摘要Multidrug-resistant Klebsiella pneumoniae(MDR-KP)is characterized by high mortality and risk of nosocomial transmission,and biofilm constitutes the primary challenge in the treatment of its implant-associated and refractory pulmonary infections.Notably,the hypoxic microenvironment and the physical barrier of biofilm leading to the increased tolerance of the bacteria to antibiotics.Herein,a hypoxia-responsive hybrid nanoparticle(CHLip@FLD/COL)loaded separately with anti-biofilm candidate fingolimod(FLD)and antibiotic colistin(COL)is achieved targeting antibacterial efficacy against MDR-KP in vitro and in vivo.CHLip@FLD/COL is composed of hybridizing hypoxia-responsive lipids(HLipid)and lipid A targeting materials DSPE-mPEG-COL.HLipid is synthesized by hexadecanedioic acid esterified with nitroimidazole,while DSPE-mPEG is coupling with vector COL via amide reaction.The relative level of extracellular polymeric substances and the NIR-IIb sO2 images of the infection site are used as indicators to establish mature biofilm models.CHLip@FLD/COL readily releases FLD and COL in hypoxic conditions,and its MIC against MDR-KP is only one-sixteenth of that when COL is used alone in vitro.The nanoparticle exhibits bacterial targeting ability and antibacterial effect in the pulmonary infection and biofilm infection mice models.Bacterial loads eliminated by 4 Log10 CFU and 2 Log10 CFU,respectively.The strategy provides a valuable reference for the treatment of refractory infections caused by MDR-KP.