Vitamin D Status Modulates the Regenerative Potential of Serum Exosomes: A Therapeutic Strategy for Wound Healing

Background: Vitamin D is a critical factor in immune regulation and epithelial regeneration. Vitamin D deficiency is commonly observed in diabetic patients and is associated with impaired wound healing. Circulating exosomes transport bioactive molecules and influence cellular behavior relevant to tissue repair. Aim: This study aimed to investigate the capacity of serum exosomes derived from individuals with/without diabetes and with different vitamin D statuses to enhance keratinocyte-mediated wound healing. Methods: Serum samples were collected from diabetic patients and healthy nondiabetic controls [22 participants in total: eight healthy volunteers and 14 patients with type 2 diabetes, of whom six were vitamin D-sufficient (>20 ng/mL) and eight were vitamin D-deficient (<20 ng/mL)]. Exosomes were isolated using ExoQuick™ and quantified using the ExoView R200 platform. HaCaT keratinocytes (HaCaT cells—human immortalized keratinocytes) were subjected to a wound healing assay and treated with serum-derived exosomes or with different concentrations of 1α,25(OH)₂D₃. Expressions of cytokeratin 14, E-cadherin, and vitamin D receptor were measured using immunofluorescence. Results: Exosomes from vitamin D-sufficient donors enhanced keratinocyte healing, while those from deficient diabetics were ineffective. 1α,25(OH)₂D₃ promoted proliferation up to a concentration of 100 nM, with inhibition at 200 nM. This biphasic response aligns with those of previous studies and suggests a threshold beyond which calcitriol may exert feedback-inhibitory or cytostatic effects. Regenerative efficacy aligned more with vitamin D status than glycemic metrics. Conclusion: Vitamin D status influences the regenerative efficacy of circulating exosomes. Stratifying diabetic patients by vitamin D levels may improve the outcomes of exosome-based therapies.