Wang Liying, Tian Mengxiang, Dong Bingzhi, Li Weiqi, Shi Liang, Tong Yifan, Chen Wei, Yu Xin, Xu Hongxia, Shen Bo, Yu Hong
Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, China.
Zhejiang Key Laboratory of Precise Diagnosis and Treatment of Abdominal Infection, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, China.
Biomater Sci. 2025 Aug 5;13(16):4461-4481. doi: 10.1039/d5bm00018a.
Acute pancreatitis (AP) is a common abdominal inflammatory disease, characterized by pancreatic autodigestion, acinar cell necrosis, and systemic inflammation. Currently, there is a lack of specific drugs in the treatment of AP. Traditional Chinese medicine (TCM) is an effective approach in the prevention and treatment of AP, with rheum being one of the key components in commonly used TCM formulas for treating AP. We screened emodin as the core active ingredient of rheum and developed a heparin-modified emodin carrier, EMO@ZIF-8/Heparin (HEZ), which specifically delivers emodin to the inflamed pancreatic tissue CD44-targeted macrophage activation. The HEZ exhibited higher macrophage uptake efficiency in the inflammatory microenvironment, restored the mitochondrial membrane potential, alleviated oxidative stress, and effectively reduced the levels of cytokines in the AP cell model. Moreover, the formulation exhibited targeted enrichment and retention in the pancreas under AP conditions, blocking the systemic inflammatory amplification cascade, reducing approximately 50% of pathological damage in both pancreatic and lung tissues, decreasing the proportion of apoptotic pancreatic cells, and increasing the 15-day survival rate of AP mice from 15% to around 50%. Mechanistically, the formulation restored impaired macrophage mitochondrial function to a healthy state by inhibiting the JNK pathway. In summary, the multifunctional HEZ provides an upstream therapeutic strategy by targeting macrophages in AP, offering a novel and effective approach to potentially enhance AP treatment in the future.
急性胰腺炎（AP）是一种常见的腹部炎症性疾病，其特征为胰腺自身消化、腺泡细胞坏死和全身炎症反应。目前，AP治疗中缺乏特效药物。中医药是防治AP的有效方法，大黄是治疗AP常用中药方剂中的关键成分之一。我们筛选出大黄素作为大黄的核心活性成分，并开发了一种肝素修饰的大黄素载体EMO@ZIF-8/肝素（HEZ），其可将大黄素特异性递送至炎症胰腺组织，靶向激活CD44巨噬细胞。HEZ在炎症微环境中表现出更高的巨噬细胞摄取效率，恢复线粒体膜电位，减轻氧化应激，并有效降低AP细胞模型中的细胞因子水平。此外，该制剂在AP条件下在胰腺中表现出靶向富集和滞留，阻断全身炎症放大级联反应，使胰腺和肺组织的病理损伤减少约50%，降低胰腺细胞凋亡比例，并将AP小鼠的15天生存率从15%提高至约50%。机制上，该制剂通过抑制JNK通路将受损的巨噬细胞线粒体功能恢复至健康状态。总之，多功能HEZ通过靶向AP中的巨噬细胞提供了一种上游治疗策略，为未来潜在增强AP治疗提供了一种新颖有效的方法。
