“内外兼治”策略逆转慢性炎症促进糖尿病足溃疡创面愈合

创面慢性炎症是造成糖尿病足溃疡（DFUs）创面难愈的主因，目前尚无逆转创面慢性炎症的药物。DFUs创面慢性炎症与中性粒细胞过度释放胞外诱捕网（NETs）（内因）和细菌生物被膜感染（外因）密切相关。基于NETs和细菌生物被膜富含胞外DNA，本项目提出“内外兼治”新策略，利用表面聚多巴胺修饰银纳米粒（PDA-AgNPs）与脱氧核糖核酸酶-I（DNase-Ⅰ）间结构和功能互补性，构建长效DNase-Ⅰ递送系统，经荷载于光固化凝胶后，获得多功能凝胶敷料。创面给药后可控释放的长效DNase-Ⅰ递送系统，不仅破坏NETs（内治）和细菌生物被膜（外治），且放大PDA-AgNPs抗菌活性，最终协同逆转慢性炎症，促进DFUs创面愈合。本项目将深入研究多功能凝胶敷料发挥“内外兼治”新策略的协同作用过程和机制，阐明该策略治疗DFUs的生物学意义。为逆转慢性炎症而促进DFUs创面愈合的新药开发提供理论依据和参考。

Chronic inflammation is the main cause of unhealing wounds in diabetic foot ulcers (DFUs). No drug based on reversing chronic inflammation for treating DFUs has been found so far. It has reported that during DFUs chronic inflammation in unhealing wound is closely related to the excessive release of neutrophil extracellular traps (NETs) by neutrophils (internal cause) and continuous bacterial biofilm infection (external cause). Based on the fact that NETs and bacterial biofilms are rich in extracellular DNA, in this project a new strategy of “combined internal and external treatment” is applied to reverse chronic inflammation for promoting the wounds healing in DFUs. To verify this strategy of “combined internal and external treatment”, a long-acting DNase-I delivery system (DNase-I/AgNPs) is constructed by self-assembly based on the complementarity of structure and function between polydopamine modified silver nanoparticles (PDA-AgNPs) and deoxyribonuclease-I (DNase-I). In addition, a multifunctional hydrogel dressing (GelMA@DNase-I/AgNPs) with the function of “combined internal and external treatment” is also prepared by loading DNase-I/AgNPs into the light-cured gel using gelatin methacryloyl (GelMA) as gel material. After wound administration of GelMA@DNase-I/AgNPs, the controlled release of DNase-I/AgNPs not only destroys NETs (internal treatment) and bacterial biofilm (external treatment), but also amplifies the antimicrobial activity of PDA-AgNPs. Finally, this multifunctional hydrogel dressing could synergistically reverse the chronic inflammation in unhealing wounds and promote the wound healing in DFUs. In this project, the process and mechanism of the new “combined internal and external treatment”strategy are investigated. The biological significance of the above strategy in the treatment of DFUs will also be illustrated, which will provide a theoretical basis and reference for the development of new drugs to reverse chronic inflammation and promote wound healing in DFUs.