Synergistic catalytic therapy of severe acute pancreatitis using gold-doped prussian blue nanozymes via targeting ROS-NLRP3 inflammatory cascade

Abstract

Severe acute pancreatitis (SAP) is characterized by a complex and poorly understood pathogenesis, with a lack of specific therapeutic agents. Herein, we develop morphology-engineered gold-doped Prussian blue nanozymes (AuPB), designed as reactive oxygen species (ROS) scavengers for synergistic therapy of SAP. A programmable structural switching strategy is achieved by precise control over the sequence and concentration of HAuCl 4 introduction. This allows regulation of the Au 3 ⁺/Ca 2 ⁺ exchange kinetics to achieve on demand synthesis of well-defined AuPB nanostructures, including uniform nanorods (AuPBNR), nanospheres (AuPBNS), and nanocubes (AuPBNC). Consequently, a direct synthesis -structure-performance relationship is established, whereby the tailored nanostructure dictates both catalytic activity and anti-inflammatory efficacy. Among these, AuPBNS nanospheres (~20 nm) exhibit superior multi enzyme mimicking activities and broad spectrum radical scavenging capacity, enabling effective ROS clearance in vivo and in vitro. Notably, AuPBNS exerts a precise immunomodulatory effect by not only reducing key inflammatory cytokines (IL-6, TNF-α, IL-1β, and IL-18), but also specifically antagonizing NLRP3 inflammasome activation, inhibiting caspase-1 and Gasdermin D (GSDMD) cleavage to suppress pyroptosis. Density functional theory simulations provide further mechanistic insight by revealing the morphology-dependent structure-activity relationship of these nanozymes. By integrating programmable synthesis with systematic activity evaluation, this study not only validates AuPBNS as a high performance biomimetic nanozyme but also proposes a structure-driven catalytic therapeutic strategy, offering a distinct and innovative approach for SAP treatment.