Oral delivery of therapeutics, particularly peptides, proteins, and nucleic acids, remains a major challenge due to multiple biological barriers within the gastrointestinal (GI) tract. There is a pressing need for systems to stabilize and orally deliver peptides with high bioavailability. Current nanoparticle systems, such as metal-based, lipid-based, and synthetic polymers, have had limited success toward oral delivery due to toxicity, poor mucus penetration, and instability in acidic and enzymatic conditions. Silk nanoparticles (SNPs) offer an effective alternative, combining biodegradability, biocompatibility, tunable size and surface properties, inherent stabilizing effects, and aqueous processing conditions. In this study, we investigated a nanotechnology-based platform using SNPs to enhance peptide-based oral drug absorption. Ourfindings demonstrate that surface modifications like poly(ethylene glycol) allow SNPs to readily penetrate mucus layers, facilitating improved access to the epithelial surface in anintestinal tissue model. Intestine epithelial tight junctions transiently opened after exposure to all particle types and then recovered, suggesting improved permeation of peptide drugs and thus higher bioavailability. SNPs provided high loading efficiency (>80%), sustained release of loaded semaglutide with bioactivity maintained after loading, and exhibited slow degradation under simulated intestinal enzymatic conditions, preserving drug integrity during transit to support oral delivery goals. These findings highlight the potential of SNPs to overcome key GI tract barriers and significantly improve the oral bioavailability of sensitive peptide-based therapeutics. in vitro in vitro in vitro
