A pH‐Triggered Self‐Unpacking Capsule Containing Zwitterionic Hydrogel‐Coated MOF Nanoparticles for Efficient Oral Exendin‐4 Delivery

Abstract 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 CO 2 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.