Relieving Macrophage Dysfunction by Inhibiting SREBP2 Activity: A Hypoxic Mesenchymal Stem Cells‐Derived Exosomes Loaded Multifunctional Hydrogel for Accelerated Diabetic Wound Healing

Abstract Macrophage dysfunction is one of the primary factors leading to the delayed healing of diabetic wounds. Hypoxic bone marrow mesenchymal stem cells‐derived exosomes (hyBMSC‐Exos) have been shown to play an active role in regulating cellular function through the carried microRNAs. However, the administration of hyBMSC‐Exos alone in diabetic wounds usually brings little effect, because the exosomes are inherently unstable and have a short retention time at the wounds. In this study, a multifunctional hydrogel based on gallic acid (GA) conjugated chitosan (Chi‐GA) and partially oxidized hyaluronic acid (OHA) is prepared for sustained release of hyBMSC‐Exos. The hydrogel not only exhibits needs‐satisfying physicochemical properties, but also displays outstanding biological performances such as low hemolysis rate, strong antibacterial capacity, great antioxidant ability, and excellent biocompatibility. It has the ability to boost the stability of hyBMSC‐Exos, leading to a continuous and gradual release of the exosomes at wound locations, ultimately enhancing the exosomes’ uptake efficiency by target cells. Most importantly, hyBMSC‐Exos loaded hydrogel shows an excellent ability to promote diabetic wound healing by regulating macrophage polarization toward M2 phenotype. This may be because exosomal miR‐4645‐5p and antioxidant property of the hydrogel synergistically inhibit SREBP2 activity in macrophages. This study presents a productive approach for managing diabetic wounds.