Fate reversal: Exosome-driven macrophage rejuvenation and bacterial-responsive drug release for infection immunotherapy in diabetes

Abstract

Superficial surgical site infection (SSI) is a significant risk factor for the development of periprosthetic joint infection (PJI), particularly in diabetic patients. A high-glucose microenvironment is observed to compromise phagocytosis by inducing cellular senescence, which leads to impaired antibacterial immune function. Exosomes derived from umbilical cord stem cells (H-Exos) can reverse the immunosuppressive microenvironment by rejuvenating senescent cells, thereby terminating excessive, persistent, and ineffective inflammatory responses. Thus, a novel exosome-based immunotherapeutic antibacterial strategy to reverse fate is proposed. Vancomycin & lysostaphin-loaded exosomes are incorporated in a customizable microneedle patch (ExoV-ExoL@MN) for controlled release, enabling tailored treatments for diverse clinical scenarios. While rejuvenating macrophage senescent phenotype, the antibiotics encapsulated within exosomes can be responsively released by the hemolysin secreted by bacteria, triggering rapid bacterial killing. Post-infection clearance, they induce a shift from M1 to M2 macrophage polarization, thereby enhancing anti-inflammatory and reparative responses. Furthermore, the components can be mixed on demand and at any time, allowing for real-time customization and fabrication directly at the clinic (fabrication@clinic). This strategy reverses the immunosuppressive microenvironment by rejuvenating senescent macrophages and effectively combats bacterial invasion into deep tissues through bacteria-responsive antibiotic release, providing a promising approach for preventing and treating SSI-induced PJI.