Zein-based nanoparticles enable oral co-delivery of insulin and liraglutide, restoring glucose in hyperglycemic zebrafish.

Oral delivery of peptide therapeutics faces significant hurdles, primarily enzymatic degradation within the gastrointestinal tract and poor intestinal permeability, leading to low bioavailability. Current injectable therapies, while effective for conditions like type 2 diabetes mellitus and obesity, often suffer from patient adherence issues. Developing a stable, orally administrable platform for peptides like insulin and glucagon-like peptide-1 (GLP-1) analogs, which target GLP-1 receptors to regulate glucose metabolism, represents a critical unmet need to enhance patient convenience and treatment efficacy.

Researchers developed hybrid zein-Eudragit RS100-chitosan nanoparticles (Z-ERS-CS/I-LIRA) for the oral co-delivery of insulin and liraglutide. The nanoparticles were prepared via nanoprecipitation and characterized for physicochemical properties, including size, polydispersity, and zeta potential. Structural and thermal analyses (FTIR, XRD, TGA, DSC) confirmed peptide incorporation. In vitro, stability under refrigerated conditions, mucoadhesion, and peptide release profiles were assessed in PBS (pH 7.4) and simulated gastrointestinal conditions. Preliminary in vivo evaluation was performed in adult zebrafish using a glucose-induced hyperglycemia model, comparing Z-ERS-CS/I-LIRA treatment to healthy controls and unloaded nanoparticles for toxicity and antidiabetic activity.

The developed Z-ERS-CS/I-LIRA nanoparticles exhibited suitable physicochemical properties, with a nanoscale size of approximately 230 nm, low polydispersity (PDI <0.1), and a positive zeta potential of ~+46 mV. Structural analyses confirmed effective incorporation of both peptides into a predominantly amorphous and molecularly dispersed system. Under simulated gastrointestinal conditions, the nanoparticles provided significant protection, showing minimal peptide release (<15%). In contrast, a biphasic release profile was observed in PBS (pH 7.4), with cumulative release values of approximately 87% for insulin and 58% for liraglutide after 48 h. Unloaded nanoparticles demonstrated preliminary biocompatibility in adult zebrafish, causing no mortality or significant toxicological alterations. > In the glucose-induced hyperglycemia model, oral administration of Z-ERS-CS/I-LIRA effectively reduced blood glucose levels to those comparable with healthy controls, preserving the antidiabetic activity of the encapsulated peptides. However, hemorrhagic and pancreatic alterations were noted in liraglutide-containing groups.