Silk nanoparticles enhance oral semaglutide delivery by improving mucus penetration and transiently opening tight junctions in vitro.

Oral delivery of peptides, proteins, and nucleic acids faces significant hurdles due to the harsh environment of the gastrointestinal (GI) tract, including enzymatic degradation, acidic conditions, and poor permeability across biological barriers. Current nanoparticle systems often fall short due to toxicity, instability, or inadequate mucus penetration, limiting the bioavailability of sensitive therapeutics. There's a critical need for biocompatible and stable platforms to overcome these challenges and enable effective oral peptide absorption.

Researchers developed Silk nanoparticles (SNPs), some surface-modified with poly(ethylene glycol), to investigate their potential for oral peptide delivery in vitro. They assessed SNP performance by evaluating mucus layer penetration and transient opening of epithelial tight junctions in an in vitro intestinal tissue model. The study also measured the loading efficiency, sustained release profile, and degradation kinetics of loaded semaglutide under simulated intestinal enzymatic conditions to mimic GI transit.

The study demonstrated that surface modifications, such as poly(ethylene glycol), enabled SNPs to readily penetrate mucus layers, significantly improving access to the epithelial surface in an in vitro intestinal tissue model. Epithelial tight junctions transiently opened after exposure to all particle types, subsequently recovering, suggesting enhanced permeation of peptide drugs. This transient opening could lead to higher bioavailability. SNPs also provided a high loading efficiency of >80% for semaglutide. > The loaded semaglutide maintained its bioactivity and exhibited sustained release, along with slow degradation under simulated intestinal enzymatic conditions, preserving drug integrity during transit.