2026-05-19 デューク大学
＜関連情報＞
- https://pratt.duke.edu/news/oral-glp-1/
- https://www.cell.com/cell-biomaterials/fulltext/S3050-5623(26)00116-9
ペプチド薬の経口投与のための内在性無秩序タンパク質コーティング Intrinsically disordered protein coating for oral delivery of peptide drugs
Max Ney ∙ Parul Sirohi ∙ Yulia Shmidov ∙ … ∙ Yun-Xing Wang ∙ Priya R. Banerjee ∙ Ashutosh Chilkoti
Cell Biomaterials Published:May 13, 2026
DOI:https://doi.org/10.1016/j.celbio.2026.100460
Graphical abstract
The bigger picture
Oral peptide delivery remains a major challenge because therapeutics, such as glucagon-like peptide-1 (GLP-1) receptor agonists, are rapidly degraded in the stomach and exhibit poor bioavailability. Although bioderived pH-responsive protein coatings were once used to protect sensitive biologics, they were largely replaced by chemically defined synthetic polymers to simplify manufacturing. Advances in gene synthesis and protein design now allow recombinant materials to surpass synthetic polymers in sequence precision and control over supramolecular interactions. Building on these capabilities, we engineered a synthetic intrinsically disordered protein (SynIDP), inspired by the phase-transition behavior of cellular condensates, to create a programmable, sequence-defined enteric coating.
The SynIDP undergoes temperature-triggered liquid-liquid phase separation followed by acid-driven solidification, enabling orthogonal control over assembly and morphology. This dual responsiveness allows us to sculpt arrested spherical condensates with low surface-area-to-volume ratios that maximize protection in gastric acid. SynIDP condensates remain intact beyond typical stomach retention times and then undergo a reversible transition to release active peptide cargo in the neutral intestinal environment. In obese, free-fed mice, SynIDP-coated GLP-1 peptides—combined with a permeation enhancer—produce weight loss outcomes comparable to those of subcutaneous injections. By protecting the drug during fed conditions, this platform may eliminate the fasting requirements associated with current oral formulations such as semaglutide. The SynIDP described here represents the first protein-based coacervate enteric coating with independent pH and temperature control. Its reversible phase behavior also enables scalable, chromatography-free purification, addressing a major bottleneck in protein-based materials manufacturing. This sequence-defined platform offers a bioinspired alternative to synthetic polymers for oral delivery of peptide therapeutics for metabolic disease.
Highlights
- Engineered protein responds to GI environments for intestinal cargo release
- Orthogonal control of phase separation by temperature and solidification by pH
- Solidification and larger droplets enable cargo protection in stomach acid
- SynIDP-coated GLP-1 peptides reduce free-fed mouse weight and blood sugar
Summary
Advancing oral delivery of peptide therapeutics requires innovative materials that overcome gastrointestinal barriers. We introduce an engineered synthetic intrinsically disordered protein (SynIDP) that self-assembles into an enteric coating, encapsulating peptide drugs to enhance gastric acid resistance and intestinal targeting. This SynIDP recapitulates the molecular design principles and phase transitions of native intrinsically disordered proteins (IDPs), enabling it to exhibit temperature-controlled condensation and pH-controlled solidification, with both transitions being reversible in response to intestinal cues. Through analysis of the kinetics of the liquid-to-solid phase transition, we achieve control over the nano-to-microscale morphology of the protein coating, optimizing drug encapsulation and protection. The coating protects peptide-based drugs for over 60 min under simulated gastric conditions, then dissolves to release the active compound. Oral delivery to obese mice results in more consistent weight loss compared with the unencapsulated drug. This modular, protein-based coating is a promising platform technology for enhancing oral peptide drug delivery and improving patient compliance.
