Mesenchymal Stem Cell‐Derived Extracellular Vesicles Embedded in a Self‐Adaptive Multifunctional Hydrogel for Rapid Healing of Infected Wounds

A PF127/CMCS/GA/EVs composite hydrogel is developed for enhanced wound healing. This hydrogel employs Schiff base crosslinking and exhibits thermosensitive gelation along with microenvironment self-adaptability. Under microenvironmental changes, it enables self-responsive release of EVs, contributing to antibacterial, anti-inflammatory, and antioxidant effects, promoting vascular formation and collagen regeneration, thus accelerating wound healing.

Abstract

Wound healing represents a major clinical concern, disrupted by cellular dysfunction due to infection, metabolic imbalance, and immune response, resulting in physical and economic burden to the patients. Despite the widespread recognition of mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) in wound healing research, ensuring their release and retention at the wound site and maximizing their therapeutic efficacy remain significant challenges. To address these issues, a self-adaptive multifunctional hydrogel is introduced that allows the self-adaptive release of MSC-EVs at the wound sites. This approach prevents the rapid clearance of MSC-EVs, enabling them to effectively activate wound healing signaling pathways and promote angiogenesis, cell migration, proliferation, and re-epithelialization. Moreover, the incorporation of gallic acid (GA) endows the hydrogel with antibacterial, anti-inflammatory, and antioxidant properties, which synergistically enhance the reparative effects of MSC-EVs. The potential of the MSC-EV-embedded multifunctional hydrogel is evaluated in a methicillin-resistant Staphylococcus aureus (MRSA)-infected full-thickness wound mouse model, demonstrating its high performance in accelerating the healing of infected complex wounds.