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<p>Ulcerative colitis (UC) is an immune-mediated chronic inflammatory bowel disease that severely impairs patients’ quality of life. Efficient oral colon-targeted delivery systems are urgently needed to improve local therapeutic efficacy while minimizing systemic exposure. Herein, we developed a pH-responsive Eudragit S100-coated coacervate microdroplet system for the oral delivery of natural <i>Bletilla striata</i> polysaccharide (BSP), termed BSP@EU-Coac. The optimized BSP@EU-Coac microdroplets exhibited a spherical morphology with an average hydrodynamic diameter of 3.86 ± 0.82&#xa0;μm, an encapsulation efficiency of 85.03 ± 3.66%, and a drug loading capacity of 9.29 ± 0.93%. In vitro release studies showed that BSP@EU-Coac effectively limited premature BSP release under simulated gastric and small intestinal conditions, while achieving pH-triggered sustained release in simulated colonic medium, with a cumulative release of approximately 88.25% within 96&#xa0;h. In vitro assays further demonstrated that BSP@EU-Coac showed good cytocompatibility at the working concentration and markedly reduced intracellular ROS levels, with ROS fluorescence intensity decreased by 53.95% and 51.13% in RAW264.7 macrophages and Caco-2 cells, respectively. After oral administration, fluorescence imaging confirmed that BSP@EU-Coac preferentially accumulated in the inflamed colon and maintained detectable colonic retention for up to 24&#xa0;h. In a DSS-induced colitis mouse model, BSP@EU-Coac significantly alleviated UC symptoms, as evidenced by improved body weight recovery, reduced disease activity index, and restoration of colon length from 4.99 ± 1.23&#xa0;cm in the model group to 8.66 ± 1.92&#xa0;cm. Mechanistically, BSP@EU-Coac modulated macrophage polarization by reducing the M1-like CD86⁺CD206⁻ population from 29.26% to 8.95% and increasing the M2-like CD86⁻CD206⁺ population to 20.70%, accompanied by suppressed pro-inflammatory cytokine expression, enhanced tight junction protein expression, reduced oxidative stress, and partial restoration of gut microbiota homeostasis. Overall, this study demonstrates that BSP@EU-Coac is a promising oral colon-targeted polysaccharide delivery platform for UC therapy through integrated regulation of oxidative stress, immune response, epithelial barrier repair, and gut microbiota.</p> Graphical Abstract <p></p>

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Colon-targeting pH-responsive Bletilla striata polysaccharide coacervate microdroplets for ulcerative colitis therapy via macrophage reprogramming

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月20日

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  • Qiantao Zhang,
  • Lai Chai,
  • Hui Liu,
  • Xueer Hu,
  • Yujing Niu,
  • Hongli Cao,
  • Xin Rao,
  • Mingyuan Zhou,
  • Yuchi Chen,
  • Xiaoqing Ye,
  • Fangmei Zhou,
  • Zhishan Ding,
  • Bingqi Zhu

摘要

Ulcerative colitis (UC) is an immune-mediated chronic inflammatory bowel disease that severely impairs patients’ quality of life. Efficient oral colon-targeted delivery systems are urgently needed to improve local therapeutic efficacy while minimizing systemic exposure. Herein, we developed a pH-responsive Eudragit S100-coated coacervate microdroplet system for the oral delivery of natural Bletilla striata polysaccharide (BSP), termed BSP@EU-Coac. The optimized BSP@EU-Coac microdroplets exhibited a spherical morphology with an average hydrodynamic diameter of 3.86 ± 0.82 μm, an encapsulation efficiency of 85.03 ± 3.66%, and a drug loading capacity of 9.29 ± 0.93%. In vitro release studies showed that BSP@EU-Coac effectively limited premature BSP release under simulated gastric and small intestinal conditions, while achieving pH-triggered sustained release in simulated colonic medium, with a cumulative release of approximately 88.25% within 96 h. In vitro assays further demonstrated that BSP@EU-Coac showed good cytocompatibility at the working concentration and markedly reduced intracellular ROS levels, with ROS fluorescence intensity decreased by 53.95% and 51.13% in RAW264.7 macrophages and Caco-2 cells, respectively. After oral administration, fluorescence imaging confirmed that BSP@EU-Coac preferentially accumulated in the inflamed colon and maintained detectable colonic retention for up to 24 h. In a DSS-induced colitis mouse model, BSP@EU-Coac significantly alleviated UC symptoms, as evidenced by improved body weight recovery, reduced disease activity index, and restoration of colon length from 4.99 ± 1.23 cm in the model group to 8.66 ± 1.92 cm. Mechanistically, BSP@EU-Coac modulated macrophage polarization by reducing the M1-like CD86⁺CD206⁻ population from 29.26% to 8.95% and increasing the M2-like CD86⁻CD206⁺ population to 20.70%, accompanied by suppressed pro-inflammatory cytokine expression, enhanced tight junction protein expression, reduced oxidative stress, and partial restoration of gut microbiota homeostasis. Overall, this study demonstrates that BSP@EU-Coac is a promising oral colon-targeted polysaccharide delivery platform for UC therapy through integrated regulation of oxidative stress, immune response, epithelial barrier repair, and gut microbiota.

Graphical Abstract