Extracellular Vesicles in Osteonecrosis of the Femoral Head: An Integrated Review of Experimental and Bioinformatic Evidence.

Background/Objectives: Osteonecrosis of the femoral head (ONFH) is a progressive condition characterized by bone necrosis, impaired vascularization, and immune dysregulation, often resulting in femoral head collapse. Effective strategies to halt disease progression are limited. Extracellular vesicles (EVs), including exosomes and microvesicles, mediate intercellular communication and influence osteogenesis, angiogenesis, and immune responses. This review summarizes current evidence on EVs in ONFH and their translational potential. Methods: A structured narrative review of PubMed, Scopus, Web of Science, and Cochrane Central databases was conducted, including in vitro, preclinical, and clinical studies on EVs in ONFH. Data on EV sources, molecular cargo, signaling pathways, functional effects, and translational implications were qualitatively synthesized. No pooled statistical analysis was performed because the extracted data were heterogeneous. Bioinformatic analyses such as Gene Ontology, KEGG enrichment, and protein-protein interaction networks were also summarized. Results: In vitro, EVs from bone marrow mesenchymal stem cells, endothelial cells, and M2 macrophages modulate osteogenic differentiation, angiogenesis, and inflammation. Preclinical studies demonstrate that EV administration reduces femoral head necrosis, improves trabecular structure, and enhances neovascularization. Clinical studies have identified EV-associated molecules (SAA1, C4A, RPS8) linked to disease stage and the risk of femoral head collapse. Bioinformatic analyses connect EV cargo to pathways regulating bone formation, vascularization, immunity, and metabolism. Conclusions: EVs appear to play key roles in ONFH pathogenesis and may represent promising candidates for diagnostic and therapeutic applications. However, current clinical evidence remains limited and requires validation in larger studies. Nonetheless, heterogeneity and limited clinical data require standardized, longitudinal studies to validate their translational relevance.