxidative stress and ferroptosis with responsive biomaterial carriers.