Engineered Peptide Nanoparticle Targeting Both Bacterial Load Reduction and Bone Repair for the Treatment of Bone Infections

Abstract Bone infection is a common and serious complication in orthopedic surgery. Conventional antibiotic strategies frequently induce antibiotic resistance, leading to the persistence of bone infections. In this study, an engineered peptide nanoparticle named C8-IK21 was designed based on the coiled-coil motif. Specifically, C8-IK21 effectively targeted bacterial cell membranes, further exacerbating bacterial death through lipid peroxidation. At safe doses, local administration of C8-IK21 demonstrated high efficacy in treating S. aureus-infected cortical bone defects in mice. No detectable resistance emerged under the tested experimental conditions. Additionally, C8-IK21 exhibited anti-inflammatory activity. Furthermore, C8-IK21 could enter cells by binding to ADAM9, activating the ERK signaling pathway to regulate osteoblast differentiation. Meanwhile, C8-IK21 reduced the expression of ITGB1 via ADAM9, thereby inhibiting osteoclast differentiation and function. Moreover, the pro-osteogenic effect of C8-IK21 was validated in organoids. In conclusion, C8-IK21 represents a promising therapeutic approach for the treatment of refractory bacterial infections and bone homeostasis disorders.