Immunomodulatory Nanozymes Eradicate Intracellular Infections and Rescue Immunoparalysis for Treating Multidrug‐Resistant Bacterial Sepsis

ABSTRACT Sepsis and their sequelae are the leading causes of death in intensive care units, with limited therapeutic options. Immunoparalysis plays a vital role in the pathophysiological progression of sepsis, leading to intracellular persistent infections and high mortality of septic patients. Eradicating intracellular infections and rescuing immunoparalysis are critical for sepsis management, yet effective tactics remain elusive. Here, we report immunomodulatory nanozymes (named PdIr@OMVs) that enable intracellular bacteria elimination and reinvigorate systemic innate‐adaptive immune response during immunoparalysis to tackle multidrug‐resistant (MDR) bacterial sepsis. The PdIr@OMVs are designed by encapsulating plasmonic PdIr nanocatalysts with immunostimulants of biocompatible bacterial outer membrane vesicles (OMVs). PdIr@OMVs exhibit unique localized surface plasmon response‐enhanced peroxidase‐like catalytic activity, and inherit the remarkable immunocyte‐targeting capability and adjuvanticity of OMVs. We demonstrate that PdIr@OMVs not only potentiate the phagolysosomal killing effect of impaired macrophages via in situ catalysis to eradicate intracellular MDR bacteria and burst antigen release, but also allow rapid activation/maturation of dendritic cells to boost the presentation of bacterial antigen and orchestrate innate‐adaptive immunity for rescuing immunoparalysis. In two immunocompromised mouse models of MDR bacterial sepsis, PdIr@OMVs collaboratively reduce bacterial burden and restore immune homeostasis, thereby circumventing organ damage and enabling the recovery of septic mice. Our work offers a promising therapeutic modality for sepsis and septic shock.