Multifunctional macrophage mimetic nanoplatform modulates vascular and epithelial double gut barriers to alleviate...

Rationale: In ulcerative colitis (UC), microbial products or metabolites, coupled with inflammatory stimuli, result in simultaneous damage to both the intestinal epithelial barrier (IEB) and gut vascular barrier (GVB). Current UC treatments usually focus on modulating IEB, whereas GVB-which critically regulates the translocation of gut microbiota and metabolites into systemic circulation-has been largely overlooked. Here, we developed a facile, biomimetic strategy to engineer anti-inflammatory berberine/magnolol self-assembled nanoparticles (BM NPs) using macrophage membrane camouflage, enabling targeted UC accumulation and dual restoration of both the IEB and GVB. Methods: BM NPs employing macrophage membranes to camouflage mimetic nanoplatform. The mimetic nanoplatform on targeting capacity of inflamed intestinal epithelial cells, M1/M2 polarization, macrophage and intestinal epithelial cell inflammatory factors, and vascular endothelial cell migration and tube-forming were evaluated in vitro. Furthermore, its therapeutic efficacy was assessed in a mice UC model, demonstrating significant reductions in bacterial translocation, restoration of both the IEB and GVB, and modulation of the inflammatory immune microenvironment. Results: The biomimetic nanoplatform demonstrates superior targeting specificity and prolonged retention in inflamed intestinal epithelium and vascular tissues. Macrophage membranes achieve GVB repair by mechanical traction and physical adsorption of inflammatory factors. Besides, efficient delivery of the loaded anti-inflammatory drugs also achieves the repair of the IEB. GVB repair effectively prevents systemic dissemination of gut-derived microbes and their metabolites, thereby attenuating UC-induced inflammatory cascades. Collectively, this approach significantly ameliorates colonic pathology in UC. Conclusion: Our study proposes the synergistic repair of IEB and GVB through the mechanical traction and physical adsorption of macrophage membranes, assisted by anti-inflammatory components, which provide new insights as well as a new paradigm for the treatment of UC.