Engineered macrophage-derived exosomes via click chemistry for the treatment of osteomyelitis

Osteomyelitis is a severe bone condition caused by bacterial infection that can lead to lifelong disabilities or fatal sepsis. Given that the infection is persistent and penetrates deep into the bone tissue, targeting and rapidly treating osteomyelitis remain a significant challenge. Herein, a triblock targeting peptide featuring ROS-cleavable linkage/antibacterial/bone-targeting unit was grafted onto the macrophage-derived exosomes (RAB-EXO). In vitro, the effective eradication of osteomyelitis pathogens MRSA/E. coli and induction of M2 macrophage differentiation were triggered by RAB-EXO. In vivo, after the intravenous administration of RAB-EXO, it can target the bone tissue and release antimicrobial peptides in the high ROS environment of osteomyelitis. The released antimicrobial peptides markedly inhibit bacterial growth at the infection sites. Moreover, M2 differentiation of the bone tissue macrophages are facilitated by EXO, thereby decreasing the inflammatory factors and achieving the anti-inflammatory effect. Finally, the complete healing of osteomyelitis without adverse effects associated with traditional treatments is achieved within 28 days in rat models. Our findings confirm that RAB-EXO, as a targeted treatment for osteomyelitis, offers promising directions for addressing other bacterial infection diseases, such as periodontitis and rheumatoid arthritis, through similar mechanisms.