Intrinsically disordered protein coating for oral delivery of peptide drugs.

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.