A Review of Osteosarcoma-Derived Exosomes in Tumor Progression, Chemoresistance, and Bone Regeneration, and Their Potential in Drug Delivery

Exosomes, as critical mediators of intercellular communication, transport nucleic acids, proteins, and lipids that drive osteosarcoma (OS) progression and dynamically remodel the tumor microenvironment.Their distinctive biological properties-including low immunogenicity, high stability, and inherent targeting capability-position them as versatile tools across the entire OS management continuum, from early non-invasive diagnosis via liquid biopsy to targeted biotherapy and postoperative bone regeneration through coordinated osteogenesis-angiogenesis coupling.This review first outlines the epidemiological features and principal clinical bottlenecks of OS, then systematically summarizes exosome biogenesis, cellular uptake mechanisms, and the key molecular pathways through which exosomal cargoes regulate OS malignancy.We highlight emerging evidence that exosomal biomarkers enable real-time disease monitoring and that engineered exosomes serve as precision nanocarriers for therapeutic delivery.Notably, we emphasize recent insights into exosome-mediated crosstalk with immune cells within the osteoimmune microenvironment, their role in orchestrating vascularized bone formation, and advances in exosome-functionalized biomaterial scaffolds that effectively bridge tissue engineering with oncology.The clinical relevance of these findings lies in their potential integration into a unified diagnostic-therapeutic-regenerative paradigm, which may help overcome current limitations in surgical outcomes and chemoresistance.Nevertheless, clinical translation remains hindered by persistent challenges, including the lack of standardized isolation and characterization protocols, suboptimal in vivo delivery efficiency, batch-to-batch variability, and insufficient long-term safety data.Addressing these obstacles will require further mechanistic studies and multicenter clinical trials to establish robust regulatory frameworks.This article aims to review the roles of osteosarcoma-derived exosomes in tumor progression, chemoresistance, and bone regeneration, as well as their potential for drug delivery.