Bioengineered Probiotic‐Prebiotic Hierarchical Microspheres With pH‐Responsive Architecture Reprogram Immunometabolism in Obesity‐Related Disorders

ABSTRACT Obesity is increasingly recognized as a chronic immunometabolic disorder driven by dysregulated gut‐adipose communication and microbiota imbalance. Here, we present bioengineered pH‐responsive probiotic‐prebiotic hierarchical microspheres (MicroSym) that coordinate localized microbial restoration with systemic immune reprogramming to treat obesity‐related disorders. MicroSym is fabricated via microfluidic‐assisted phase separation coupled with electrostatic spraying, embedding probiotic bacteria within a lotus‐derived prebiotic matrix to form a protective yet responsive microenvironment that preserves viability during gastric transit. At intestinal pH, the hierarchical architecture selectively disassembles to release probiotics and prebiotic substrates, fostering beneficial colonization and metabolite production. This symbiotic modulation reshapes the gut immune landscape, suppresses proinflammatory macrophage polarization, and restores adipose tissue homeostasis. In diet‐induced obese mice, oral treatment with MicroSym remodels the gut microbiota, improves glucose tolerance, reduces lipid accumulation, and normalizes cytokine profiles without overt toxicity. Transcriptomic profiling and microbiome analyses further validate comprehensive systemic immunometabolic benefits. Collectively, this work establishes a biofabricated symbiotic microsphere platform for controlling microbiota‐immune‐metabolic crosstalk and offers a translatable therapeutic strategy for obesity‐associated immunometabolic disease.