Bacterial outer membrane vesicles at the Host–Pathogen interface: Biochemical mechanisms, immunomodulation, clinical and biotechnological applications

Abstract Bacterial outer membrane vesicles (OMVs) are bilayered spherical nanostructures that are naturally secreted by Gram-negative bacteria. Formerly considered a byproduct of cell envelope regeneration, OMVs are now defined as a highly regulated type zero secretion system that contributes to horizontal gene transfer, biofilm structure, and host-pathogen communication. This paper reviews the molecular mechanisms that govern the formation of these vesicles, selective load packing, cellular uptake, and intracellular transport. It also critically evaluates how OMVs modify host innate and adaptive immunity, their role in disease pathogenesis, and their use as versatile platforms for clinical and biotechnological applications. The formation of OMVs is stimulated by cell envelope remodeling, including disruption of the interlaced bonds between peptidoglycan and the outer membrane, accumulation of asymmetric phospholipids, intercalation of Pseudomonas quinolone signal, and endolysin-mediated explosive cell lysis. Dynamic molecular screening mechanisms, such as lipoprotein export signal (LES) in Bacteroides and lipopolysaccharide (LPS) directed sorting in Porphyromonas gingivalis , control the specific load encapsulation. When they reach host cells, OMVs use various phagocytic pathways and direct fusion of membranes to communicate pathogen-associated molecular patterns (PAMPs) and virulence agents. This delivery stimulates immune responses via pattern recognition receptors (PRRs), including Toll-like receptors (TLRs), NOD-like receptors, and the cytoplasmic cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway. Clinically, these properties are being exploited in Bexsero's approved meningococcal vaccine and in engineered next-generation platforms for cancer-targeted immunotherapy and drug delivery. Ultimately, the understanding of these biophysical and immunophysiological principles will accelerate the rational design of personalized vaccines and synthetic biology tools.