Orchestration of macrophage polarization dynamics by fibroblast-secreted exosomes during skin wound healing

Macrophages undertake pivotal yet dichotomous functions during skin wound healing, mediating both early pro-inflammatory immune activation and late anti-inflammatory tissue remodeling processes. The timely phenotypic transition of macrophages from inflammatory M1 to pro-resolving M2 activation states is essential for efficient healing. However, the endogenous mechanisms calibrating macrophage polarization in accordance with the evolving tissue milieu remain undefined. Here, we reveal an indispensable immunomodulatory role for fibroblast-secreted exosomes in directing macrophage activation dynamics. Fibroblast exosomes permitted spatiotemporal coordination of macrophage phenotypes independent of direct intercellular contact. Exosomes enhanced macrophage sensitivity to both M1 and M2 polarizing stimuli, yet also accelerated timely switching from M1 to M2 phenotypes. Exosomes inhibition dysregulated macrophage responses resulting in aberrant inflammation and impaired healing, while provision of exogenous fibroblast exosomes corrected defects. Topical application of fibroblast exosomes onto chronic diabetic wounds normalized dysregulated macrophage activation to resolve inflammation and restore productive healing. Our findings elucidate fibroblast-secreted exosomes as remote programmers of macrophage polarization that calibrate immunological transitions essential for tissue repair. Harnessing exosomes represents a previously unreported approach to steer productive macrophage activation states with immense therapeutic potential for promoting healing in chronic inflammatory disorders.