ACS nanoFeb 7, 2015

Nanoparticles that help insulin pass through mucus and gut lining for oral delivery

GLP-1 Therapies Weekly Brief ↗PubMed ↗DOI ↗

Updated Mar 26, 2026

Abstract

The nanoparticles exhibit 20-fold higher absorption than free insulin on mucus-secreting epithelial cells.

Nanoparticles are designed for the oral delivery of insulin, addressing the challenge of limited oral bioavailability.
Efficient absorption and mucus permeation require distinct surface properties, which the nanoparticles successfully combine.
The nanoparticles feature a core of insulin and cell penetrating peptide, with a hydrophilic coating that dissociates during mucus passage.
Testing on mucus-secreting epithelial cells shows the nanoparticles achieve excellent mucus permeation and high epithelial absorption.
Orally administered nanoparticles lead to a significant hypoglycemic response and increased serum insulin levels in diabetic rats.

Simplified

Nanoparticles (NPs) have demonstrated great potential for the oral delivery of protein drugs that have very limited oral bioavailability. Orally administered NPs could be absorbed by the epithelial tissue only if they successfully permeate through the mucus that covers the epithelium. However, efficient epithelial absorption and mucus permeation require very different surface properties of a nanocarrier. We herein report self-assembled NPs for efficient oral delivery of insulin by facilitating both of these two processes. The NPs possess a nanocomplex core composed of insulin and cell penetrating peptide (CPP), and a dissociable hydrophilic coating of N-(2-hydroxypropyl) methacrylamide copolymer (pHPMA) derivatives. After systematic screening using mucus-secreting epithelial cells, NPs exhibit excellent permeation in mucus due to the "mucus-inert" pHPMA coating, as well as high epithelial absorption mediated by CPP. The investigation of NP behavior shows that the pHPMA molecules gradually dissociate from the NP surface as it permeates through mucus, and the CPP-rich core is revealed in time for subsequent transepithelial transport through the secretory endoplasmic reticulum/Golgi pathway and endocytic recycling pathway. The NPs exhibit 20-fold higher absorption than free insulin on mucus-secreting epithelium cells, and orally administered NPs generate a prominent hypoglycemic response and an increase of the serum insulin concentration in diabetic rats. Our study provides the evidence of using pHPMA as dissociable "mucus-inert" agent to enhance mucus permeation of NPs, and validates a strategy to overcome the multiple absorption barriers using NP platform with dissociable hydrophilic coating and drug-loaded CPP-rich core.

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Nanoparticles that help insulin pass through mucus and gut lining for oral delivery

Abstract

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