Cockroach‐Derived Leucokinin VIII Peptide Accelerates Diabetic Skin Wound Healing by Enhancing Keratinocyte Filopodia Formation

ABSTRACT Cockroach‐derived extracts have shown therapeutic potential for dermatologic and mucosal wound repair. Although recent studies have identified several active components such as exosomes and specific peptides, the therapeutic efficacy and underlying mechanisms of novel short peptides like leucokinin VIII (LK‐VIII) remain to be fully elucidated. Here, we identify LK‐VIII as a potent promoter of keratinocyte migration that effectively alleviates diabetes‐induced migration impairment. Transcriptomic profiling of LK‐VIII‐treated keratinocytes revealed remarkable upregulation of ACTG1 , encoding γ‐actin. Mechanistically, LK‐VIII activates the FAK‐ACTG1 axis to promote keratinocyte migration and induces filopodia formation, as confirmed by scanning electron microscopy. We then developed an LK‐VIII‐loaded thermosensitive hydrogel system, based on poly(lactide‐co‐glycolide)‐block‐poly(ethylene glycol)‐block‐poly(lactide‐co‐glycolide) (PLGA‐PEG‐PLGA) triblock copolymer, capable of sustained peptide release. In streptozotocin/high fat diet‐induced diabetic mice and db/db mice, hydrogel‐delivered LK‐VIII significantly accelerated cutaneous wound closure. These findings support that the cockroach‐derived LK‐VIII peptide potently accelerates diabetic wound healing via FAK‐ACTG1‐mediated filopodia formation. The novel PLGA‐PEG‐PLGA thermosensitive hydrogel developed in this study represents a promising therapeutic approach for sustained peptide delivery.