<p>This study introduces an approach to wound healing through the development of psoralen-loaded electrospun nanofiber Mats, leveraging the synergistic properties of polyvinyl alcohol (PVP) and polycaprolactone (PCL) for enhanced topical drug delivery. A meticulously optimized electrospinning process, guided by a 3² factorial design, yielded nanofibers with diameters ranging from 290 to -542 nm, exhibiting a uniform and highly porous structure. These nanofibers demonstrated rapid drug release (90% within 10 minutes) and excellent biocompatibility. Key to this enhanced performance was the amorphous nature of psoralen within the Mat, confirmed by DSC and XRD, and the established compatibility between psoralen, PVP, and PCL via FTIR. Notably, in vivo evaluation on diabetic rats revealed significantly enhanced wound contraction with the psoralen nanofiber treatment, underscoring its potential to accelerate excision wound healing. Further analysis demonstrated a marked reduction in pro-inflammatory cytokines (IL1-β, IL-6, and TNF-α) in treated groups, highlighting the anti-inflammatory mechanism of the psoralen nanofibers. These combined results position psoralen-loaded PVP/PCL nanofibers as a promising, fast-acting therapeutic intervention with significant biopharmaceutical advantages for effective wound management through translational research.</p> Graphical Abstract <p></p>