Third-degree, large-area skin injuries impose a significant socioeconomic burden on victims each year. The liver demonstrates extensive regenerative properties, and its exosomes are rich in organic selenium protein (SELENOP) with a high bioavailability. In this study, we established hepatic exosomes as a distinct biological nanoparticle and considering its unique cargo to investigate their regenerative effects on skin cells, including upregulation of cell growth, antioxidant molecules, and angiogenic properties, which have not been previously explored. Building on these promising findings, we designed a novel three-dimensional (3D) bio-printed multicellular skin organoid scaffold using hepatic exosome-encapsulated GECM (GelMa-ECM) bio-ink to mimic native skin structure. In vivo, the skin construct orchestrates wound healing by boosting key tissue regenerative markers, biological processes, and signaling pathways, while also downregulating various pro-inflammatory pathways during the proliferative stage of healing. Our study highlights a new strategy for wound healing and offers potential insights into the treatment of other chronic and recalcitrant skin diseases.