Intracellular bacteria destruction via traceable enzymes-responsive release and deferoxamine-mediated ingestion of antibiotics

Abstract

Intracellular bacteria (ICBs) are among the most life-threatening causes of drug resistance. Challenges remains in the intracellular drug release specific to ICB-infected cells and efficient uptake into ICBs. In this study, mannose-grafted polymers containing enzymes-responsive and tetraphenylethylene segments (mPET) are assembled into nanoparticles with loading complexes of deferoxamine-ciprofloxacin conjugates with Fe3+ (DFeC). The aggregation-induced emission (AIE) of tetraphenylethylene segments is overlapped with DFeC absorptions, leading to fluorescence resonance energy transfer (FRET)-caused quenching of mPET@DFeC nanoparticles. Nanoparticles are efficiently acquired by infected macrophages via mannose mediation, and the DFeC release is triggered by intracellular lipase and alkaline phosphatase specific to ICB-engulfed macrophages, followed by deferoxamine-mediated ingestion of ciprofloxacin into ICBs. The gradual alleviation of FRET effect and the concurrent restoration of AIE activity demonstrate capabilities of dynamically tracking the drug release and ICB treatment outcome. The mPET@DFeC treatment inhibits the hematological, hepatic and nephric toxicities caused by ICB infections, and all the infected mice survive with dramatic reductions of bacterial levels in livers (over 430 folds), spleens (over 240 folds) and kidneys (5.6 × 104 folds). Thus, this study has provided a feasible strategy to achieve intracellular enzymes-responsive and traceable release of antibiotics and then deferoxamine-mediated bacterial ingestion for ICB destruction.