A Bispecific Nanovehicle Disarms a Biofilm Amyloid Shield for Implant-Related Osteomyelitis Therapy.

Abstract

As the formation of a biofilm shields the pathogens from antimicrobials, implant-associated osteomyelitis (IAOM) remains a clinical challenge in orthopedic practice. However, existing drug delivery systems for IAOM are often hampered by insufficient targeting and poor retention at the infection site, limiting their therapeutic efficacy. For site-specific delivery and controlled release of antibiofilm agents, here we proposed a bispecific nanovehicle (PPTV@M_Sa) by coencapsulating thymol (Thy) and vancomycin (Van) within alendronate (ALN)-functionalized polydopamine nanoparticles to combat IAOM. A macrophage membrane (M_Sa), which is pretreated with methicillin-resistant <i>Staphylococcus aureus</i> (MRSA), was further used to camouflage the nanoparticles and facilitate targeted accumulation of PPTV@M_Sa at the infection site. When bacterial toxins disrupt the outer membrane of PPTV@M_Sa, the inner ALN is exposed and the particles are thus able to anchor to the bone matrix, resulting in increased local drug concentration and enhanced biofilm eradication. Specifically, Thy suppresses the expression of phenol-soluble modulins and disarms the amyloid structures of the biofilm, which eventually destabilizes the biofilm and facilitates Van to effectively eradicate the embedded bacteria. In vivo studies further confirmed the precise targeting and strong antibiofilm efficacy of the proposed nanovehicle. The dual-targeting method proposed in this study is a promising strategy for treating IAOM.