A pH‐Triggered Self‐Unpacking Capsule Containing Zwitterionic Hydrogel‐Coated MOF Nanoparticles for Efficient Oral Exendin‐4 Delivery
A pH‐Triggered Self‐Unpacking Capsule Containing Zwitterionic Hydrogel‐Coated MOF Nanoparticles for Efficient Oral Exendin‐4 Delivery
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DOI：
10.1002/adma.202102044
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发表时间：
2021-07
影响因子：
29.4
通讯作者：
Yuhao Zhou;Zhixiong Chen;Dan Zhao;Dong Li;Chaoliang He;Xuesi Chen
中科院分区：
文献类型：
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作者：
Yuhao Zhou;Zhixiong Chen;Dan Zhao;Dong Li;Chaoliang He;Xuesi Chen
口服肽或蛋白质输送被认为是每日皮下注射的革命性替代方案；然而，胃肠道环境和由粘液和上皮细胞层组成的肠上皮的障碍仍然存在重大挑战，导致生物利用度低。为了防止胃肠道降解并促进穿过肠粘膜的渗透，我们设计了一种 pH 触发的自解包胶囊，该胶囊封装了两性离子水凝胶涂层的金属有机框架 (MOF) 纳米颗粒。 MOF纳米颗粒具有高exendin-4负载能力，两性离子水凝胶层赋予了独特的跨粘液层渗透能力和上皮细胞对纳米载体的有效内化能力。除了耐胃功能外，pH响应胶囊在肠道环境中由于快速产生大量二氧化碳气泡而急剧解离，从而引发纳米颗粒的突然释放。糖尿病大鼠模型口服Exendin-4纳米粒胶囊后，血浆Exendin-4水平在8小时以上显着升高，导致内源性胰岛素分泌显着增加，降血糖效果显着，相对药理利用度为17.3%。由于低血糖风险较低，这种口服 Exendin-4 策略将为日常且简便的糖尿病治疗提供巨大潜力。
Oral peptide or protein delivery is considered a revolutionary alternative to daily subcutaneous injection; however, major challenges remain in terms of impediments of the gastrointestinal environment and the intestinal epithelium consisting of mucus and the epithelial cell layer, leading to low bioavailability. To protect against gastrointestinal degradation and promote penetration across the intestinal mucosa, a pH‐triggered self‐unpacking capsule encapsulating zwitterionic hydrogel‐coated metal‐organic framework (MOF) nanoparticles is engineered. The MOF nanoparticles possess a high exendin‐4 loading capacity, and the zwitterionic hydrogel layer imparts unique capability of permeation across the mucus layer and effective internalization by epithelial cells to the nano‐vehicles. In addition to the gastro‐resistant feature, the pH‐responsive capsules are dissociated drastically in the intestinal environment due to the rapid generation of abundant CO2 bubbles, which triggers a sudden release of the nanoparticles. After oral administration of the capsules containing exendin‐4‐loaded nanoparticles into a diabetes rat model, markedly enhanced plasma exendin‐4 levels are achieved for over 8 h, leading to significantly increased endogenous insulin secretion and a remarkable hypoglycemic effect with a relative pharmacological availability of 17.3%. Owing to the low risk of hypoglycemia, this oral exendin‐4 strategy will provide a vast potential for daily and facile diabetes treatment.