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

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.