Background: Recent attention is gaining towards polysaccharides derived from mushrooms like Morchella esculenta for their biocompatibility, antioxidant, and wound healing properties. It is necessary to promote alternatives for skin regeneration, as Chronic wounds remain a significant clinical challenge in healing. Aim: This research is aimed at evaluating the wound healing activity of polysaccharides extracted from M. esculenta through comprehensive in vitro and in vivo experimental models. Methods: Polysaccharides were extracted via a hot water–ethanol precipitation method. Cytotoxicity and fibroblast migration were evaluated in HaCaT cells and L929 fibroblasts using MTT and scratch assays. 36 Wistar albino rats were assigned to the excision wound model and treated topically with formulations containing 500 mg/kg and 1000 mg/kg M. esculenta polysaccharides for 28 days. Outcomes included wound contraction, epithelialization time, ELISA assays for hydroxyproline, catalase, TNF-α, IL-6, RT-PCR for VEGF-A, and histopathological and immunohistochemical analysis. The study was done after obtaining ethical clearance from the Institutional Animal Ethics Committee (IAEC 1 / Proposal: 156/A. Lr:118/ Dt: 20:02:2024) of Chettinad Academy of Research and Education, Kelambakkam, Tamil Nadu 6030103. Results: M. esculenta-derived polysaccharides significantly enhanced fibroblast migration at 12.5 μg/mL in vitro. In the in vivo model, the 1000 mg/kg dose demonstrated enhanced wound contraction. ELISA analysis showed increased hydroxyproline and catalase levels, along with reduced TNF-α and IL-6 concentrations. VEGF-A expression was significantly upregulated, indicating strong pro-angiogenic activity. Improved re-epithelialization, greater collagen deposition, and better tissue organisation in the treated groups compared to both control and standard drug-treated animals were observed in histopathological examinations. Conclusion: Multi-targeted wound-healing activity, such as fibroblast migration, reducing inflammation, and promoting angiogenesis were achieved by M. esculenta-derived polysaccharides. Although limited to animal models, these findings justify future translational studies Major Findings: Polysaccharides from Morchella esculenta showed antioxidant and anti-inflammatory effects and improved fibroblast migration. High doses sped up wound healing similar to silver sulfadiazine. They lowered TNF-α and IL-6 and increased collagen formation.
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