肠上皮在受伤后会经历再生，这一过程的破坏可能导致炎症性肠病和肿瘤发生。隐窝中的肠干细胞（ISC）对于维持肠上皮的稳态和促进损伤后的再生至关重要。然而，DGCR8（microRNA (miRNA) 生物发生的关键组成部分）在肠道再生中的确切作用仍知之甚少。在这项研究中，我们提供了令人信服的证据，证明上皮 miRNA 在遭受 5-FU 或辐射诱导损伤的小鼠肠道再生中发挥着不可或缺的作用。通过对 Dgcr8 缺陷类器官中 miRNA 功能的全面汇总筛选，我们观察到 miR-200 家族的缺失导致 p53 通路过度激活，从而减少 ISC 并损害上皮再生。值得注意的是，在活动性溃疡性结肠炎 (UC) 患者的结肠组织中证实了 miR-200 家族的下调和 p53 通路的过度激活。最重要的是，通过口服携带 miR-200 的脂质纳米粒子 (LNP) 瞬时供应 miR-200 可恢复 ISC，并促进小鼠急性损伤后的肠道再生。我们的研究表明，miR-200/p53 通路是 miR-200 家族水平降低的活动性 UC 患者的一个有希望的治疗靶点。此外，我们的研究结果表明，LNP-miRNA 的临床应用可以提高现有肠道疾病治疗方式的有效性、安全性和可接受性。

Intestinal epithelium undergoes regeneration after injuries, and the disruption of this process can lead to inflammatory bowel disease and tumorigenesis. Intestinal stem cells (ISCs) residing in the crypts are crucial for maintaining the intestinal epithelium's homeostasis and promoting regeneration upon injury. However, the precise role of DGCR8, a critical component in microRNA (miRNA) biogenesis, in intestinal regeneration remains poorly understood. In this study, we provide compelling evidence demonstrating the indispensable role of epithelial miRNAs in the regeneration of the intestine in mice subjected to 5-FU or irradiation-induced injury. Through a comprehensive pooled screen of miRNA function in Dgcr8-deficient organoids, we observe that the loss of the miR-200 family leads to the hyperactivation of the p53 pathway, thereby reducing ISCs and impairing epithelial regeneration. Notably, downregulation of the miR-200 family and hyperactivation of the p53 pathway are verified in colonic tissues from patients with active ulcerative colitis (UC). Most importantly, the transient supply of miR-200 through the oral delivery of lipid nanoparticles (LNPs) carrying miR-200 restores ISCs and promotes intestinal regeneration in mice following acute injury. Our study implies the miR-200/p53 pathway as a promising therapeutic target for active UC patients with diminished levels of the miR-200 family. Furthermore, our findings suggest that the clinical application of LNP-miRNAs could enhance the efficacy, safety, and acceptability of existing therapeutic modalities for intestinal diseases.