Single cell multi-omics guided hydrogel enables closed-loop therapy for renal osteodystrophy.

Fracture repair in renal osteodystrophy remains challenging because impaired bone quality compromises fixation stability, while current systemic therapies regulating bone metabolism do not sufficiently address the disease-specific mechanisms underlying defective repair. An integrated strategy combining early fracture stabilization with mechanism-guided local treatment is therefore needed. Here, integrated single-cell RNA sequencing and multi-omics analyses identify inflammatory macrophages as a key pathogenic population, characterized by glycolytic reprogramming driven by hypoxia-inducible factor 1 alpha and phosphofructokinase-2/fructose-2,6-bisphosphatase 3, together with acidic metabolite accumulation. We show that this inflammatory acidic niche suppresses bone formation, enhances bone resorption and impairs regeneration. Guided by this mechanism, we develop a microenvironment-responsive adhesive hydrogel formed from a gelatin-boronic acid conjugate and sodium alginate and loaded with Epimedium-derived extracellular vesicle-like nanoparticles. We demonstrate that the hydrogel provides early local stabilization, enables microenvironment-responsive nanoparticle release and regulates the pathological niche. In vitro and in vivo, we find that the system suppresses inflammatory macrophage activation, promotes osteogenesis, inhibits osteoclastogenesis and accelerates fracture healing in a renal osteodystrophy model. These findings reveal a disease-specific mechanism of defective bone repair and provide a closed-loop therapeutic strategy that integrates local stabilization with microenvironment-directed treatment for fractures associated with renal osteodystrophy.