Self-Adaptive Release of Stem Cell-Derived Exosomes from a Multifunctional Hydrogel for Accelerating MRSA-Infected Diabetic Wound Repair

Abstract

Chronic diabetic wounds are prone to severe skin necrosis and bacterial infections, with elevated reactive oxygen species (ROS) and persistent inflammation further hindering the healing process. Developing smart dressings with multifunctional therapeutic capabilities to simultaneously combat infections, reduce oxidative stress, alleviate inflammation, and promote tissue regeneration remains a significant challenge. Here, we introduce a self-adaptive yet multifunctional hydrogel (Exo-Gel) designed to accelerate methicillin-resistant <i>Staphylococcus aureus</i> (MRSA)-infected diabetic wound repair. Exo-Gel utilizes choline phosphate (CP) groups to both anchor stem cell-derived exosomes (Exo) via electrostatic interactions and disrupt bacterial membranes, providing inherent bacteriostatic effects. Additionally, ROS-responsive thioketal (TK) linkers enable the self-adaptive release of exosomes based on local ROS levels while also scavenging excess ROS. This synergistic system facilitates wound healing by modulating oxidative stress, reducing inflammation, promoting M2 macrophage polarization, and enhancing cell proliferation, myofibroblast migration, angiogenesis, and collagen deposition to accelerate tissue regeneration. In diabetic Sprague-Dawley rats with MRSA-infected full-thickness wounds, Exo-Gel achieved remarkable bacteriostatic activity and accelerated wound healing. Exo-Gel offers a cost-effective, multifunctional, and self-adaptive therapeutic strategy for managing chronic diabetic wounds, requiring no external components or operations, making it highly practical and translatable for clinical applications.