Dual Antibiotics‐Based pH‐Responsive Carrier‐Free Nanodrug against Bacterial Mixed Infection for Accelerated Wound Healing

Abstract Mixed infections caused by multiple bacteria are a key challenge hindering wound healing in the field of trauma care. Although antibiotics have exhibited efficient therapeutic efficacy, it is difficult for a single antibiotic to exert synergistic bactericidal effects against both Gram‐positive (G⁺) and Gram‐negative (G ‐ ) bacteria in mixed infection. Meanwhile, long‐term treatment in high doses is prone to induce drug toxicity and accelerate the emergence of drug‐resistance. Therefore, in this study, polymyxin B (PMB, targeting G ‐ bacteria) and bornyl p ‐aldehyde benzoate (BF, targeting G⁺ bacteria) are introduced to construct pH‐responsive carrier‐free nanodrug (PBN) via a molecular self‐assembly strategy based on dynamic Schiff‐base bonding. Once triggered by the acidic microenvironment in infection site, PBN can specifically release PMB and BF synchronously through Schiff‐base bond breaking, which then targeting and killing multidrug‐resistant Pseudomonas aeruginosa (MDR‐PA) and Staphylococcus aureus (MDR‐SA), respectively. Compared with PMB/BF dual‐drug administration, PBN presents higher efficiency for disrupting the membrane integrity of mixed infection. Furthermore, in vivo experiments confirm that PBNs can efficiently eliminate bacterial mixed infection to accelerate wound healing. Considering the good biosafety, the carrier‐free self‐assemble strategy based on different antibiotics provides an innovative route for the treatment of bacterial mixed infections.