Reversing LSEC Capillarization with Precision: Nucleic Acid Spheres Show Promise in Tackling Liver Fibrosis (PRJCA037846)

Liver sinusoidal endothelial cell (LSEC) capillarization is a critical feature of liver fibrosis progression. Although mesenchymal stem cell (MSC) therapy has shown significant potential in reversing LSEC capillarization and alleviating fibrosis, its clinical application remains limited due to concerns such as tumorigenicity, immune rejection, ethical dilemmas, technical complexities, and high costs. In this study, we unveil a novel mechanism by which MSC-secreted miR-325-3p modulates the cytoskeleton of LSECs, effectively restoring their fenestrations and sieve plates, which are critical to their differentiated phenotype and essential for maintaining proper liver function. Building on this discovery, we engineered spherical nucleic acids (SNAs) composed of miR-325-3p, which are assembled into spheroid polyhedrons via aurophilic interactions. These SNAs selectively target fibrotic LSECs through Scara-mediated clathrin-dependent endocytosis, resulting in an efficient reversal of LSEC capillarization. In several mouse models of liver fibrosis, SNAs demonstrated superior therapeutic efficacy and a highly favorable safety profile compared to MSC therapy. This research highlights SNAs as a highly promising alternative to MSCs, offering a targeted, scalable, and clinically translatable solution for liver fibrosis treatment, with far-reaching implications for the development of nucleic acid-based therapeutics aimed at targeting LSECs and other cell types involved in hepatopathy.