AggreArch: A Programmable Nano-to-Micro Assembly Platform for Redox-Active Metal Microarchitectures in Infected Wound Repair

Abstract

Chronic infected wounds, particularly under diabetic conditions, require antimicrobial biomaterials that combine potent bacterial suppression with host-tissue compatibility. Here, we report AggreArch, a tunable aqueous nano-to-micro assembly platform for constructing hierarchical metal-based microarchitectures with programmable composition, morphology, and biological activity. Using this strategy, we generated Ag-, Cu-, and Mn-based AggreArch variants to demonstrate the compositional extensibility of the platform. Among these variants, the dendritic silver architecture AAAg4 was identified as a representative lead candidate, achieving 99.7% inhibition against multidrug-resistant Escherichia coli (E. coli) at 30 μg mL−1 and 99.8% inhibition against methicillin-resistant Staphylococcus aureus (S. aureus) at 100 μg mL−1, while maintaining >85% cell viability and favorable short-term biosafety. Comparative release studies showed that AAAg4 released only 1–2% of total silver in PBS over 7 days vs ∼7% for conventional AgNPs, confirming architecture-regulated silver availability. Integrated transcriptomic and biochemical analyses indicated that AAAg4 induced a coordinated redox-metabolic stress program involving oxidative imbalance, Fe-S-dependent functions, and respiratory electron-transfer-related processes, while imposing a lower oxidative burden on host cells than freely available Ag+. In diabetic infected wound models, AAAg4 accelerated wound closure (approximately 92% by day 12), markedly reduced bacterial burden, and enhanced collagen deposition to 83.1% vs 36.1% in controls. Similar repair-promoting trends were observed in rabbit ear wounds. Collectively, these findings establish AAAg4 as a representative lead architecture within the AggreArch platform and demonstrate that hierarchical microarchitecture engineering can expand the antibacterial-biosafety window of metal-based wound-facing antimicrobial materials.