Time-programmed Losmapimod release enhances ANXA1-associated efferocytosis for diabetic wound repair

Impaired macrophage efferocytosis is a major barrier to timely inflammatory resolution in chronic diabetic wounds. We developed an aligned core-shell gelatin/chitosan dressing for local delivery of losmapimod, a p38 MAPK inhibitor, and achieved a controlled, time-decreasing release profile while preserving wet-state structural integrity. In vitro, losmapimod upregulated ANXA1 and enhanced both macrophage efferocytosis and phagocytic activity. In db/db wounds, the losmapimod-loaded scaffold accelerated healing and improved multiple histological features of pro-healing remodeling, including reduced fibrotic signaling, enhanced vascularization, increased epithelial progenitor-associated signals, and more mature collagen organization. Transcriptomic analysis further supported attenuation of inflammatory recruitment-associated programs together with enrichment of epidermal repair-related pathways. Gain- and loss-of-function studies in macrophages, together with in vivo pharmacological modulation, implicated ANXA1-related signaling as an important contributor to these effects. Together, these findings support a local, time-programmed pro-resolution biomaterial strategy for diabetic wound repair and identify macrophage clearance-associated remodeling as a relevant therapeutic axis.