ROS-mitochondria-NLRP3/STING axis mediates the enhanced anti-coronavirus activity of ZIF8 nanoparticles

Coronaviruses (CoVs) pose serious threats to both animal and human health, underscoring the urgent need for broad-spectrum antiviral strategies that can provide rapid and immune-independent protection beyond vaccination. In this study, we developed zeolitic imidazolate framework-8 (ZIF8) as an innovative zinc-based anti-coronavirus nanoagent and revealed that ZIF8 exhibits markedly enhanced antiviral activity relative to the commonly used zinc oxide (ZnO). Using porcine epidemic diarrhea virus (PEDV) as a model α-coronavirus, mechanistic studies demonstrated that ZIF8 alleviates excessive reactive oxygen species (ROS) accumulation and preserves mitochondrial homeostasis, while simultaneously promoting cytosolic mtDNA release through moderate opening of the mitochondrial permeability transition pore (mPTP) and coordinately regulates NLRP3 inflammasome activation and STING signaling, thereby enhancing host antiviral responses. Consistent with this mechanism, ZIF8 nanoparticles displayed broad-spectrum inhibitory effects against representative β-, γ-, and δ-coronaviruses, including bovine coronavirus (BCoV), infectious bronchitis virus (IBV), and porcine deltacoronavirus (PDCoV). Moreover, in a PDCoV-infected mouse model, ZIF8 provided effective in vivo protection by reducing viral replication and preventing intestinal damage under both preventive and therapeutic regimens. Collectively, these findings establish the ROS-mitochondria-NLRP3/STING axis as a key mechanistic basis for ZIF8-mediated antiviral activity and provide new insights for the rational design of nanomaterial-based broad-spectrum antiviral therapeutics.