Metabolic glycoengineered exosome-A2M nanoplatform reprograms macrophage polarization and orchestrates bone regeneration in ONFH.

Osteonecrosis of the femoral head (ONFH), driven by glucocorticoid-induced M1 macrophage polarization and disrupted inflammatory homeostasis, poses a critical challenge in orthopedics. Here, we engineered adipose-derived mesenchymal stem cell exosomes (ADMSC-Exos) via metabolic glycoengineering (MGE) to deliver α2-macroglobulin (A2M), generating DS-exo@A2M. This nanoconstruct synergistically suppressed M1 polarization ( ↓ TNF-α, ↓IL-6) and promoted M2 polarization (↑CD206, ↑Arg-1) in M1 macrophages through IL-4 signaling activation, evidenced by transcriptomic/proteomic profiling and shRNA-mediated IL-4 knockdown. DS-exo@A2M further enhanced osteogenic differentiation of bone marrow-derived mesenchymal stem cells (BMSCs) by upregulating RUNX2, ALP, and OCN. In a rat ONFH model, DS-exo@A2M restored trabecular architecture ( ↑ BV/TV, ↓Tb.Sp) and reduced bone marrow edema. Mechanistically, IL-4 silencing abolished DS-exo@A2M-mediated macrophage reprogramming and osteogenesis, confirming pathway specificity. This study establishes a precision nanotherapeutic strategy for ONFH by integrating exosome engineering, immunomodulation and biosafety assessment, offering a translational framework for treating inflammation-associated bone disorders.