Engineered synbiotic microspheres enable system-level reprogramming of the gut-immune-vascular axis in chronic inflammatory vascular disease.

Chronic inflammatory vascular diseases are increasingly recognized as systemic disorders sustained by maladaptive cross-organ immunometabolic coupling, yet current therapeutic strategies remain largely lesion-centered and fail to address upstream drivers of disease persistence. Here, we identify the gut-immune-vascular axis as a system-level pathogenic unit that integrates gut microbial dysbiosis, intestinal barrier dysfunction, metabolic imbalance, and vascular immune activation into a self-reinforcing pathological circuit. Through integrated clinical profiling and cross-species validation, we demonstrate that disruption of this axis is characterized by coordinated probiotic depletion, expansion of proinflammatory taxa, translocation of microbial endotoxins, accumulation of microbiota-derived metabolites, and macrophage polarization toward a proinflammatory phenotype along the gut-vascular continuum. To therapeutically target this axis, we engineer enzyme-responsive synbiotic microspheres that codeliver probiotics, a microbial metabolic pathway inhibitor, and a prebiotic within a protective polymeric matrix, enabling site-specific intestinal activation and coordinated microbiota-metabolic modulation. This engineered system restores intestinal barrier integrity, reprograms microbial ecology and metabolite output, suppresses immunometabolic dysfunction, and robustly attenuates pathological vascular remodeling across cellular, murine, and large-animal models, with in-stent restenosis serving as a representative disease context. Collectively, this work establishes axis-oriented immunometabolic reprogramming as a generalizable therapeutic paradigm and highlights engineered synbiotic platforms as scalable tools for system-level intervention in chronic inflammatory diseases.