Engineered bacterial extracellular vesicles as next-generation precision postbiotics: strategies, challenges and prospects

Postbiotics, defined as inactivated microorganisms and/or their components conferring a health benefit, represent a paradigm shift from traditional probiotics by offering superior safety, stability, and precise dosing. Bacterial extracellular vesicles (BEVs), natural nanoparticles secreted by bacteria, are key mediators of microbiota-host communication. BEVs have emerged as promising natural postbiotic agents due to their ability to transport bioactive cargo and modulate host physiology. However, the therapeutic application of natural BEVs (nBEVs) is constrained by limitations, including potential safety concerns, lack of target specificity, low yield, and compositional heterogeneity. To overcome these barriers, the concept of engineered BEVs (eBEVs) has been introduced. By employing genetic modification of parent bacteria, surface functionalization, and tailored cargo loading, eBEVs can be precisely designed. This engineering transforms nBEVs into advanced, targeted delivery platforms that significantly expand the scope and efficacy of postbiotics. This review explores the vast potential of eBEVs as next-generation precision postbiotics to treat multiple disorders. Despite the transformative potential, translating eBEVs into clinical practice faces challenges. These include scalable manufacturing processes, comprehensive in vivo safety and pharmacokinetic profiling, and the establishment of regulatory frameworks. Future progress hinges on interdisciplinary efforts to develop smart, stimulus-responsive BEVs, enhance endosomal escape efficiency, and conduct rigorous clinical trials. Ultimately, eBEVs stand at the forefront of a new era in microbiota-based therapeutics, merging the biocompatibility of natural vesicles with the precision of synthetic nanomedicine.