Iron–Quercetin Nanocomplex Preconditioning Reprograms the Mesenchymal Stem Cell Secretome to Drive Angiogenic, Fibroblast, and Immunoregulatory Wound Repair

Chronic wounds remain a major clinical challenge characterized by impaired angiogenesis, persistent inflammation, and dysfunctional stromal responses. Increasing evidence indicates that the therapeutic effects of mesenchymal stem cells (MSCs) are largely mediated by paracrine signaling, making MSC-derived secretomes promising cell-free regenerative therapies. However, conventional culture conditions do not fully harness MSC plasticity to enhance secretion of pro-regenerative factors. In this study, we investigated an iron–quercetin nanocomplex (IronQ) as a biocompatible preconditioning strategy to improve the therapeutic secretome of adipose-derived MSCs (ADSCs). IronQ priming preserved cell viability and phenotypic integrity while allowing efficient intracellular uptake. Transcriptomic analysis demonstrated coordinated ADSC reprogramming, with enrichment of pathways related to extracellular matrix organization, angiogenesis, immune regulation, iron homeostasis, and tissue morphogenesis. Consistently, IronQ-preconditioned ADSC secretomes showed increased levels of key trophic and immunomodulatory factors, including VEGF-A, HGF, EGF, FGF-2, PDGF-AA, SDF-1α, G-CSF, CCL-2, and IL-10. Functionally, the conditioned secretome enhanced endothelial proliferation and tube formation, promoted fibroblast migration and activation, and induced macrophage polarization toward a reparative M2 phenotype in vitro. Collectively, these findings identify IronQ as an effective secretome-modulating strategy with strong translational potential for scalable, cell-free treatment of chronic and diabetic wounds.