Self-assembled redox-responsive prodrug nanoparticles based on thioketal-geraniol conjugate for ulcerative colitis therapy

Ulcerative Colitis (UC) is a multifaceted disease characterized by disruptions in the intestinal microenvironment and gut microbiota homeostasis, which is exacerbated by increased reactive oxygen species (ROS). Geraniol is a natural acyclic monoterpene with potent antioxidant and anti-inflammatory properties. However, its clinical translation is severely constrained by poor water solubility and low bioavailability. To overcome these limitations, we exploited the ROS-responsive thioketal linkage to construct a prodrug nano-delivery system that enhances the biocompatibility, stability, and targeted transport characteristics of geraniol. The resulting TKG@NPs exhibited ROS-responsive release behavior, preferential geraniol release within the oxidative microenvironment of the inflamed colon. In vitro, TKG@NPs improved the cellular uptake of geraniol, markedly suppressed ROS overproduction and inhibited the polarization of macrophages toward the pro-inflammatory M1 phenotype. In vivo, TKG@NPs effectively alleviated dextran sodium sulfate colitis (DSS)-induced colitis and preserved colonic tissue integrity, as evidenced by the suppression of pro-inflammatory mediators and the concomitant upregulation of anti-inflammatory mediators. Furthermore, TKG@NPs not only maintained the expression of tight junction proteins (ZO-1 and Occludin) but also supported intestinal homeostasis by enriching beneficial bacteria while suppressing pathogenic bacteria. In conclusion, the geraniol delivery system shows potential for oral administration of hydrophobic bioactive compounds in UC interventions.