Exosome‐Guided Phenotypic Switch of M1 to M2 Macrophages for Cutaneous Wound Healing

Abstract Macrophages (Mϕs) critically contribute to wound healing by coordinating inflammatory, proliferative, and angiogenic processes. A proper switch from proinflammatory M1 to anti‐inflammatory M2 dominant Mϕs accelerates the wound healing processes leading to favorable wound‐care outcomes. Herein, an exosome‐guided cell reprogramming technique is proposed to directly convert M1 to M2 Mϕs for effective wound management. The M2 Mϕ‐derived exosomes (M2‐Exo) induce a complete conversion of M1 to M2 Mϕs in vitro. The reprogrammed M2 Mϕs turn Arginase (M2‐marker) and iNOS (M1‐marker) on and off, respectively, and exhibit distinct phenotypic and functional features of M2 Mϕs. M2‐Exo has not only Mϕ reprogramming factors but also various cytokines and growth factors promoting wound repair. After subcutaneous administration of M2‐Exo into the wound edge, the local populations of M1 and M2 Mϕs are markedly decreased and increased, respectively, showing a successful exosome‐guided switch to M2 Mϕ polarization. The direct conversion of M1 to M2 Mϕs at the wound site accelerates wound healing by enhancing angiogenesis, re‐epithelialization, and collagen deposition. The Mϕ phenotype switching induced by exosomes possessing the excellent cell reprogramming capability and innate biocompatibility can be a promising therapeutic approach for various inflammation‐associated disorders by regulating the balance between pro‐ versus anti‐inflammatory Mϕs.