Engineered IGF-I–loaded extracellular vesicles restore hepatic regeneration capacity after partial hepatectomy in fibrotic livers

Liver regeneration following surgical resection is frequently compromised in clinically relevant settings, including extended hepatectomy, increasing the risk of post-hepatectomy liver failure. Extracellular vesicles (EVs) derived from mesenchymal stem cells (MSCs) are emerging as a cell-free therapeutic platform with regenerative and immunomodulatory activity through delivery of bioactive cargo. Here, we evaluated EVs derived from human umbilical cord perivascular cells (HUCPVCs), an MSC population engineered to express insulin-like growth factor 1 (IGF-I), in partial hepatectomy models in healthy and fibrotic livers in mice. Administration of IGF-I-EVs reduced early liver injury and significantly enhanced liver mass recovery and hepatocyte proliferation. Mechanistically, IGF-I-EVs activated core regenerative gene programs in whole-liver tissue and in isolated hepatocytes. In parallel, IGF-I-EV treatment reprogrammed hepatic macrophages toward a pro-resolutive/regenerative phenotype, characterized by IGF-I receptor signaling activation and induction of hepatotrophic factors. IGF-I-EVs also directly modulated hepatic stellate cells, reducing fibrogenic marker expression and inducing Hgf, through both direct EV action and indirect effects mediated by the macrophage secretome. Notably, IGF-I-EVs partially restored regenerative competence in established fibrosis and promoted remodeling of the fibrotic architecture. Together, these findings support IGF-I-engineered MSC-derived EVs as a cell-free strategy to enhance liver regeneration after partial hepatectomy in settings of impaired regenerative capacity.