Aptamer-functionalized exosomal delivery of species-matched Anti-PD-1 antibodies modulates the tumor immune microenvironment during cirrhosis-to-HCC malignant transformation

Hepatocellular carcinoma (HCC) often arises from hepatic cirrhosis, yet interventions that block this malignant transition are lacking. This study developed an aptamer-functionalized exosomal nanoplatform carrying an anti-PD-1 antibody to enable targeted immunomodulation. Single-cell and spatial transcriptomics of HCC specimens revealed reduced CD8 + T cell infiltration alongside elevated PD-1 expression in CD8 + T cells. Integrated proteomic and metabolomic profiling highlighted suppression of CD8 + T cell-related proteins, upregulation of proteasome 20 S subunit alpha 1 (PSMA1), and enrichment of altered metabolites within lipid metabolic pathways, indicating immune-metabolic dysregulation during cirrhosis-to-HCC progression. The engineered exosomal platform was evaluated in a 3D co-culture system containing HCC cells, cirrhotic hepatocytes, and CD8 + T cells, where it enhanced T cell-associated cytotoxic readouts and reduced fibrosis-related changes. In a mouse model of cirrhosis-associated malignant transformation, the platform showed preferential lesion-associated fluorescence, improved measured liver injury and lesion-burden endpoints, and enhanced CD8 + T cell effector readouts. These findings support exosome/aptamer-assisted anti-PD-1 delivery as a preclinical strategy for immune modulation during cirrhosis-associated malignant transformation, while further validation in human immune-cell systems or humanized models remains necessary.