A multivalent 9-O-acetylated sialic acid-conjugated bacteriophage platform for antiviral and immunomodulatory therapy for human coronavirus OC43

Coronaviruses pose significant global health and economic challenges due to their capacity for rapid mutation and immune evasion, which limit the effectiveness of current treatments. Here, we present an engineered antiviral platform based on filamentous bacteriophages conjugated with multivalent 9-O-acetylated sialic acid ligands (Ac-SLPhage), designed to target conserved viral entry pathways of human coronavirus OC43 (HCoV-OC43), a surrogate for SARS-CoV-2. This nanomaterial competitively blocks viral attachment through high-affinity interactions with host sialic acid receptors, while simultaneously modulating host responses by enhancing antioxidant defenses and suppressing inflammation. Comprehensive structural and biophysical analyses confirmed efficient ligand presentation and viral binding. In vitro assays demonstrated robust inhibition of OC43 infectivity, restoration of cell viability, and suppression of pro-inflammatory cytokines. In vivo studies using a murine model validated the therapeutic efficacy of Ac-SLPhage, with improved survival, reduced viral loads, lung-targeted biodistribution, anti-inflammatory macrophage polarization and minimal immunogenicity. These results position Ac-SLPhage as a dual-function nanomaterial for antiviral and immunomodulatory therapy, offering broad applicability for respiratory coronavirus infections, including SARS-CoV-2, and contributing to pandemic preparedness strategies.