Microbial‐Engineered Fluorescent Nanocarrier for Ion Ratiometric Sensing and sTREM‐1‐Mediated EBV Inhibition

Epstein-Barr virus (EBV), a widespread human γ-herpesvirus, is associated with infectious mononucleosis and several malignancies, posing a major public health challenge. Acyclovir (ACV), the first-line antiviral drug, is limited by poor solubility, short half-life, and low bioavailability. To overcome these drawbacks, we designed a hyaluronic acid-based nanocarrier modified with microbial extracts and a fluorescent small molecule (1-HA-2), and constructed an ACV-loaded nanosystem (1-HA-2@ACV) with improved drug loading, fluorescence responsiveness, and aqueous stability, enabling both therapeutic delivery and ion sensing. Notably, 1-HA-2@ACV allows sensitive detection of Na+ and PO4 3-, two clinically relevant ions whose dysregulation is closely linked to EBV-associated disease progression, drug safety, and therapeutic monitoring. In EBV-susceptible cells, EBV infection markedly increased EBNA1 and sTREM-1 expression, whereas treatment with 1-HA-2@ACV significantly inhibited viral replication and reduced sTREM-1 overexpression more effectively than free ACV, while blank nanoparticles showed no effect. These findings suggest that 1-HA-2@ACV not only enhances the therapeutic efficacy of ACV but also provides a dual-function platform for EBV-targeted therapy and real-time monitoring through modulation of sTREM-1 pathways and ion-associated biomarkers.