Nanotherapy targeting liver sinusoidal endothelial cells in liver fibrosis

Liver fibrosis represents a common pathological process in the progression of most chronic liver diseases. While hepatic stellate cells (HSCs) have long been recognized as central drivers of fibrogenesis, growing evidence highlights the critical role of liver sinusoidal endothelial cells (LSECs) in maintaining hepatic homeostasis, regulating vascular tone, and facilitating bidirectional molecular exchange between the bloodstream and hepatocytes through their unique fenestrated architecture. During liver fibrosis, however, LSECs undergo capillarization, namely the loss of fenestrae, the formation of a basement membrane, and the adoption of a continuous endothelial phenotype. This structural shift disrupts the exchange of nutrients, lipoproteins, and even drugs between the sinusoidal lumen and the space of Disse, fueling hepatocellular dysfunction and driving fibrosis progression. Recent findings further reveal that dysfunctional LSECs actively engage in aberrant crosstalk with other hepatic cells, creating a self-perpetuating pro-fibrotic microenvironment that promotes the initiation and progression of liver fibrosis. This review summarizes recent advances in understanding LSECs-mediated cellular communication and highlights innovative nanotherapeutic strategies designed to restore LSECs function or disrupt pathogenic intercellular networks in liver fibrosis, providing a promising and unique avenue toward next-generation anti-fibrotic therapies.