Andrias davidianus Derived Glycosaminoglycans Direct Diabetic Wound Repair by Reprogramming Reparative Macrophage Glucolipid Metabolism

Abstract Harnessing cross‐species regenerative cues to direct human regenerative potential is increasingly recognized as an excellent strategy in regenerative medicine, particularly for addressing the challenges of impaired wound healing in aging populations. The skin mucus of Andrias davidianus plays a critical role in self‐protection and tissue repair, yet the fundamental regenerative factors and mechanisms involved remain elusive. Here, this work presents evidence that glycosaminoglycans (GAGs) derived from the skin secretion of Andrias davidianus (SAGs) serve as potent mediators of angiogenesis and inflammatory remodeling, facilitating efficient healing of diabetic wounds. Mechanistic studies reveal that SAGs promote macrophage polarization toward an anti‐inflammatory and pro‐regenerative phenotype (CD206 + /Arg1 + ) via glucolipid metabolic reprogramming. This process suppresses excessive inflammation and enhances the expression of VEGF and IL‐10 to create a facilitative microenvironment for tissue regeneration. Additionally, this work develops SAGs‐GelMA composite microspheres that address multiple stages of wound healing, including rapid hemostasis, exudate control, and activation of endogenous regenerative processes. This engineered approach significantly improves the scarless healing of diabetic wounds by facilitating the recruitment and activation of reparative macrophages. The findings offer new insights into the regenerative mechanisms of Andrias davidianus and highlight the potential therapeutic application of SAGs in tissue repair.