Harnessing nanozyme-immunomodulation for antiviral defense via Fe–nordihydroguaiaretic acid nano-networks

Enveloped viruses such as coronaviruses are highly transmissible, necessitating effective prevention and inactivation strategies. In this study, we engineered uniform, small-sized (∼57 nm) iron-phenolic nano-networks (NA-Fe) that exhibit high lipoxidase-like activity for the inactivation of enveloped virus, encompassing both DNA virus (Pseudorabies, PRV) and RNA virus (Transmissible Gastroenteritis, TGEV; and Porcine epidemic diarrhea virus, PEDV). Theoretical studies indicate that NA-Fe facilitates the adsorption of pentadiene moieties within the viral envelope through interactions between the <i>d</i>-orbital electrons of iron and the π-electrons of pentadiene. This interaction leads to activation of the C=C bonds, potentially resulting in disruption of the viral envelope. Besides its extracellular antiviral effects, NA-Fe also suppresses intracellular viral replication by stimulating antiviral innate immune responses, and upregulate the expression of interferon-stimulating genes (ISGs). <i>In vivo</i> studies demonstrate that NA-Fe exhibits favorable biosafety, and intranasal administration significantly reduces viral titers while providing effective antiviral protection in PRV-infected mice. Notably, surfaces coated with NA-Fe, such as fences and air purifiers in farm facilities, provide effective antiviral protection. Collectively, these findings demonstrate that NA-Fe exhibits potent broad-spectrum antiviral activity against both extracellular and intracellular viruses, highlighting its potential for application in comprehensive biosecurity and infectious disease control.