Abstract
In addition to oxidative stress and impaired angiogenesis, the overexpression of metalloproteinases (MMPs) and proinflammatory cytokines, which are promoted by hyperglycemia, causes chronic inflammation in diabetic wounds. Herein, TA-siRNA nanogels are prepared for the first time on the basis of the self-assembling interaction between tannic acid (TA) and short interfering RNA (siRNA). The efficient, biodegradable nanogels are cross-linked with poly(vinyl alcohol) (PVA), human-like collagen (HLC), TA, and borax to prepare adaptive, conductive PHTB (TA-siRNA) hydrogels. In response to high levels of reactive oxygen species (ROS), the ROS-responsive borate ester bonds in the hydrogels are oxidized and broken, and TA-siRNA nanogels are released into cells to reduce the expression of the MMP-9. Moreover, the TA and HLC promote collagen expression, reduce inflammation, and ROS level. It is found that electrical stimulation (ES) promotes the in vivo release of TA-siRNA nanogels from PHTB (TA-siRNA) hydrogels and endocytosis of the nanogels. The combination therapy using ES and PHTB (TA-siRNA) hydrogels accelerates the healing of diabetic wounds by reducing the levels of ROS and MMP-9 and promoting the polarization of macrophages, production of collagen, and angiogenesis. This study provides insights on the design of functional gene-delivery and efficient therapeutic strategies to promote the repair of diabetic chronic wounds.