ENGINEERING OUTER MEMBRANE VESICLES FOR THERAPEUTIC APPLICATIONS: ADVANCES, CLINICAL TRANSLATION AND FUTURE PERSPECTIVES

Abstract

Outer membrane vesicles (OMVs) are naturally released lipid-bilayer nanovesicles produced by Gram-negative bacteria that contain diverse bacterial components, including proteins, lipids, lipopolysaccharides (LPS), nucleic acids and enzymes. Their nanoscale architecture, biological activity and intrinsic capacity to interact with host cells make OMVs attractive platforms for therapeutic delivery and immunomodulation. However, naturally produced OMVs exhibit substantial heterogeneity and may possess undesirable inflammatory activity, particularly because of their LPS content. Engineering approaches have therefore been developed to control vesicle production, composition, cargo loading, surface properties and biological activity.

This review examines recent advances in the engineering of OMVs for therapeutic applications, including genetic engineering, hypervesiculation, LPS detoxification, cargo loading, surface functionalization, hybrid systems, stimuli-responsive approaches and programmable engineering. Particular emphasis is placed on emerging applications in cancer therapy, antimicrobial delivery, nucleic acid delivery and immunotherapy. The review further evaluates key barriers to clinical translation, including scalable manufacturing, purification, characterization, batch-to-batch consistency, pharmacokinetics, biodistribution, safety, immunogenicity and regulatory requirements. Finally, emerging opportunities involving synthetic biology, computational design and artificial intelligence are discussed in the context of rational OMV engineering.

Overall, engineered OMVs represent a promising biological nanoplatform, but their clinical development will require reproducible manufacturing, well-defined quality attributes, controlled immunogenicity, validated therapeutic efficacy and appropriate regulatory frameworks.