An engineering thermosensitive hydrogel enema encapsulating 5-amino salicylic acid-based deep eutectic solvent for enhanced and targeted ulcerative colitis therapy

A multiscale engineering strategy integrates THEDES with thermosensitive hydrogels. • THEDES enhances 5-ASA solubility, permeability, and anti-inflammatory efficacy. • THEDES-Gel enables prolonged colonic retention and controlled release. • THEDES-Gel provides a versatile platform for insoluble drugs for UC treatment. Overcoming the low aqueous solubility, poor mucosal permeability, and imprecise delivery of drugs remains a critical challenge in pharmaceutical engineering. Herein, we designed a novel therapeutic deep eutectic solvent (THEDES) using 5-aminosalicylic acid (5-ASA) and L-arginine (Arg) at a molar ratio of 1: 1.4, which functioned as both a solubilizer and osmotic enhancer of 5-ASA. THEDES showed satisfactory viscosity (61.7 ± 1.3 Pa·s), pH (8.9), zeta potential (−12.0 ± 1.4 mV), and anti-inflammatory activity when using in colonic microenvironment. To address the subsequent challenges of rapid clearance and leakage of THEDES at the colon lesion site, THEDES was loaded into a poloxamer 407 hydrogel with methylcellulose as the adhesive to construct an in-situ gelling enema system (THEDES-Gel). Notably, the engineered THEDES-Gel significantly prolonged colonic retention compared to THEDES alone, while achieving a high cumulative release rate of 5-ASA (97.0 ± 0.8% at 6 h) under the effect of “Push-Pull-Permeate”. Furthermore, THEDES-Gel was demonstrated to have a significant alleviating effect during the treatment of UC in mice by reducing inflammation and maintaining the normal structure of colonic tissue. THEDES-Gel demonstrates a rational materials design strategy that couples molecular-scale solvent engineering of drugs with macroscopic drug delivery system fabrication for the efficient utilization of insoluble drugs.