Outer membrane vesicles: Versatile nanocarriers for therapeutic delivery and immune modulation

Outer membrane vesicles (OMVs) are nanoscale lipid-bilayer vesicles naturally released by Gram-negative bacteria. By packaging membrane proteins, lipopolysaccharide-derived pathogen-associated molecular patterns, nucleic acids, and metabolites, OMVs integrate intrinsic bioactivity with cargo capacity and have emerged as a versatile platform for therapeutic delivery and immune modulation. In this review, we summarize current understanding of OMV biogenesis, composition, and physicochemical features that shape biodistribution and immunogenicity. We then discuss engineering strategies ranging from genetic rewiring of parental strains and detoxification of lipid A to surface functionalization, hybrid membrane assembly, and stimuli-responsive formulations that enable controllable targeting, loading, and release. Recent progress is highlighted in anti-tumor therapy, nanovaccines for infectious diseases and cancer, and nucleic acid delivery for gene regulation. Finally, we analyze key barriers to clinical translation, including endotoxin-associated safety, batch-to-batch heterogeneity, scalable manufacturing, and standardization of quality attributes. Addressing these challenges through rational design and robust production pipelines will be essential to advance OMV-based therapeutics toward safe, effective, and manufacturable clinical products.