Abstract

Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by oxidative stress, and impaired intestinal barrier. Current therapies often fail to address the multifaceted nature of the disease. Herein, we developed a novel therapeutic small-molecule coacervate microdroplets formed by the multiple physical interaction between thioctic acid (TA) and spermidine (SP). TA-SP coacervate microdroplet is easily prepared by simply dispersing TA powders in SP solution, without addition of any toxic organic solvents. Besides, this TA-SP coacervate microdroplet exhibits the exceptional wetting and mucoadhesive properties. Crucially, upon rectal administration, it undergoes an in-situ phase transition from a liquid-like microdroplet to a dense hydrogel, significantly prolonging its retention at the colonic site. In DSS-induced murine colitis model, TA-SP coacervate microdroplets demonstrated the superior therapeutic efficacy compared to individual components, effectively alleviating disease severity, reducing colon shortening, and restoring histological architecture. Moreover, the pro-inflammatory cytokines (TNF-α, IL-6, IL-1β) inside colitis colon was potently suppressed by TA-SP coacervate microdroplets via promoting the restorative M2 macrophage phenotype. Importantly, it repaired the gut mucosal barrier by restoring goblet cell function, mucin secretion, and tight junction proteins (ZO-1, OCLN and CLDN-5). Besides, TA-SP coacervate could effectively normalized gut microbial ecosystem of colitis mice via suppressing the expansion of pro-inflammatory pathobionts while promoting the recovery of beneficial commensals. Mechanistic studies revealed dual modes of action, that was, TA-SP not only functioned as a ROS scavenger to rebalance the oxidative-redox homeostasis via the Nrf2-Keap1 pathway but also severed as a potent autophagy-inducer to repair the epithelial