The spread of Carbapenem-Resistant Enterobacteriaceae (CRE) has emerged as a critical global health concern, with mortality rates exceeding 30% in infected patients due to limited therapeutic options. Recent studies highlight outer membrane vesicles (OMVs) as potent mediators of bacterial communication and antibiotic resistance. These nanosized proteoliposomes, secreted by Gram-negative bacteria, transport functional proteins, nucleic acids, and enzymes across biological barriers, enabling intercellular interactions without direct contact. Notably, OMVs from β-lactamase-producing strains degrade antibiotics extracellularly and protect susceptible bacteria, suggesting a non-genetic route for resistance spread. This study provides the first evidence that OMVs secreted by gut-colonized CRE translocate into the bloodstream, carrying active carbapenemases and resistance genes. Using proteomic and functional assays, we demonstrate that plasma-derived OMVs degrade imipenem and meropenem, rescuing susceptible bacteria in vitro and in a Galleria mellonella infection model. Importantly, while these OMVs failed to transfer resistance genes horizontally, their enzymatic activity significantly reduced antibiotic efficacy, revealing a novel extracellular resistance mechanism. Our findings redefine the paradigm of carbapenem resistance dissemination and underscore OMVs as potential therapeutic targets to combat treatment failure.
