Biofilm-associated bacterial infection brings serious threats to global public health owing to serious antibiotic resistance. It is urgently needed to develop innovative strategies to combat biofilm-associated bacterial infections. Polymyxins stand out as the last line of defense against Gram-negative bacteria. However, serious nephrotoxicity of polymyxins severely limits their clinical utility. Herein, a hypoxia-responsive liposome is designed as the nanocarrier of polymyxin B (PMB) to combat biofilms developed by Gram-negative bacteria. A metronidazole modified lipid (hypoxia-responsive lipid (HRLipid)) is synthesized to fabricate hypoxia-responsive liposomes (HRLip). PMB loaded hypoxia-responsive liposomes (HRL-PMB) is then prepared to mitigate the nephrotoxicity of PMB while preserving its excellent bactericidal activity. HRL-PMB shows very low hemolysis and cytotoxicity due to liposomal encapsulation of PMB. PMB can be readily released from HRL-PMB in response to hypoxic biofilm microenvironment, exerting its bactericidal activity to realize biofilm eradication. The excellent in vivo antibiofilm ability of HRL-PMB is confirmed by a Pseudomonas aeruginosa infected zebrafish model and a P. aeruginosa pneumonia infection model. Meanwhile, HRL-PMB can greatly reduce the nephrotoxicity of PMB after intravenous injection. The hypoxia-sensitive liposomes held great promise to improve the biosafety of highly toxic antibiotics while preserving their intrinsic bactericidal ability, which may provide an innovative strategy for combating biofilm-associated infections.

Antibiotic resistance is an increasingly serious threat to global public health, which can lead to the decrease of the effectiveness of antibiotics. The combination therapy of antibiotic and mild temperature photothermal therapy (PTT) is adopted to address this issue in this work. An antibiotic-loaded nanoplatform is fabricated based on two-dimensional (2D) molybdenum disulfide (MoS₂) nanoflakes as effective near-infrared (NIR) photothermal agent. The MoS₂ nanoflakes is modified with positively charged quaternized chitosan (QCS) to improve the dispersion stability and enhance the interaction between MoS₂ nanoflakes and bacterial membrane. The QCS modified MoS₂ nanoflakes (QCS-MoS₂) is expected to adhere onto the membrane of methicillin-resistant Staphylococcus aureus (MRSA) and depolarize the bacterial membrane by local hyperthermia under NIR irradiation. A first-line antibiotic, ofloxacin (OFLX), can be loaded onto QCS-MoS₂ by π-π stacking and hydrophobic interaction. Due to the combined antibiotic-photothermal therapy, superior bactericidal ability was achieved at mild temperature (45 °C) and low antibiotic concentration. Such synergistic mild-temperature photothermal/antibiotic therapy can not only avoid the damage to neighboring tissue by PTT, but also reduce the development of drug resistance, providing an innovative way for the treatment of bacterial infections.