Sonodynamic Inorganic Nanomaterials In The Treatment Of Bacterial Pneumonia

Bacterial infections usually induce many diseases,such as pneumonia,meningitis,sepsis,cholera,skin ulcers and stomach cancer,and pose a great threat to human life and health.However,the misuse of antibiotics has led to a massive explosion of multi-drug resistant bacteria(MDR),leaving fewer and fewer antibiotics available for treatment.In recent years,with tthe development of nanotechnology,researchers have developed a variety of nanomaterial antimicrobial therapies that can replace antibiotics,such as photodynamic therapy(PDT),photothermal therapy(PTT)and sonodynamic therapy(SDT).The common feature of all these treatments is their ability to eliminate MDR bacteria while not easily developing resistance.Given the powerful tissue penetration of ultrasound(US),SDT has great potential for the treatment of deep tissue disease.With sonosensitizers activated by US waves,SDT produces ROS,mainly 1O2 and ·OH,to kill bacteria.In this experiment,the amount of 1O2 and ·OH produced by the nano-sonosensitizer-ZIF-8 derived carbon@TiO2 nanoparticles(ZTNs)under US activation was much higher than that of the conventional inorganic sonosensitizer TiO2,thus enabling the killing of gram-negative MDR bacteria(K.pneumoniae.A.baumannii,P.aeruginosa.K.aerogenes)with bactericidal efficiencies of 99.2%,87.1%,95.6%,and 81.5%,respectively.On this basis,the bactericidal mechanism of SDT film-breaking was explored by SEM observation and detection of supernatant components(protein,nucleic acid,ATP)of bacterial medium.In vivo,we successfully established the BALE/c(immunocompetent)and SCID(partially immunodeficient)multi-drug resistant bacteria lung infection models by pulmonary inhalation infection with Klebsiella pneumonia e,and subsequently performed SDT on them.The killing efficiency of ZTNs was evaluated in vivo by examining the bacterial load of major organs,assessing the pathological damage and detecting the level of cytokines via ELISA.The results showed that ZTNs effectively cleared Klebsiella pneumoniae in mouse lungs after US activation and reduced the corresponding inflammatory responses,as evidenced by a significant decrease in bacterial load and neutrophil infiltration,and a reduced expression of inflammatory factors(IL-6,IL-12.TNF-?,IFN-?)in the treated group.In addition,we evaluated both the hemolytic and biological toxicity of ZTNs by assessment of pathological damage and ELISA detection of cytokines.The results showed that ZTNs had no significant biotoxicity and were a safe inorganic acoustically sensitive material.In summary,we developed ZIF-8-derived carbon@TiO2 nanoparticles(ZTNs)as an inhalable acoustic sensitizer for the treatment of bacterial pneumonia.ZTNs showed the ability to efficiently produce reactive oxygen species(ROS)under the activation of US,which could kill MDR gram-negative bacteria in vitro.Subsequently,we took advantage of endotracheal inoculation of lung-delivered aerosols to deliver ZTNs precisely to the site of lung infection and activated them in the lung by US in mice infection model to induce effective elimination of MDR gram-negative bacteria.MOF-derived nanoparticles,as safe and highly effective inhaled acoustic sensitizers,have great potential for clinical antibiotic replacement therapy for MDR bacterial pneumonia.This study proposes a new strategy for SDT-based treatment of deep tissue bacterial infections and will expand the nanomedical applications of inorganic acoustic sensitizers.