Modulating phage susceptibility with membrane vesicles and bacteriophage cocktails for Acute Hepatopancreatic Necrosis Disease (AHPND) management in shrimp aquaculture.

Acute Hepatopancreatic Necrosis Disease (AHPND) is one of the most destructive bacterial diseases in shrimp aquaculture and is caused by virulent Vibrio parahaemolyticus strains carrying the pVA1 plasmid encoding the binary toxins PirA and PirB, resulting in severe economic losses and threatening sustainable production worldwide. Although lytic bacteriophages have emerged as promising alternatives to antibiotics because of their specificity and self-amplifying properties, their long-term effectiveness is constrained by the rapid evolution of bacterial resistance through multiple mechanisms, including surface receptor modification. Recent evidence indicates that membrane vesicles (MVs) can modulate phage-bacterium interactions through mechanisms that vary among bacterial systems. In Bacillus subtilis, MVs can transfer phage attachment molecules and transiently restore phage sensitivity, whereas in Vibrio parahaemolyticus, MVs have been reported to enhance phage efficacy, although the underlying mechanism remains unresolved. This review synthesizes current knowledge on AHPND epidemiology, phage infection and resistance, MV biology, phage cocktail design, formulation, and delivery strategies. It further evaluates the potential of MV-assisted phage approaches as a complementary strategy for sustainable AHPND management, while highlighting the need to validate functional receptor restoration in resistant Vibrio and address challenges in MV standardization, biosafety, and field application.