Ultrasound-Stimulated "Exocytosis" by Cell-Like Microbubbles Enhances Antibacterial Species Penetration and Immune Activation Against Implant Infection

Host immune systems serving as crucial defense lines are vital resisting mechanisms against biofilm-associated implant infections. Nevertheless, biofilms hinder the penetration of anti-bacterial species, inhibit phagocytosis of immune cells, and frustrate host inflammatory responses, ultimately resulting in the weakness of the host immune system for biofilm elimination. Herein, a cell-like construct is developed through encapsulation of erythrocyte membrane fragments on the surface of Fe3O4 nanoparticle-fabricated microbubbles and then loaded with hydroxyurea (EMB-Hu). Under ultrasound (US) stimulation, EMB-Hu undergoes a stable oscillation manner to act in an "exocytosis" mechanism for disrupting biofilm, releasing agents, and enhancing penetration of catalytically generated anti-bacterial species within biofilms. Additionally, the US-stimulated "exocytosis" by EMB-Hu can activate pro-inflammatory macrophage polarization and enhance macrophage phagocytosis for clearance of disrupted biofilms. Collectively, this work has exhibited cell-like microbubbles with US-stimulated "exocytosis" mechanisms to overcome the biofilm barrier and signal macrophages for inflammatory activation, finally achieving favorable therapeutic effects against implant infections caused by methicillin-resistant Staphylococcus aureus (MRSA) biofilms. Under ultrasound (US) stimulation, erythrocyte membrane fragments encapsulated microbubbles loaded with hydroxyurea (EMB-Hu) can contract in an oscillatory manner for agent release. Such US-stimulated "exocytosis" by EMB-Hu can disrupt biofilm structure by the generation of microstream, enhance the penetration of antibacterial species within biofilms, and also activate macrophages for efficient elimination of residual biofilms during implant infection.image