Li Yu, Xu Yinggang, Li Yuxi, Wang Lijuan, Zhu Yuruchen, Liu Yingying, Zhu Ping, Zhou Yanyu, Zou Zhijing, Dong Yuhui, Wang Yao, Chao Tianhui, Wang Lihua, Wang Yue, Zou Wenbin, Wang Meitang, Zhang Yinan
Department of Gastroenterology, Changhai Hospital, Naval Medical University, Shanghai 200433, China.
Stem Cell and Regeneration Medicine Institute, Research Center of Translational Medicine, Naval Medical University, Shanghai 200433, China.
JACS Au. 2025 Jun 20;5(7):3521-3532. doi: 10.1021/jacsau.5c00549. eCollection 2025 Jul 28.
Acute pancreatitis (AP) is an inflammatory pancreatic disorder characterized by tissue damage and necrosis. It not only affects the pancreas but also triggers systemic inflammatory responses, leading to multiorgan failure and potentially death. In recent years, microRNA (miRNA) sponges have demonstrated promise to enhance AP treatment outcomes by inhibiting specific miRNAs. However, the clinical implementation of these inhibitors is often compromised by their structural instability. In this study, we developed a tetrahedron DNA nanostructure (TDN) with a single-stranded DNA segment designed to capture miR-21-3p, a potential therapeutic target for AP, forming a robust miRNA inhibitor. The TDNs exhibited enhanced stability compared to conventional single-stranded miRNA inhibitors, allowing for efficient delivery and maximizing therapeutic efficacy. Following treatment with the TDN miRNA inhibitor, we observed significant changes in serum levels of biomarkers associated with pancreatitis. Notably, there was a decrease in the expression of specific cytokines associated with both local and systemic inflammatory responses, alongside changes in proteins related to cell death and apoptosis. The mechanism of action involves RNase H-mediated cleavage, which facilitates the inhibition of the target miRNA. Overall, our findings suggest that the TDN miRNA inhibitor can mitigate acute pancreatitis and subsequent multiorgan damage in mice, presenting an effective approach for the future management of AP.
急性胰腺炎（AP）是一种以组织损伤和坏死为特征的胰腺炎症性疾病。它不仅影响胰腺，还会引发全身炎症反应，导致多器官功能衰竭甚至可能死亡。近年来，微小RNA（miRNA）海绵已显示出通过抑制特定miRNA来提高AP治疗效果的潜力。然而，这些抑制剂的临床应用常常因其结构不稳定性而受到影响。在本研究中，我们开发了一种四面体DNA纳米结构（TDN），其单链DNA片段设计用于捕获miR-21-3p（AP的一个潜在治疗靶点），形成一种强大的miRNA抑制剂。与传统的单链miRNA抑制剂相比，TDN表现出更高的稳定性，能够实现高效递送并最大化治疗效果。在用TDN miRNA抑制剂治疗后，我们观察到与胰腺炎相关的生物标志物血清水平发生了显著变化。值得注意的是，与局部和全身炎症反应相关的特定细胞因子表达下降，同时与细胞死亡和凋亡相关的蛋白质也发生了变化。其作用机制涉及核糖核酸酶H介导的切割，这有助于抑制靶miRNA。总体而言，我们的研究结果表明，TDN miRNA抑制剂可以减轻小鼠的急性胰腺炎及随后的多器官损伤，为AP的未来治疗提供了一种有效的方法。
