Functional phyto-nanozymes for dual regulation of microbial metabolism and overinflammation microenvironment in diabetic wound

Abstract

Chronic wound management demands multifunctional therapeutic strategies that simultaneously address excessive inflammation and oxidative stress. To meet this challenge, we engineered a three-dimensional biomimetic scaffold (CSSTF) by integrating collagen-based thermosensitive hydrogel, a SiO₂-supported copper single-atom catalyst (Cu-SAC-SE), and tea tree oil-encapsulated liposomes (TTO@Lpo). This composite design enables sustained release of bioactive components, achieving synergistic ROS scavenging, mitochondrial protection, and suppression of NLRP3 inflammasome-mediated pyroptosis. Notably, CSSTF exhibits dual immunomodulatory effects by attenuating neutrophil extracellular trap (NET) formation and shifting macrophage polarization from pro-inflammatory M1 to anti-inflammatory M2 phenotype, thereby mitigating inflammation-associated tissue damage. Parallelly, TTO@Lpo orchestrates microbial remodeling by selectively inhibiting pathogenic bacteria while enriching beneficial commensals, coupled with elevated production of anti-inflammatory metabolites (e.g., short-chain fatty acids), establishing a self-reinforcing "microbiota-metabolism-inflammation" regulatory loop. In diabetic murine models, CSSTF significantly accelerated wound closure through coordinated mechanisms: (1) enhanced angiogenesis via VEGF upregulation, (2) NETosis suppression that dampens cytokine storms, and (3) ECM reconstruction facilitated by fibroblast activation. Beyond material innovation, this work pioneers a phyto-bionic therapeutic platform leveraging enzymatic catalysis and microbiome reprogramming, offering a paradigm shift in chronic wound treatment through simultaneous physical barrier restoration and dynamic biological modulation.