Engineering a multifunctional nanoplatform with cascade catalytic and bidirectional immunomodulatory capacities for integrating sepsis therapy

• Novel nanocomposite design: Integration of Prussian blue nanozymes (PB NZs) with Ag + -modified metal-phenolic networks creates ARPB NZs, a multifunctional platform for sepsis therapy. • Multi-pathway therapeutic efficacy: Simultaneously targets bacterial clearance (Ag + -mediated), immune homeostasis (DCs pyroptosis inhibition, T-cell activation), and organ protection (ROS scavenging via nanozyme activity). • Superior in vitro performance: Demonstrates broad-spectrum antibacterial effects, catalase-/SOD-like activities, and excellent biocompatibility. • Comprehensive in vivo validation: Significantly reduces hyperinflammation, prevents secondary infections, and mitigates multi-organ dysfunction in septic models. • Translational innovation: Proposes a first-in-class strategy to address sepsis complexity, with potential applications in infectious and inflammatory diseases. Sepsis is a life-threatening condition characterized by organ dysfunction due to a dysregulated immune response to infection. Despite extensive research into its complex pathogenesis, effective clinical treatments remain limited, necessitating novel therapeutic strategies. This study aims to develop a multifunctional nanozyme-based therapy for severe sepsis, combining broad-spectrum antimicrobial activity and reactive oxygen species (ROS) scavenging to counteract organ injury, immune dysregulation, and high mortality. We designed biocompatible resveratrol-Ag + -Prussian blue nanozymes (ARPB NZs) and evaluated their therapeutic effects in two murine sepsis models: E. coli-induced abdominal infection and cecal ligation/puncture (CLP). Mechanistic studies focused on oxidative stress attenuation, cytokine storm suppression, lymphocyte function, and dendritic cell pyroptosis via the NLRP3/caspase-1/GSDMD pathway. ARPB NZs effectively alleviated organ damage, maintained immune homeostasis by reducing inflammation and oxidative stress, and significantly improved survival rates in both sepsis models. They also inhibited lymphocyte apoptosis and dampened dendritic cell pyroptosis. ARPB NZs represent a promising synergistic strategy for severe sepsis by simultaneously targeting infection and immune dysregulation. This approach may translate into broader applications for infectious diseases.