Self-carrier nanodrugs with dual antibacterial agents to overcome tobramycin resistance in multidrug-resistant Staphylococcus aureus

Multidrug-resistant (MDR) bacterial infections have emerged as a significant threat to global public health, with antibiotic resistance mechanisms-such as alterations in bacterial membrane permeability-substantially limiting therapeutic options and exacerbating infection persistence. In this study, we developed a novel self-carrier nanodrug formulation by directly assembling antibiotic tobramycin (Tob) and antimicrobial borneol 4-formylbenzoate (BF) into Tob-BF nanodrugs (TBN) <i>via</i> dynamic Schiff base linkages, without the need for additional adjuvants. The resultant TBN exhibits minimal bactericidal activity under physiological conditions but undergoes decomposition and activation specifically within the microenvironment of bacterial infections. Confocal microscopy analysis demonstrates that TBN is preferentially taken up and accumulates intracellularly in multidrug-resistant <i>Staphylococcus aureus</i> (MDRSA) to a greater extent than either Tob or BF alone. In both <i>in vitro</i> and <i>in vivo</i> assays, TBN outperforms Tob, BF, and physically mixed Tob + BF (with equal dose to TBN) in terms of antibacterial efficacy, particularly in promoting the recovery of xenograft infection with MDRSA in mice. Collectively, these findings highlight the potential of our self-carrier nanodrug platform, which integrates two distinct antibacterial agents, as an innovative and effective strategy to overcome tobramycin resistance in MDRSA and eliminate MDRSA infections.