Oxygen-Loaded Lipid Nanobubbles for Biofilm Eradication by Combined Trimodal Treatment of Oxygen, Silver, and Photodynamic Therapy

The hypoxic microenvironment of bacterial biofilms isone of themain causes of their recalcitrance. The combined therapy of photodynamictherapy (PDT) and silver nanoparticles (AgNPs) has shown its potentialfor biofilm eradication. However, hypoxia can not only restrict theefficiency of the oxygen-dependent PDT but also encumber the oxidizingrelease of the Ag+ cations from the AgNPs, thus greatlyimpeding the therapeutic performance of the combined treatment. Here,a liposomal delivery system is developed using cationic phospholipidfor the synergistic ablation of both Gram-positive and Gram-negativebacteria and their biofilms, which is formed using cationic phospholipidand loaded with oxygen, Ce6, and silver nanoparticles. The positivelycharged micelles increased the adhesion and penetration to the negativelycharged biofilm, and the loaded perfluorohexane (PFH) acted as anoxygen carrier to overcome the hypoxia microenvironment and promotedthe performance of PDT. The reactive oxygen species generated in thePDT then stimulated the oxidative dissolution of the Ag+. In vivo antibacterial therapy on mice with subcutaneousabscess demonstrated its strong sterilizing capability on living tissues.This research developed a trimodal treatment for effective biofilmeradication, providing a way for the management of biofilm-associatedinfections.