<p>Liver ischemia-reperfusion injury (LIRI) is a severe and nearly unavoidable complication in hepatectomy and liver transplantation, accompanied by intense oxidative stress and ferroptosis. Traditional clinical therapies often face challenges such as poor bioavailability, short circulation time, and low stability, which restrict their efficacy in regulating complex pathological microenvironments. Here, we developed a biocompatible and multi-bioactive nanoplatform, Se@MelP, comprising a selenium nanoparticle (SeNP) core encapsulated within a melanin-like shell. Specifically, selenium (Se) was incorporated into selenoproteins in the form of selenocysteine to regulate redox reactions, while the melanin-like shell simultaneously scavenged reactive oxygen species (ROS) and chelated Fe²⁺, together synergistically alleviating LIRI. Se@MelP possessed excellent ROS scavenging activity, strong iron chelating capability, and favorable biosafety. In vitro experiments confirmed that Se@MelP effectively eliminated excessive ROS, alleviated Fe²⁺ overload, and mitigated mitochondrial damage, protecting cells from oxidative stress and ferroptosis. Upon intravenous administration in the LIRI model, Se@MelP markedly improved liver function, attenuated tissue injury, and mitigated oxidative stress, inflammatory responses, and ferroptosis. Notably, Se@MelP activated the AMPK/Nrf2 pathway, enhancing the endogenous antioxidant defenses and anti-ferroptotic capacity, thereby conferring protection against liver injury. This multi-bioactive nanoplatform offers a promising therapeutic strategy for LIRI and other oxidative stress‑related liver diseases.</p> Graphical Abstract <p></p>