Immunomodulatory Nanozymes Eradicate Intracellular Infections and Rescue Immunoparalysis for Treating...

Area of Science:

• Biomedical Engineering
• Nanotechnology
• Immunology

Background:

• Sepsis is a leading cause of intensive care unit mortality with limited treatment options.
• Immunoparalysis contributes to persistent intracellular infections and high mortality in sepsis patients.
• Effective strategies for eradicating intracellular infections and reversing immunoparalysis are urgently needed.

Purpose of the Study:

• To develop novel immunomodulatory nanozymes (PdIr@OMVs) for treating multidrug-resistant (MDR) bacterial sepsis.
• To investigate the capacity of PdIr@OMVs to eliminate intracellular bacteria and reinvigorate the immune response during sepsis-induced immunoparalysis.
• To assess the therapeutic potential of PdIr@OMVs in preclinical models of MDR bacterial sepsis.

Main Methods:

• PdIr@OMVs were engineered by encapsulating plasmonic Palladium-Iridium (PdIr) nanocatalysts within biocompatible bacterial outer membrane vesicles (OMVs).
• The catalytic activity and immunomodulatory properties of PdIr@OMVs were characterized.
• The efficacy of PdIr@OMVs in eradicating intracellular MDR bacteria, enhancing macrophage phagolysosomal activity, and promoting dendritic cell maturation was evaluated in vitro and in vivo.
• Therapeutic effects were assessed in immunocompromised mouse models of MDR bacterial sepsis.

Main Results:

• PdIr@OMVs demonstrated enhanced peroxidase-like catalytic activity and retained the immunocyte-targeting and adjuvant properties of OMVs.
• PdIr@OMVs effectively eradicated intracellular MDR bacteria by potentiating macrophage phagolysosomal killing and facilitating antigen release.
• PdIr@OMVs promoted dendritic cell activation and maturation, orchestrating innate and adaptive immune responses to counteract immunoparalysis.
• In vivo studies showed that PdIr@OMVs reduced bacterial burden, restored immune homeostasis, mitigated organ damage, and improved survival rates in septic mice.

Conclusions:

• PdIr@OMVs represent a promising therapeutic modality for combating MDR bacterial sepsis and septic shock.
• This nanozyme system effectively targets intracellular pathogens and rejuvenates the host immune system, addressing critical challenges in sepsis management.
• The findings highlight the potential of combining nanocatalysis with OMV-based immunotherapy for treating complex infectious diseases.