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

The hypoxic microenvironment of bacterial biofilms is one of the main causes of their recalcitrance. The combined therapy of photodynamic therapy (PDT) and silver nanoparticles (AgNPs) has shown its potential for biofilm eradication. However, hypoxia can not only restrict the efficiency of the oxygen-dependent PDT but also encumber the oxidizing release of the Ag+ cations from the AgNPs, thus greatly impeding the therapeutic performance of the combined treatment. Here, a liposomal delivery system is developed using cationic phospholipid for the synergistic ablation of both Gram-positive and Gram-negative bacteria and their biofilms, which is formed using cationic phospholipid and loaded with oxygen, Ce6, and silver nanoparticles. The positively charged micelles increased the adhesion and penetration to the negatively charged biofilm, and the loaded perfluorohexane (PFH) acted as an oxygen carrier to overcome the hypoxia microenvironment and promoted the performance of PDT. The reactive oxygen species generated in the PDT then stimulated the oxidative dissolution of the Ag+. In vivo antibacterial therapy on mice with subcutaneous abscess demonstrated its strong sterilizing capability on living tissues. This research developed a trimodal treatment for effective biofilm eradication, providing a way for the management of biofilm-associated infections.