Self‐Crosslinked Oxidized Xyloglucan Hydrogels Enhance Macrophage Metabolism for Diabetic Wound Healing via the cAMP‐PKA Pathway

Xyloglucan, an immunomodulatory hemicellulose, shows potential for promoting chronic wound healing. However, tunable hydrogels composed solely of xyloglucan with a defined anti-inflammatory mechanism remain elusive. To address this, we developed a single-component, inherently bioactive oxidized xyloglucan (OXG) hydrogel that integrates anti-inflammatory functionality with extracellular matrix (ECM)-mimetic properties. The hydrogel forms autonomously via dynamic hemiacetal crosslinking between aldehyde and hydroxyl groups on the OXG backbone, eliminating the need for exogenous crosslinkers or drug loading. This strategy enables OXG to function both as an immunomodulator and as a supportive scaffold, exhibiting tissue adhesion, injectability, self-healing, and stability in physiological environments. In vitro and in vivo results demonstrated that the OXG hydrogel promotes M2 macrophage polarization and suppresses pro-inflammatory responses by activating the cAMP-PKA signaling pathway, leading to a metabolic shift and inflammation resolution without exogenous cytokines. These actions collectively accelerated diabetic wound closure, enhanced angiogenesis, and facilitated orderly tissue regeneration. This work established a drug-free hydrogel dressing with a well-defined anti-inflammatory mechanism by leveraging the inherent biological activity and self-gelling capability of a single polysaccharide, achieving active remodeling of the immune environment in chronic diabetic wounds. These findings position OXG as a promising natural anti-inflammatory biomaterial for tissue engineering and therapeutics.