Therapeutic Potential of Exosomes in Bone Infection: Mechanisms of Action, Engineering Strategies, and Translational...

Bone infections, including chronic osteomyelitis, implant-associated infection, and infected bone defects, remain among the most refractory challenges in orthopedics, as they involve persistent microbial retention together with defective bone regeneration. Their pathogenesis extends beyond bacterial colonization and reflects a complex interplay among pathogen persistence, dysregulated host immunity, sustained inflammation, impaired bone remodeling, vascular insufficiency, and compromised tissue repair. Exosomes have emerged as promising candidates for bone infection management because of their intrinsic biocompatibility, nanoscale delivery capacity, and ability to integrate multiple biological signals. Accumulating evidence indicates that exosomes can modulate inflammatory amplification, macrophage polarization, pyroptosis, oxidative stress, and immune-bone crosstalk through the transfer of functional cargos, including miRNAs, proteins, lipids, and metabolites. In parallel, exosomes participate in osteogenesis, osteoclast regulation, angiogenesis, and extracellular matrix remodeling, thereby supporting reconstruction of the infected bone microenvironment after pathogen control. Recent advances in engineered exosomes, targeted delivery strategies, and exosome-integrated biomaterials, such as hydrogels, scaffolds, and bone cement, further expand their potential as localized multifunctional therapeutic platforms. Beyond treatment, infection-associated alterations in exosome size distribution, concentration, and cargo profiles suggest their value as liquid biopsy tools for early diagnosis, stratification, and dynamic monitoring of therapeutic response. This review systematically summarizes the pathological basis of bone infection, the biological properties of exosomes, and the emerging mechanisms and applications of exosome-based interventions in infected bone disorders. Particular attention is given to natural and engineered exosomes, drug-loading systems, and exosome-biomaterial composites, as well as their diagnostic and monitoring potential. By integrating antibacterial activity, immune remodeling, vascular restoration, and bone regeneration within the continuum of persistent infection, inflammatory destruction, and regenerative failure, we propose that exosomes are more likely to evolve into integrated therapeutic platforms rather than standalone biological agents.