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Existing vaccines show reduced efficacy against newly emerged variants, and the ongoing risk of new outbreaks highlights the importance of alternative strategies to prevent infection and viral transmission. As respiratory viruses primarily enter through the nose, formulations targeting the nasal epithelium are attractive candidates to neutralize pathogens and thus prevent or minimize infection. Enoxaparin, a low-molecular-weight heparin (LMWH) widely used as an anticoagulant, also exhibits antiviral and anti-inflammatory properties. We found that in highly differentiated human nasal and upper respiratory tract 3D models, enoxaparin inhibited influenza A\/H3N2 and B\/Victoria infection, reduced release of proinflammatory cytokines and chemokines, and mitigated epithelial damage caused by infection. Our study highlights the LMWH inhibitory effect on respiratory viruses. 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