Chitosan-Coated Nanoparticles Achieved 13% Oral Bioavailability for the GLP-1 Drug Exenatide | Research

The takeaway

Chitosan-coated core-shell nanoparticles delivered the GLP-1 drug exenatide orally with 13.29% pharmacological bioavailability, effectively controlling blood sugar and lipids in long-term animal testing.

13.29% oral bioavailability
Remarkably high for an oral peptide drug — achieved by chitosan-coated nanoparticles that doubled cellular uptake while only slightly reducing mucus penetration

What the researchers found

Chitosan-coated EDB nanoparticles (CS-EDB NPs) achieved 83.5% exenatide encapsulation efficiency, ~277 nm particle size, and -16.2 mV zeta potential. Compared to uncoated NPs, the chitosan coating reduced mucus penetration by 1.1-fold but increased cellular uptake by 2.15-fold and transepithelial transport by 1.77-fold. Uptake was primarily energy-dependent endocytosis with partial macropinocytosis. The NPs achieved 13.29% pharmacological bioavailability and effectively regulated blood glucose, serum lipids, and improved islet function with long-term oral administration.

Why it matters

Oral delivery of peptide drugs is one of the biggest challenges in pharmaceutical science. Most approaches achieve less than 5% bioavailability. Achieving 13.29% with exenatide is a significant accomplishment. If this technology can be scaled and translated to humans, it could eliminate injections for GLP-1 therapy — a major barrier to patient compliance, especially considering the millions of people now taking these drugs for diabetes and obesity.

How the study worked

Double emulsification combined with interfacial crosslinking to create EXT-loaded core-shell nanoparticles coated with chitosan. Mucus penetration measured using Transwell model. Cellular uptake and transepithelial transport tested in Caco-2/E-12 co-culture model. Pharmacological bioavailability and metabolic outcomes measured in vivo (animal species not specified in abstract but mesh terms indicate rats).

What this study cannot tell us

The 13.29% bioavailability, while impressive for oral peptides, still means nearly 87% of the drug is lost. The study used cell culture models and animal testing — human gut physiology differs significantly. Chitosan nanoparticle manufacturing at pharmaceutical scale presents challenges. Long-term stability and cost-effectiveness haven't been addressed.

How to read the evidence

This is a pharmaceutical technology study combining in vitro characterization (encapsulation, mucus penetration, cell uptake) with in vivo pharmacological testing in rats. The bioavailability and metabolic outcome data are promising but preclinical.

When this study was published

Published in 2025, this is a very recent contribution to the rapidly advancing field of oral peptide delivery nanotechnology.

The bigger picture

Oral semaglutide (Rybelsus) already exists but uses a different approach — an absorption enhancer (SNAC) that creates a local high-concentration environment in the stomach. This nanoparticle approach targets the intestine instead, using chitosan to enhance cellular uptake. Both approaches achieve similar bioavailability ranges (oral semaglutide is roughly 1% bioavailable, but at much higher doses). The nanoparticle approach could potentially be applied to multiple peptide drugs beyond exenatide.

Questions still open

Could this chitosan nanoparticle platform be adapted for oral semaglutide or tirzepatide to improve on current oral formulations?
What is the manufacturing cost comparison between this nanoparticle approach and the current SNAC-based oral GLP-1 technology?
Would the 13.29% bioavailability translate similarly in humans, given differences in gut transit and mucus composition?

Common questions

Why is it so hard to make peptide drugs into pills?

Three major barriers: (1) stomach acid and digestive enzymes destroy peptides; (2) the mucus layer coating the intestine acts as a physical barrier; (3) intestinal cells don't easily absorb large peptide molecules. This study addresses all three — the nanoparticle core protects the drug, and the chitosan coating helps it get absorbed through intestinal cells, achieving 13% bioavailability.

How does this compare to oral semaglutide (Rybelsus)?

Rybelsus uses a completely different strategy — an absorption enhancer (SNAC) that creates a high local drug concentration in the stomach. This nanoparticle approach targets the intestine instead, using chitosan to enhance cellular uptake. The 13.29% bioavailability is significantly higher than Rybelsus' estimated ~1% (though Rybelsus compensates with much higher doses). Both approaches show that oral peptide delivery is possible but challenging.

Read the original research

Chitosan based surface modulation of core-shell nanoparticles for oral delivery of exenatide via balancing mucus penetration and cellular uptake.

International journal of pharmaceutics, 672, 125319

View on PubMed ↗Publisher’s paper ↗

Citation

Li, Yiyao; Tian, Huixian; Zeng, Han; Zhang, Yu; Yin, Tian; He, Haibing; Gou, Jingxin; Tang, Xing. (2025). Chitosan based surface modulation of core-shell nanoparticles for oral delivery of exenatide via balancing mucus penetration and cellular uptake.. International journal of pharmaceutics, 672, 125319. https://doi.org/10.1016/j.ijpharm.2025.125319