Macrophage‐Derived Extracellular Vesicles Deliver Progranulin to Alleviate Skin Wound Fibrosis

Optimal wound healing is crucial for patient recovery. Macrophage-fibroblast crosstalk is central to this process. Progranulin (PGRN) is involved in tissue repair, yet its intercellular transport and signaling mechanisms remain unclear. This study investigates how macrophage-derived PGRN, via extracellular vesicles (EVs), regulates fibroblast behavior during healing. Using murine scRNA-seq and transwell co-culture, we found that macrophages suppress fibroblast activation. Mechanistically, macrophage-derived PGRN was packaged into EVs and internalized by fibroblasts, upregulating DnaJ heat shock protein family member C3 (DNAJC3). Rescue experiments confirmed that DNAJC3 is essential for PGRN to inhibit the serum response factor (SRF)/alpha-smooth muscle actin (α-SMA)/connective tissue growth factor (CTGF) pathway. In a mouse wound model, PGRN-enriched EVs accelerated healing and improved healing quality, while EVs from Grn-silenced macrophages were less effective. We identify a novel EV-mediated pathway: macrophage PGRN targets fibroblast DNAJC3 to suppress fibrotic signaling. This reveals a fundamental regulatory mechanism and highlights macrophage EVs as promising natural therapeutics for fibrotic skin disorders.