rhFGF21-loaded P hydrogel promoted diabetic wound repair by regulating the inflammatory cytokine expression and phagocytic function of macrophages via the STING-mediated autophagy pathway.

Macrophage dysfunction serves as a pivotal factor in the delayed healing of diabetic wounds. Fibroblast growth factor 21 (FGF21) inhibits inflammation and promotes tissue regeneration, but it's limited by short half-life and poor stability. Poloxamer (P) hydrogel is a sustained drug delivery system. Therefore, this study aimed to investigate the role of macrophage dysfunction on the promotion of wound healing by rhFGF21-P hydrogel in type 2 diabetes mellitus (T2DM) murine models and murine peritoneal macrophages (MPMs) stimulated with high glucose and LPS (HG + LPS) for in vitro studies. P hydrogel sustained the release and enhanced the stability of rhFGF21. RhFGF21-P administration accelerated diabetic wound closure and reduced the levels of TNF-α, IL-6, MCP-1 and MIP-2 in diabetic mouse serum and skin tissues as well as in HG + LPS-stimulated MPMs. RhFGF21-P attenuated the fluorescence intensity of F4/80 and increased the level of autophagy in T2DM wound mice. RhFGF21 enhanced phagocytic capacity and the expression of LC3II protein in HG + LPS-stimulated MPMs, and the regulation of rhFGF21 in inflammatory cytokines and phagocytosis was reversed by autophagy inhibitors (3MA and CQ). In addition, rhFGF21 downregulated the levels of STING in vivo and in vitro. Furthermore, rhFGF21 increased the expression of LC3II protein, inhibited the mRNA levels of inflammatory cytokines (TNF-α and IL-6) and enhanced phagocytosis in HG + LPS-treated MPMs, but these effects were reversed by the STING agonist Vadimezan. These results demonstrated that rhFGF21-P promoted diabetic wound healing through inhibiting the expression of inflammatory cytokines and enhancing phagocytic function of macrophages via the modulation of STING-mediated autophagy.