Local delivery of siRNA using lipid-based nanocarriers with ROS-scavenging ability for accelerated chronic wound healing in diabetes.

Diabetic wound healing poses a significant clinical challenge with limited therapeutic efficacy due to uncontrolled reactive oxygen species (ROS), inflammatory responses, and extracellular matrix (ECM) degradation caused by abnormal macrophage activity in the wound microenvironment. To address these concerns, we propose a novel formulation that combines Tempo-conjugated lipid with the commercially cationic lipid DOTAP to expedite diabetic wound healing through targeted siRNA delivery (cLpT@siRNA) and restoration of the wound microenvironment. The developed cLpT@siRNA nanocomplexes effectively scavenge excessive ROS levels, facilitate polarization of proinflammatory M1 macrophages towards an anti-inflammatory M2 phenotype, and suppress MMP9 gene expression in macrophages. In the ICR mouse model of diabetic wounds, cLpT@siRNA nanocomplexes significantly accelerate wound healing, promoting neovascularization and collagen deposition. Overall, the cLpT@siRNA nanocomplexes based on antioxidant and cationic lipids provide a promising strategy for delivering siRNA in diabetic wound treatment and hold great potential for clinical translation.