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 <i>Staphylococcus aureus</i> (MRSA) <i>in vivo</i>. 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 (<i>icaA</i>), bacterial growth (<i>ftsZ</i>), and antimicrobial resistance (<i>mecA</i>), as well as their multi-targeting ability <i>in vitro</i>. We next examined the integration of BTN with MB, resulting in synergistic effects in biofilm removal and antimicrobial activity in an <i>ex vivo</i> porcine skin model. We further investigated the therapeutic efficacy <i>in vivo</i> 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.