Muco-infiltrating prodrug coacervates with prolonged colonic retention enhance IBD-associated depression therapy

Abstract

Oral delivery of small-molecule drugs to the distal intestine is often hindered by short colonic retention, a key requirement for ensuring sustained colonic drug availability. Herein, we developed a library of minimalist, muco-infiltrating prodrug coacervates by exploiting the interfacial physics of liquid–liquid phase separation (LLPS). By systematically tuning the length of poly(ethylene glycol) (PEG) spacer and the hydrophobicity of drug stickers in PEG–drug conjugates, we precisely modulated the molecular amphiphilicity to generate liquid coacervates with ultralow interfacial tension against water (< 1 mN/m). These liquid coacervates actively spread across and infiltrate the freshly isolated intestinal mucus in vitro. As a proof-of-concept, butyrate coacervate (P6-ButCoa) accumulated in the cecum and colon within 2 hours post-oral administration and persisted for over 18 hours. The prolonged colonic retention time facilitates sustained, enzyme-responsive drug release, which significantly ameliorates dextran sulfate sodium (DSS)-induced colitis and associated depressive behaviors by markedly enhancing drug availability primarily in the colon, with subsequent bioavailability in the brain. These findings demonstrate that leveraging interfacial physics to guide mucus infiltration of coacervates offers a versatile strategy for sustained oral drug delivery to the distal intestine.