Colon‐Targeted Oral Delivery of Hydroxyethyl Starch–Curcumin Microcapsules Loaded with Multiple Drugs Alleviates DSS‐Induced Ulcerative Colitis in Mice

Abstract Combination therapy through colon‐targeted oral delivery of multiple drugs presents a promising approach for effectively treating ulcerative colitis (UC). However, the codelivery of drugs with diverse physicochemical properties in a single formulation remains a formidable challenge. Here, microcapsules are designed based on hydroxyethyl starch–curcumin (HES─CUR) conjugates to enable the simultaneous delivery of hydrophobic dexamethasone acetate (DA) and hydrophilic cefazolin sodium (CS), yielding multiple drug‐loaded microcapsules (CS/DA‐loaded HES─CUR microcapsules, CDHC‐MCs) tailored for colon‐targeted therapy of UC. Thorough characterization confirms the successful synthesis and exceptional biocompatibility of CDHC‐MCs. Biodistribution studies demonstrate that the microcapsules exhibit an impressive inflammatory targeting effect, accumulating preferentially in inflamed colons. In vivo experiments employing a dextran‐sulfate‐sodium‐induced UC mouse model reveal that CDHC‐MCs not only arrest UC progression but also facilitate the restoration of colon length and alleviate inflammation‐related splenomegaly. These findings highlight the potential of colon‐targeted delivery of multiple drugs within a single formulation as a promising strategy to enhance UC treatment, and the CDHC‐MCs developed in this study hold great potential in developing novel oral formulations for advanced UC therapy.