Genistein-Derived ROS-Responsive Nanoparticles Relieve Colitis by Regulating Mucosal Homeostasis
Genistein-Derived ROS-Responsive Nanoparticles Relieve Colitis by Regulating Mucosal Homeostasis
复制标题
染料木黄酮衍生的活性氧响应型纳米颗粒通过调节黏膜稳态缓解结肠炎
DOI：
10.1021/acsami.1c09215
复制
发表时间：
2021-08-23
影响因子：
9.5
通讯作者：
Song, Suquan
中科院分区：
文献类型：
--
作者：
Fan, Wentao;Zhang, Shuo;Song, Suquan
肠道内环境平衡紊乱是炎症性肠病(IBD)发生发展过程中的重要事件，染料木素(Genistein，GEN)是预防IBD的候选药物。然而，Gen口服生物利用度低，限制了其临床应用。本文制备了一种含超氧化物歧化酶模拟时间偶联的β-环糊精和4-羟甲基苯基硼酸频那醇酯修饰的活性氧(ROS)响应型纳米材料(Gen-NP2)。Gen-NP2有效地将Gen运送到炎症部位，并保护Gen不会在胃肠道内快速代谢和消除。作为对高ROS水平的反应，Gen被定位地释放并在炎症部位蓄积。机制上，Gen-NP2能有效增加雌激素受体β(ERβ)的表达，同时降低促炎介质(凋亡相关的SPECK样含卡蛋白(ASC)和Caspase1-p20)的表达，减轻炎症细胞的渗透，促进肠上皮细胞的自噬，抑制白介素1β(IL-1β)和肿瘤坏死因子-α(TNF-α)的分泌，调节肠道微生物区系，最终减轻结肠炎。此外，口服这些纳米颗粒显示出极好的安全性，从而为进一步开发IBD的精确治疗方法提供了信心。
Disruption of intestinal homeostasis is an important event in the development of inflammatory bowel disease (IBD), and genistein (GEN) is a candidate medicine to prevent IBD. However, the clinical application of GEN is restricted owing to its low oral bioavailability. Herein, a reactive oxygen species (ROS)-responsive nanomaterial (defined as GEN-NP2) containing superoxidase dismutase-mimetic temporally conjugated beta-cyclodextrin and 4-(hydroxymethyl)phenylboronic acid pinacol ester-modified GEN was prepared. GEN-NP2 effectively delivered GEN to the inflammation site and protected GEN from rapid metabolism and elimination in the gastrointestinal tract. In response to high ROS levels, GEN was site-specifically released and accumulated at inflammatory sites. Mechanistically, GEN-NP2 effectively increased the expression of estrogen receptor beta (ER beta), simultaneously reduced the expression of proinflammatory mediators (apoptosis-associated speck-like protein containing a CARD (ASC) and Caspase1-p20), attenuated the infiltration of inflammatory cells, promoted autophagy of intestinal epithelial cells, inhibited the secretion of interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha), modulated the gut microbiota, and ultimately alleviated colitis. In addition, the oral administration of these nanoparticles showed excellent safety, thereby providing confidence in the further development of precise treatments for IBD.