Anti-microbial/oxidative/inflammatory nanogels accelerate chronic wound healing

The most common cause of delayed healing in chronic wounds is microbial pathogenesis, in which localized colonization can cause severe inflammation, systemic infection, and even sepsis in some cases. Towards this end, we have developed a multifunctional nanogel possessing antimicrobial/oxidative/inflammatory characteristics for rapid wound healing. We first employed quercetin (Qu) to prepare carbonized nanogels (CNGs) through polymerization and mild carbonization. The Qu–CNGs with antioxidant activity were further used as templates to prepare multifunctional nanogels containing copper sulfide (CuS) nanoclusters that possess superior catalytic and photoresponsive properties. The minimum inhibitory concentration of the nanogels (CuS/Qu–CNGs) towards tested bacteria is ∼125-folds lower than monomeric Qu or Qu–CNGs under NIR-II light irradiation. Furthermore, CuS/Qu–CNGs demonstrated efficient penetration into the extracellular biofilm matrix, resulting in eradication of methicillin-resistant Staphylococcus aureus (MRSA) associated biofilm on diabetic mice wounds. The CuS/Qu–CNGs nanogels suppressed proinflammatory cytokines (IL-1β) in the infectious wound sites and regulated the expression of anti-inflammatory IL-10 and TGF-β1 during and after recovery from infection, respectively. Along with in vivo bactericidal effects, the CuS/Qu–CNGs promote angiogenesis, epithelialization, and collagen synthesis to accelerate wound healing. Faster wound healing was attributed to the triple features (i) antioxidant Qu-CNGs reduced the pathogen-induced oxidative stress, (ii) enhanced bacterial contact due to polyphenolic groups of Qu facilitated CuS induced localized photothermal and photodynamic therapies, and (iii) enzyme mimic response of CuS nanoclusters contributed to the elimination of microbial pathogenesis.