Xu Qinyuan, Cao Ziqi, Yan Hongyu, Xu Lingling, Liu Yixiao, Cai Xiaojun, Zheng Yuanyi
Department of Ultrasound in Medicine, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, P. R. China.
Shanghai Key Laboratory of Neuro-Ultrasound for Diagnosis and Treatment, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, P. R. China.
ACS Appl Mater Interfaces. 2025 Aug 20;17(33):46733-46743. doi: 10.1021/acsami.5c10593. Epub 2025 Aug 11.
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%. 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.
肝纤维化是一种由氧化应激、慢性炎症和肝星状细胞（HSC）激活驱动的进行性病理状态，目前缺乏有效的治疗干预措施，是一个尚未满足的关键医疗需求。在此，我们提出普鲁士蓝（PB）纳米酶作为一种创新的多功能纳米治疗平台，旨在同时破坏驱动纤维化形成的致病三联征。这些PB纳米酶呈现出明确的晶体结构，具有显著的多功能酶促级联活性，表现出过氧化物酶、超氧化物歧化酶和过氧化氢酶样催化能力，以及70±5%的羟基自由基清除效率。研究表明，PB纳米酶可抑制脂多糖诱导的促炎细胞因子分泌，同时减弱转化生长因子-β介导的活化HSCs中胶原蛋白-1/α-平滑肌肌动蛋白的上调。在四氯化碳诱导的肝纤维化小鼠模型中，用PB纳米酶预处理可显著减轻血清丙氨酸转氨酶和天冬氨酸转氨酶水平的升高，减少肝脏羟脯氨酸积累，并改善组织病理学纤维化评分。机制研究表明，纤维化肝脏中HSC激活标志物受到显著抑制，同时胶原蛋白沉积减少。值得注意的是，PB纳米酶表现出优异的生物相容性，通过增强的渗透和滞留效应显示出选择性肝脏蓄积。PB纳米酶平台展示了一种治疗协同三联机制，包括活性氧（ROS）清除、免疫调节干预和HSC静止诱导。临床前评估显示其具有优化的药代动力学特征，具有持续的生物利用度和良好的毒理学参数，确立了PB纳米酶作为纤维化肝病管理的一种有前景的治疗策略。
