Immunomodulatory copper-based polyphenol nanozyme for diabetic infectious wound healing via NIR amplified cuproptosis bacteriostat in synergy with ferroptosis inhibition anti-inflammation.

Abstract

Diabetic infectious wound is usually in the environment of high glucose levels and immune disorder. It always results in high reactive oxygen species (ROS) levels, serious immune dysfunction, and extreme susceptibility to infection, delaying wound healing. Herein, we prepared an immunomodulatory polyphenol metal organic framework nanozyme (CE) combined with near infrared (NIR) irradiation for diabetic infectious wound healing. This nanozyme was formed by the self-assembly of Cu ions and ellagic acid. <i>In vitro</i> experiments confirmed that CE + NIR could efficiently lower the inflammatory factors (IL-6 (50.72 %), IL-1β (61.44 %) and iNOS (57.33 %)) expression, and upregulate anti-inflammatory factor (IL-10 (111.44 %)) expression of lipopolysaccharide induced RAW264.7, decreasing the ROS levels, promoting cellular migration (527.91 %), and accelerating angiogenesis (91.81 %) of high glucose treated L929, together with inhibiting the bacterial growth of <i>E. coli</i> (92.21 %) and <i>MRSA</i> (95.89 %). Transcriptome sequencing results and their related validation experiments demonstrated that CE + NIR achieved antioxidant and anti-inflammation through ferroptosis inhibition. And transcriptomics and metabolomics analysis proved the efficient antibacterial activity of CE + NIR through NIR amplified cuproptosis. Markedly, it also confirmed that the strategy of CE + NIR was helpful to immunoregulation activation via inducing macrophage M2 directional polarization, and immune activating T cells number, thereby restoring immune homeostasis, and accelerating tissue repair. It might offer an efficient strategy of other infectious diseases' immunotherapy with high efficacy and biosafety.