Hydroxyethyl starch serves as a superior vehicle for colon-targeted delivery of indole-3-acetic acid to enhance therapeutic efficacy against colitis.

Indole-3-acetic acid (IAA), a crucial tryptophan-derived metabolite, exerts anti-inflammatory and immunomodulatory effects primarily through activation of aryl hydrocarbon receptor (AhR) and modulation of gut immune homeostasis, providing a mechanistic rationale for its use in colitis. Colon-targeted delivery of IAA to colon remains essential for maximizing its efficacy. Hydroxyethyl starch (HES), a biocompatible biodegradable polymer, is an ideal drug delivery platform. Its multi-branched structure enables efficient loading and colon-targeted sustained release of IAA. HESIAA was synthesized by esterifying IAA to HES using 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride in DMSO. The degree of substitution (DS) was controlled by varying the IAA-to-HES molar ratio (0.5:1, 0.7:1, and 1:1) and confirmed by NMR integration. The changes in structure, physicochemical properties and in vivo colon-targeted delivery effect of HESIAA with different DSs were comparatively investigated. SEM revealed disrupted granule surfaces with increased roughness, which enhanced surface area for drug loading and facilitated subsequent release. Among the tested DS values, DS 0.37 showed the most favorable colon-targeted delivery profile, supported by release/biodistribution data.16S rRNA sequencing showed that HESIAA increased beneficial gut bacteria like S24-7 and Bacteroidetes while lowering the Firmicutes/Bacteroidetes ratio. In vivo studies demonstrated that HESIAA (DS 0.37) showed enhanced therapeutic efficacy against colitis compared to IAANa under consistent IAA administration, by upregulating anti-inflammatory cytokines (IL-10 and IL-22), downregulating pro-inflammatory mediators (IL-1β, IL-6, and IFN-γ), and reinforcing intestinal barrier integrity via upregulation of tight junction proteins (Claudin-1 and ZO-1). These findings establish HESIAA with a DS of 0.37 as a promising therapeutic candidate for colitis intervention.