Raspberry-like gold nanozyme-hybrid liposomes for hypoxia-enhanced biofilm eradication

Bacterial biofilm-associated infection has been one of the largest threats to global public health due to serious antibiotic resistance. It is urgently needed to develop new bactericides beyond antibiotics for bio-film eradication. Herein, we repurpose a hypoxia-activated anticancer drug tirapazamine (TPZ) to treat biofilm-associated infections based on the hypoxic biofilm microenvironment. A "hypoxia-enhanced" strategy is adopted to improve the therapeutic efficacy of TPZ by encapsulating TPZ into raspberry-like gold nanoparticle-hybrid liposomes (Lip@Au-TPZ). The gold nanoparticles on the hybrid liposomes can be used as nanozymes to catalyze glucose oxidation, which will consume oxygen to aggravate biofilm hypoxia. The aggravation of biofilm hypoxia is a critical step to metabolize TPZ into fatal oxidising radicals to induce DNA damage. The radical-induced damage of bacterial DNA by hypoxia-activated TPZ is fully investigated by multiple characterizations, including comet assay, nucleic acid gel electrophoresis, and bacterial gene transcriptome sequencing. Compared to liposome encapsulated TPZ (Lip-TPZ), Lip@Au-TPZ can lead to two orders of magnitude more reduction of bacterial cells due to the gold nanozyme-aggravated biofilm hy-poxia. The biofilm eradication effect of Lip@Au-TPZ is further investigated in vivo by a mouse pneumonia model and a mouse wound healing model. The "hypoxia-enhanced" antibiofilm strategy by combining gold nanozymes and TPZ provides a new strategy for combating biofilm-associated infections. Data Availability: All data supporting the findings of the current study are available in the article and its Supplemental Information. Additional relevant data are available from the corresponding author upon reasonable request.(c) 2023 Elsevier Ltd. All rights reserved.