Design And Applications Of Nanomaterials For Treating Bacterial Infections

The global burden of bacterial infection remains high and causes an increasing morbidity and mortality.Bacterial infection is a complex event,they have evolved multiple methods to enhance infections.Toxin producing and antibiotic resistance are top important ones among them.Although the neutralization of bacteria-secreted toxins is highly appreciated in the treatment of bacterial infections,and several studies have reported the neutralization strategies of proteinaceous toxins,the elimination strategies of non-proteinaceous toxins(such as H2O2)have rarely been reported.In addition,the mechanisms of bacterial resistance are becoming clearer and the related treatment strategies are also updated.However,there is a lack of targeted therapy to treat drug-resistant bacterial infections in specific organs or cell populations.In this dissertation,we focus on the exploration of key processes during bacterial infections and the development of nanomaterial drug delivery systems based on these processes to overcome multiple biological barriers and enhance antibacterial therapies.The main contents and conclusions of this dissertation are presented in two parts as below:(1)Streptococcus pneumoniae(S.pneumoniae)is a leading cause of pneumonia and one of the most common causes of world death totals.S.pneumoniae pneumonia is responsible for high mortality,and high health care costs.As a vital bacteria-secreted toxin,hydrogen peroxide(H2O2)can destroy infected tissues and increase vascular permeability,leading to life-threatening systemic bacteremia or sepsis.No strategy that can alleviate H2O2-induced injury and prevent systemic sepsis has been reported.Herein,as a proof of concept,we demonstrate the use of H2O2-reactive metal-organic framework nanosystems(MOFs)for treating H2O2-secreting bacteria.First,we isolated multiple S.pneumoniae strains from clinical patients and found that S.pneumoniae can form a H2O2 toxin-rich microenvironment during infection.In mice infected with Streptococcus pneumoniae(S.pneumoniae)isolated from patients,MOFs efficiently accumulate in the lungs after systemic administration due to infection-induced alveolar-capillary barrier dysfunction.Moreover,MOFs sequester pneumococcal H2O2,reduce endothelial DNA damage,and prevent systemic dissemination of bacteria.In addition,this nanosystem exhibits excellent chemodynamic bactericidal effects against drug-resistant bacteria.Through synergistic therapy with the antibiotic ampicillin,MOFs eliminate over 98%of invading S.pneumoniae,resulting in a survival rate of greater than 90%in mice infected with a lethal dose of S.pneumoniae.Overall,this work opens up new paths for the clinical treatment of toxin-secreting bacteria.(2)Bloodstream infected intracellular bacteria quickly reach the liver and persist inside the hepatic macrophages(Kupffer cells)and cause the recalcitrance and relapse of persistent bacterial infections.Methicillin-resistant Staphylococcus aureus(MRSA),a kind of special intracellular bacterium,is a major nosocomial pathogen that causes severe morbidity and mortality worldwide.Controlling the size of nanoparticles might modulate their biodistribution both in tissues and cell populations,while modification of the surface of nanoparticle could mimick bacterial behaviors and fates in the host body.Based on this,we prepared bionic silica nanoparticles(CMV@SiO2)with 4 different sizes(80,250,600,1200 nm)to spatiotemporally track invaded MRSA.By using confocal laser microscopy and flow cytometry,we studied the abilities of the nanoparticles with different sizes to track MRSA from macroscopic level(organ)to microscopic level(subcellular organelle).We found that the biodistribution of biomimetic CMV@SiO2 with the size of 600 nm in tissues and cell populations was highly consistent with that of MRSA.Next,we observed that CMV@SiO2 loaded with rifampicin(Rif)can efficiently eliminate the invaded MRSA,and improve the survival rate of infected mice.In short,this work creactively shows a strategy to spatiotemporally track and treat intracellular bacteria infection by using the size and bionic effects as guide line,which provides a reference for clinical treatment of drug-resistant bacterial infection.