Abstract

Background The natural compound celastrol (Cel) mitigates ulcerative colitis (UC) progression by modulating macrophage polarization. However, its clinical application is limited by poor solubility, a lack of specific targeting, and potential toxicity. This study aimed to develop a targeted and safe drug delivery system and evaluate its therapeutic efficacy in UC treatment. Methods Glycyrrhizic acid (GA) was used as a substitute for cholesterol (CHO) to formulate novel liposomes (LPs), GA-LPs@Cel. Macrophage membranes (MM) derived from RAW264.7 cells were then coated onto GA-LPs@Cel, creating MM-GA-LPs@Cel, which was characterized. The targeted delivery capability, pharmacological activity, and biosafety of MM-GA-LPs@Cel were evaluated via in vitro and in vivo models. Results Compared with traditional CHO-LPs@Cel, GA-LPs@Cel presented enhanced anti-inflammatory properties and reduced toxicity. MM-GA-LPs@Cel demonstrated superior active targeting and immune evasion ability. It inhibited proinflammatory factor secretion by modulating macrophage polarization, facilitated intestinal barrier repair, and exhibited significant therapeutic effects against UC. The biomimetic system also reduced Cel-associated toxicity. Conclusion This study developed MM-coated LPs (MM-GA-LPs@Cel) with superior ability and safety. In UC animal models, this delivery system improved the therapeutic efficacy of Cel and reduced toxicity, suggesting a promising approach for the clinical management of UC.