Microbubble-Controlled Delivery of Biofilm-Targeting Nanoparticles to Treat MRSA Infection

Drug-resistant microorganisms cause serious problems in human healthcare, leading to the persistence in infections and poor treatment outcome from conventional therapy. In this study, we introduce a gene targeting strategy using microbubble-controlled nanoparticles that can effectively eliminate biofilms of methicillin-resistant Staphylococcus aureus (MRSA) in vivo. We developed biofilm-targeting nanoparticles (BTN) capable of delivering oligonucleotides that effectively remove biofilm-associated bacteria upon controlled delivery with diatom-based microbubblers (MB). We validated the activity of BTN in silencing key bacterial genes related to MRSA biofilm formation (icaA), bacterial growth (ftsZ), and antimicrobial resistance (mecA), as well as their multi-targeting ability in vitro. We next examined the integration of BTN with MB, resulting in synergistic effects in biofilm removal and antimicrobial activity in an ex vivo porcine skin model. We further investigated the therapeutic efficacy in vivo in a mouse wound model infected with MRSA biofilm, which showed that MB-controlled BTN delivery substantially reduced bacterial load and led to the effective elimination of the biofilm. This study underscores the potential of the gene silencing platform with physical enhancement as a promising strategy to combat problems related to biofilms and antibiotic resistance.