Abstract
Diabetic foot ulcers (DFUs) are a complex mixture of neuropathy, peripheral arterial disease, and infection, where excessive reactive oxygen species (ROS) exacerbates inflammation and impairs healing. Therefore, there is an urgent need to design a hydrogel dressing with a 'lever' function to balance ROS levels in the wound to achieve both antimicrobial and anti-inflammatory effects on DFUs. In this study, we synthesised ROS-responsive diselenide liposomes loaded with a pro-skin healing factor (ergothioneine (ET)), thrombin, and a sonosensitizer (HMME) and constructed nanocomposite 'lever' hydrogels modulated by ultrasound (US). During early infection, sonodynamic therapy (SDT) under US generates bactericidal ROS, cleaving diselenide bonds to release ET and thrombin. Upon US cessation, thrombin/fibrinogen forms an in situ gel, while ET scavenges residual ROS and promotes M2 macrophage polarization in later stages. In addition, the potential immunomodulatory mechanisms of the nanocomposite 'lever' hydrogels were investigated via RNA sequencing. In conclusion, the novel nanocomposite 'lever' hydrogels effectively achieved a balance between ROS production and annihilation during different stages of wound repair while providing antibacterial and anti-inflammatory properties to promote neovascularisation and improve diabetic peripheral neuropathy. In conclusion, by precisely controlling ROS levels across wound-healing phases, this strategy offers a promising solution for refractory DFUs.