Versatile DNA Hydrogel‐Mediated Delivery of Ginsenoside‐Encapsulated Small Extracellular Vesicles to Boost Diabetic Wound Repair

ABSTRACT Diabetic wound healing is often hindered by poor outcomes, prolonged recovery, and high recurrence. To address this, a new therapy approach was demonstrated in this study, in which ginsenoside (GS) molecules are incorporated into small extracellular vesicles (sEV) secreted by mesenchymal stem cells (MSCs), and the formed complexes are then anchored in DNA hydrogels via aptamer‐CD63 affinity as “GS/sEV@DNAgels”. Besides the tissue‐restorative ability that sEVs inherit from MSCs, in GS/sEV@DNAgels, GS molecules provide a superior antimicrobial/anti‐inflammatory environment at wound sites, while DNA hydrogels serve as wound dressings to ensure sustained release kinetics and enhanced skin penetration. An innovative ultrasonic stimulation was developed to promote the massive production of sEVs. By triggering multiple cellular responses that alter membrane fluidity, calcium levels, and relevant protein expression, our approach achieves a 57.7‐fold increase in sEV yield. The synergistic effects of GS and sEVs enhance cell viability, migration, and angiogenesis, as well as local anti‐inflammatory and antibacterial conditions during diabetic wound healing. The upregulation of miR‐424/322 is confirmed as an essential mechanism of this GS/sEV@DNAgel system in accelerating skin restoration. Our work provides a new and promising strategy for diabetic tissue regeneration.