Xiaoyankangjun tablet (XYKJP) is a traditional Chinese medicine formulation used to treat intestinal disorders in clinical practice. However, the specific therapeutic mechanism of action of XYKJP in colitis has not yet been elucidated. This study aimed to reveal the multifaceted mechanisms of action of XYKJP in treating colitis. The model established based on DSS-induced colitis in C57BL/6 mice was employed to estimate the effect of XYKJP on colitis, which was then followed by histological assessment, 16S rRNA sequencing, RT-qPCR, ELISA, and Western blot. XYKJP alleviated the symptoms of DSS-induced colitis mainly by reducing oxidative stress, inflammatory responses, and intestinal mucosal repair in colitis tissues. In addition, XYKJP regulated the intestinal flora by increasing the relative abundance of Akkermansia and Bifidobacterium and reducing the relative abundance of Coriobacteriaceae_UCG-002. Mechanistically, XYKJP increased the content of short-chain fatty acids (SCFAs) in the feces, particularly propanoic acid and butyric acid, activated their specific receptor GPR43/41, furthermore activated the Nrf2/HO-1 pathway, and suppressed the JAK2/STAT3 pathway. XYKJP significantly alleviated the symptoms of experimental colitis and functioned synergistically by regulating the intestinal flora, increasing the production of SCFAs, and activating their specific receptors, thereby repressing oxidative stress and inflammation. Graphical Abstract

Background/Objectives: Isoliquiritigenin (ISL) possesses excellent anti–inflammatory and colonic mucosal repair activities, showing promising potential for colitis treatment. However, the clinical application of native ISL is severely restricted by its poor water solubility, low in vivo bioavailability, and insufficient colon tissue accumulation. To solve these inherent delivery defects of free ISL, this study aimed to construct a novel oral colon–targeted solid nanoparticle–hydrogel composite delivery system and explore its therapeutic efficacy and underlying mechanisms for colitis therapy. Methods: ISL–loaded poly (lactic-co–glycolic acid)/polycaprolactone solid nanoparticles (IPP NPs) were first fabricated to improve the water solubility and in vivo delivery efficiency of free ISL. Thereafter, IPP NPs were encapsulated into a composite hydrogel network consisting of sodium alginate, chitosan, and squid ink polysaccharide to prepare the colon–targeted IPP@Gels. The pH–responsive drug release behavior of the composite system in the upper gastrointestinal tract was verified via in vitro characterization experiments. A dextran sulfate sodium (DSS)–induced murine colitis model was established to evaluate the in vivo therapeutic effects of IPP@Gels. The regulatory effects of the delivery system on intestinal tight junction protein expression, proinflammatory cytokine levels, gut microbiota composition, and short–chain fatty acid (SCFA) content were further investigated. Results: The constructed IPP@Gels exhibited favorable pH–responsive performance, which effectively inhibited the premature release of ISL in the upper gastrointestinal tract and achieved precise colon localization and sustained drug release. In vivo experimental results demonstrated that IPP@Gels significantly alleviated the pathological symptoms of colitis in model mice. Mechanistically, the composite system prominently upregulated the expression of intestinal tight junction proteins, reduced the secretion of proinflammatory cytokines, effectively enriched ISL accumulation in colon tissues, reversed gut microbiota dysbiosis, and increased the content of intestinal SCFAs, thereby producing synergistic anti-colitis therapeutic effects. Conclusions: The constructed SA/CS/SIP composite hydrogel (IPP@Gels), embedded with ISL–loaded nanoparticles, exhibits favorable biocompatibility and pH-responsive release behavior, enabling colon-localized retention of ISL. This novel oral drug delivery system mitigates several delivery–related drawbacks of free ISL and confers beneficial therapeutic effects in experimental colitis. It provides a feasible oral formulation strategy for colon–localized delivery of poorly soluble drugs and offers promising prospects for the management of colitis.