Abstract
Nanoparticles are increasingly utilized for their potential in targeted drug delivery, highlighting the need for innovative approaches to enhance therapeutic and regenerative outcomes. This study investigated zinc- and iron-ion-releasing nanoparticles (ZFNs) for their ability to simultaneously deliver zinc (Zn) and iron (Fe) ions, aimed at boosting the efficacy of human mesenchymal stem cells (hMSCs) in wound healing. Engineered for pH-sensitive degradation, ZFNs enable the controlled intracellular release of these ions following endocytosis by hMSCs. Our in vitro findings include favorable release kinetics and the absence of toxicity. We observed that dual-ion delivery via ZFNs markedly modulated the key zinc transporter gene expression and enhanced the angiogenesis- and migration-related gene expression in hMSCs. This activity correlates with the activation of mitogen-activated protein kinase and AKT signaling pathways, essential for processes such as cell migration and proliferation, thereby supporting tissue regeneration. Indeed, changes in the secretion profiles of hMSCs treated with ZFNs were found to enhance the migratory and regenerative capacities of both fibroblasts and keratinocytes. In vivo experiments confirmed that hMSCs integrated with ZFNs accelerate wound healing and upregulate the expression of essential skin barrier proteins. Collectively, these findings position ZFNs as a promising tool for enhancing stem-cell-mediated tissue regeneration, with potential widespread applications in clinical stem cell therapies.