Nanoparticles are increasingly utilized for their potential in targeted drug delivery, highlightingthe need for innovative approaches to enhance therapeutic and regenerative outcomes. Thisstudy investigates zinc and iron ion-releasing nanoparticles (ZFNs) for their ability tosimultaneously deliver zinc (Zn) and iron (Fe) ions, aimed at boosting the efficacy of humanmesenchymal stem cells (hMSCs) in wound healing. Engineered for pH-sensitive degradation,ZFNs enable a controlled intracellular release of these ions following endocytosis by hMSCs.Our in vitro findings include favorable release kinetics and absence of toxicity. We observedthat dual ion delivery via ZFNs significantly modulates the key zinc transporter geneexpression and enhanced the angiogenic and migration-related gene expression in hMSCs. Thisactivity correlates with the activation of MAPK and AKT signaling pathways, essential forprocesses such as cell migration and proliferation, thereby supporting tissue regeneration.Indeed, changes in the secretion profiles of hMSCs treated with ZFNs were found to enhancethe migratory and regenerative capacities of both fibroblasts and keratinocytes. In vivoexperiments confirmed that hMSCs integrated with ZFNs accelerate wound healing andupregulate the expression of essential skin barrier proteins. Collectively, these findings positionZFNs as a promising tool for enhancing stem cell-mediated tissue regeneration, with potentialwidespread applications in clinical stem cell therapies.