Bioengineered Bacterial Vesicles and Biomimetic Hybrids Eliminate Biofilms and Balance the Gut Microbiome

Abstract Antibiotic‐resistant pathogens are a global health challenge, necessitating innovative solutions beyond conventional antibiotics. This study introduces biomimetic nanocarriers ‐ hybrids of bacteriomimetic liposomes and biocompatible Myxobacteria outer‐membrane vesicles (OMVs) ‐ as tunable platforms for targeted antibiotic delivery. Comparative analyses of their physicochemical properties and interactions with immune cells, intestinal epithelium, and biofilm‐forming pathogens reveal distinct advantages. Hybrids excel at delivering antibiotics to intracellular targets, while Myxobacteria OMVs, particularly those of strain SBSr 073, evade immune clearance and prolong extracellular drug exposure. To support clinical translation, this study optimizes antibiotic encapsulation methods for SBSr 073 OMVs and evaluates the short‐ and long‐term impact of Cystobacter ferrugineus 23 strain OMVs on the gut microbiome in mice. Summing up, this study highlights the promise of Myxobacteria OMVs and their biomimetic hybrids as versatile tools for treating Gram‐negative biofilm‐forming pathogens. These findings underscore the potential of bioengineered and biomimetic drug carriers for combating antimicrobial resistance and pave the way for their translation toward difficult‐to‐treat infections.