Mannose receptor-targeted MSC-derived exosomes as a high-affinity delivery platform for liver sinusoidal endothelial...

Liver sinusoidal endothelial cells (LSECs) play a crucial role in the progression of liver fibrosis. While mesenchymal stem cell-derived exosomes (MSC-Exos) hold potential for liver regeneration, their therapeutic efficacy is often limited by poor target specificity and rapid clearance. Here, we developed mannose receptor-targeting MSC-Exos (Man-Exos) by incorporating DSPE-PEG-Mannose via a post-insertion method to enhance LSEC-specific delivery. The physicochemical stability and targeting efficiency of Man-Exos were evaluated both in vitro and in vivo. Man-Exos exhibited high stability in various conditions and showed significantly enhanced binding affinity to LSECs compared to non-targeted exosomes. Notably, in a co-culture system of LSECs and macrophages, Man-Exos demonstrated superior selectivity for LSECs. In vivo biodistribution studies further confirmed that Man-Exos predominantly accumulated in the liver, specifically colocalizing with LSECs for up to 48 h. Our findings suggest that Man-Exos can serve as a highly efficient and stable delivery platform for LSEC-targeted therapy, providing a promising strategy for enhancing the translational potential of exosome-based regenerative medicine in liver fibrosis.