Dynamic Covalent Disulfide Exchange Mediates Oral Delivery of Biomacromolecules

Abstract The biological barriers present in the intestine thwart the absorption of orally delivered biologics, which, if overcome, would reduce the injection burdens for millions of patients. Here, we present a straightforward yet effective oral biologic formulation, which utilizes in-situ growing poly(disulfide)s as the sole excipient to circumvent all intestinal barriers in a noninvasive way. We find that, through dynamic covalent disulfide exchange initiated by the thiols in mucins, epithelial membranes, and hepatic sinusoids, digestion-resistant complex coacervates formed from insulin (as a model drug) and guanidinium-containing poly(disulfide)s readily traverse the mucus and epithelial layers without remodeling the barriers’ integrity, and then undergo dissociation to release insulin in the liver. Oral gavage of the complex coacervates with enteric capsules into diabetic mice and swine models elicited a-few-hour longer hypoglycemic effect than subcutaneously injected insulin, attaining relative bioavailabilities over 20%. 14-day dosing experiments demonstrated the postprandial and daily glycemic control capacity and the biosafety of this oral insulin. The generality of this formulation scheme was further validated with human serum albumin and salmon calcitonin.