Zinc silicate microspheres-mediated bacterial metabolic interference and microenvironment remodeling for chronic wound repair

Abstract

Chronic wounds have presented a significant clinical challenge due to persistent infection, uncontrolled inflammation, and impaired tissue regeneration. Existing therapeutic platforms have failed to integrate these critical aspects into a single, cohesive strategy. To address this, a novel multifaceted agent, zinc silicate flower-like microsphere (ZnSi FMPs), was designed with controlled hierarchical architecture to achieve chronic wound repair by mediating bacterial metabolic interference and microenvironment remodeling. The unique nanosheet structure with sustained Zn2+ release endows ZnSi FMPs with favorable pH-independent antibacterial activity. This activity is mechanistically rooted in metabolic interference against Staphylococcus aureus (S. aureus), including disruption of ABC transporters and inhibition of the biosynthesis of essential amino acids (valine, leucine, isoleucine) and ribosomes. Concurrently, ZnSi FMPs can promote microenvironment remodeling by modulating inflammatory responses and angiogenesis, evidenced by suppressed inflammation mediated by the complement and coagulation cascades pathway and robust activation of the Areg/HB-EGF-mediated ErbB signaling pathway. Hence, in both S. aureus-infected and diabetic wound models (mice and minipigs), ZnSi FMPs exhibited superior chronic wound healing capacity compared with commercial silver sulfadiazine® (AgSD) and 45S5 bioglass®. This improved healing was achieved through enhanced antibacterial activity, anti-inflammatory effects, and angiogenesis, accompanied by elevated expression of CD163, CD206, CD31 and α-SMA. By synergizing bacterial metabolic interference with microenvironment regulation, ZnSi FMPs effectively facilitate tissue healing and provide a promising candidate for clinical wound treatment.