RGD-modified M2 exosomes delivered via microneedles accelerate diabetic wound healing by enhancing angiogenesis and reducing inflammation

Effective treatment for diabetic wounds remains a significant challenge due to persistent local tissue hypoperfusion and chronic inflammation, which impair the natural healing process. Current standard-of-care often falls short in simultaneously addressing both the lack of vascularization and the prolonged inflammatory state. This study explores a novel therapeutic strategy using bioengineered exosomes to mitigate inflammation and enhance tissue vascularization, aiming to break this vicious cycle and improve clinical outcomes for diabetic wound healing.

Researchers established a stable macrophage cell line overexpressing basic fibroblast growth factor (bFGF) via lentiviral transfection. M2 polarization was induced using interleukin-4 (IL-4) and IL-10, followed by ultracentrifugation to isolate exosomes. These exosomes were then surface-functionalized with arginine-glycine-aspartic acid (RGD)-targeting peptides to create targeted engineered exosomes (TE-Exos). The reparative effects of TE-Exos were assessed on human umbilical vein endothelial cells (HUVECs) subjected to high glucose-induced injury using scratch test, EdU staining, and CCK-8 assays. A delivery system comprising soluble hyaluronic acid microneedles (MNs) loaded with these engineered exosomes was developed and evaluated in a diabetic wound mouse model. Underlying mechanisms were explored via RNA sequencing.

The study successfully prepared targeted engineered exosomes (TE-Exos) derived from bFGF-overexpressing M2 macrophages with surface RGD modification. In vitro assays demonstrated that TE-Exos exhibited specific targeting to HUVECs with high glucose-induced injury, and significantly enhanced cellular proliferation, migration, and tube formation. Furthermore, the polarization ratio of macrophages improved after TE-Exos treatment, indicating a shift towards a pro-healing phenotype. In vivo, the MN-mediated delivery of TE-Exos markedly accelerated diabetic wound healing. This acceleration was attributed to enhanced re-epithelialization, collagen deposition, and angiogenesis within the wound bed. > The treatment effectively modulated the wound microenvironment by reducing the infiltration of pro-inflammatory cells, thereby addressing a critical barrier to healing in diabetic wounds. RNA sequencing further elucidated the molecular pathways involved in this multi-faceted reparative process.