Mesenchymal Stem Cell-Derived Exosomes Loaded with Isoliquiritigenin Promote Skin Wound Healing via Regulation of the TGF-β1 Signaling Axis

Abstract

: Objective: Isoliquiritigenin (ISO) has potential wound-repair activity, but its poor aqueous solubility and incompletely defined mechanism may limit therapeutic application. In this study, we developed isoliquiritigenin-loaded mesenchymal stem cell-derived exosomes (Exo-ISO), aimed to evaluate their effects on wound repair and investigated the potential involvement of the transforming growth factor-beta 1 (TGF-β 1) signaling pathway. Methods: ISO-induced proliferation of skin repair-associated cells was evaluated using CCK-8 and EdU assays. Exo-ISO was subsequently prepared and characterized, and its effects on HaCaT cell proliferation and migration were evaluated using Ki-67 immunofluorescence, Transwell migration, and scratch wound healing assays. Mechanistic investigation was performed using bioinformatics analysis combined with a TGF-β 1 overexpression rescue experiment. Results: ISO (5–20 µ M) increased proliferation-related readouts in HaCaT, HUVEC, and NIH 3T3 cells without evident cytotoxicity. Exo-ISO increased HaCaT cell viability to approximately 113% of control ( p < 0.01) and enhanced migration-associated readouts compared with free ISO or Exo alone. Bioinformatics prioritized TGF-β 1 as a candidate mediator, and Exo-ISO reduced TGF-β 1 protein abundance to approximately 30% of control ( p < 0.001). TGF-β 1 overexpression attenuated the Exo-ISO-associated increases in migration-associated readouts and wound closure ( p < 0.05 for the main comparisons). Conclusion: The findings suggest that ISO regulates skin repair cell function through modulation of the TGF-β 1 signaling pathway, an effect amplified considerably by Exo-ISO. These findings identify a previously unrecognized mechanism by which ISO may promote wound repair and support the use of exosomes as carriers for naturally derived bioactive compounds.