Biofilm Microenvironment Activated Antibiotic Adjuvant for Implant‐Associated Infections by Systematic Iron Metabolism Interference

Abstract

Hematoma, a risk factor of implant‐associated infections (IAIs), creates a Fe‐rich environment following implantation, which proliferates the growth of pathogenic bacteria. Fe metabolism is a major vulnerability for pathogens and is crucial for several fundamental physiological processes. Herein, a deferiprone (DFP)‐loaded layered double hydroxide (LDH)‐based nanomedicine (DFP@Ga‐LDH) that targets the Fe‐rich environments of IAIs is reported. In response to acidic changes at the infection site, DFP@Ga‐LDH systematically interferes with bacterial Fe metabolism via the substitution of Ga3+ and Fe scavenging by DFP. DFP@Ga‐LDH effectively reverses the Fe/Ga ratio in Pseudomonas aeruginosa, causing comprehensive interference in various Fe‐associated targets, including transcription and substance metabolism. In addition to its favorable antibacterial properties, DFP@Ga‐LDH functions as a nano‐adjuvant capable of delaying the emergence of antibiotic resistance. Accordingly, DFP@Ga‐LDH is loaded with a siderophore antibiotic (cefiderocol, Cefi) to achieve the antibacterial nanodrug DFP@Ga‐LDH‐Cefi. Antimicrobial and biosafety efficacies of DFP@Ga‐LDH‐Cefi are validated using ex vivo human skin and mouse IAI models. The pivotal role of the hematoma‐created Fe‐rich environment of IAIs is highlighted, and a nanoplatform that efficiently interferes with bacterial Fe metabolism is developed. The findings of the study provide promising guidance for future research on the exploration of nano‐adjuvants as antibacterial agents.