Background: Hydroxy-α-Sanshool (HAS) possesses various pharmacological properties, such as analgesia and regulating gastrointestinal function. However, the low oral bioavailability of HAS has limited its oral delivery in clinical application. Methods and Results: To enhance its oral bioavailability, a nanocomposite delivery system based on chitosan (CH, as the polycation) and sodium alginate (SA, as the polyanion) was prepared using a layer-by-layer coating technique. The morphology, thermal behavior and Fourier transform infrared spectrum (FTIR) showed that the obtained sodium alginate/chitosan-coated HAS-loaded liposomes (SA/CH-HAS-LIP) with core-shell structures have been successfully covered with polymers. When compared with HAS-loaded liposomes (HAS-LIP), SA/CH-HAS-LIP displayed obvious pH sensitivity and a sustained-release behavior in in vitro studies, which fitted well to Weibull model. In vivo, the half-life of HAS from SA/CH-HAS-LIP remarkably extended after oral administration compared to the free drug. Additionally, it allowed a 4.6-fold and 4.2-fold increase in oral bioavailability, respectively, compared with free HAS and HAS-LIP. Conclusions: SA/CH-HAS-LIP could be a promising release vehicle for the oral delivery of HAS to increase its oral bioavailability.

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.