Prussian Blue Nanozymes Attenuate Hepatic Fibrogenesis by Disrupting the Oxidative-Inflammatory-Fibrotic Network

Hepatic fibrosis, a progressive pathological condition driven by oxidative stress, chronic inflammation, and hepatic stellate cell (HSC) activation, represents a critical unmet medical need with a current lack of effective therapeutic interventions. Herein, we present Prussian blue (PB) nanozymes as an innovative multifunctional nanotherapeutic platform engineered to simultaneously disrupt the pathogenic triad driving fibrogenesis. These PB nanozymes exhibited a well-defined crystalline structure with pronounced multifunctional enzymatic cascade activities, demonstrating peroxidase-, superoxide dismutase-, and catalase-like catalytic competencies, along with hydroxyl radical scavenging efficiency of 70 ± 5%. <i>In vitro</i> studies revealed that PB nanozymes suppressed LPS-induced pro-inflammatory cytokine secretion while attenuating TGF-β-mediated Collagen-1/α-SMA upregulation in activated HSCs. In a murine model of carbon tetrachloride-induced hepatic fibrosis, pretreatment with PB nanozymes significantly attenuated the elevation of serum alanine aminotransferase and aspartate aminotransferase levels, reduced hepatic hydroxyproline accumulation, and improved histopathological fibrosis scores. Mechanistic investigations demonstrated significant suppression of HSC activation markers concomitant with reduced collagen deposition in fibrotic livers. Notably, PB nanozymes exhibited superior biocompatibility profiles and demonstrated selective hepatic accumulation through enhanced permeability and retention effects. The PB nanozyme platform demonstrates a therapeutically synergistic triad mechanism comprising reactive oxygen species (ROS) scavenging, immunomodulatory intervention, and HSC quiescence induction. Preclinical evaluation reveals an optimized pharmacokinetic profile with sustained bioavailability and favorable toxicological parameters, establishing PB nanozymes as a promising therapeutic strategy for fibrotic liver disease management.