Application of stem cell-derived exosomes in bone and joint diseases: Recent advances enabled by diverse carrier...

Bone and joint diseases, such as osteoarthritis, exhibit significant pathological complexity. Current treatment modalities possess notable limitations, driving the development of cell-free regenerative treatment strategies centered on stem cell-derived exosomes, particularly mesenchymal stem cell-derived exosomes. Despite the promise of mesenchymal stem cell-derived exosomes, several challenges impede their clinical translation. These include rapid in vivo clearance of exosomes, insufficient targeting specificity, and the difficulty of dynamically regulating the pathological microenvironment with a single delivery approach. In recent years, optimizing exosome functionality and achieving precise delivery through carrier technologies has emerged as a pivotal strategy to overcome these barriers. This review systematically evaluates the latest advancements in cutting-edge carrier technologies. These encompass biomaterial scaffolds (e.g., three-dimensional bio-printed GA/HA composite scaffolds), hydrogels, engineered and modified exosomes (e.g., cartilage affinity peptide CAP-exoASO), and nanomicrosphere co-loading systems. Research findings demonstrate that these carrier technologies enhance cartilage repair and anti-inflammatory effects via multiple mechanisms, including extending the half-life of exosomes, improving cartilage-targeting specificity, and enabling synergistic immune regulation, such as promoting M2 macrophage polarization. Preclinical studies have validated the potential of these carrier technologies. However, critical issues remain, including standardizing production processes, ensuring long-term biological safety, and evaluating cross-species efficacy. Looking ahead, multimodal delivery systems integrating gene editing, intelligent responsive materials, and personalized treatment strategies are expected to revolutionize bone and joint disease treatment by transitioning from symptom alleviation to functional reconstruction.