Enhanced Stem Cell-mediated Therapeutic Immune Modulation with Zinc Oxide Nanoparticles in Liver Regenerative Therapy

Liver regenerative therapy is critical for severe liver damage, including acute liver failure, fibrosis, post-cancer resection recovery, and autoimmune liver diseases, where restoration of liver tissues is essential. Stem cell-based therapies hold significant promise in liver regeneration by modulating immune responses to create a favorable healing microenvironment. However, their clinical efficacy has been limited by challenges such as poor cell engraftment and survival within the hostile injury site. To address these limitations, we developed a zinc oxide-derived nanoparticle (PZnONP) that enhances stem cell proliferation and activation by releasing bioactive Zn and reactive oxygen species (ROS). Functionalized PZnONP exhibits pH-responsive behavior and improved dispersibility, enabling a lysosome-specific and sustained release of Zn and ROS. Stem cells labeled with PZnONP (ZnBA) demonstrated anti-inflammatory properties, with paracrine effects influencing macrophages and damaged hepatocytes. In murine models of acute and fibrotic liver injury, it effectively migrated to the liver through stem cell homing effects and promoted anti-inflammatory responses by modulating Treg and Th17 cell polarization, as well as M2 and M1 macrophage balance, while reducing collagen synthesis. This study underscores the potential of integrating stem cell-based therapy with nanomedicine to improve regenerative outcomes in liver disease treatment.