Glu and GSH double-unlocked immunomodulatory tri-cascade nanoreactor for biofilm-infected diabetic wounds healing

The treatment of diabetic wounds remains a challenge due to the interaction between hyperglycemia, immune imbalance and bacterial infection. Herein, we developed a Glu and GSH double-unlocked immunomodulatory nanocascade reactor to accelerate diabetic wounds healing which dynamically manages the wound microenvironment by controlling blood glucose levels, restoring immune regulation and eliminating bacteria. On the one hand, ultra-small gold nanoparticles with GOx activity can catalyse glucose at the diabetic wound site, which can be further enhanced by photothermal effects, thus destroying bacterial biofilm structures, reversing wounds pH, and reducing bacterial reproduction. On the other hand, the sustained controlled release of NO at specific sites was achieved by depleting over-expressed GSH in the wounds to restore normal immune regulation, which not only promotes M2 macrophage polarisation and expressions of anti-inflammatory factors such as IL-10 and TGF-β1, but also produces VEGF and CD31 via the PI3K/AKT signalling pathway. Especially, the chemical resonance energy transfer (CRET) strategy was first applied to diabetic wounds treatment, achieving chemical photodynamic therapy (PDT) while reducing the secondary tissue damage caused by catalytically-generated H2O2. In summary, the nanocascade reactor provides a new reference for bacterialy-infected diabetic wounds treatment mode by reducing blood glucose and restoring immune regulation in parallel.