LAUSR

Infectious virus diseases, particularly coronavirus disease 2019, have posed a severe threat to public health, whereas the developed therapeutic and prophylactic strategies are seriously challenged by viral evolution and mutation. Therefore, broad‐spectrum inhibitors of viruses are highly demanded. Herein, an unprecedented antiviral strategy is reported, targeting the viral glycan shields with hypervalent mannose‐binding nanoparticles. The nanoparticles exhibit a unique double‐punch mechanism, being capable of not only blocking the virus–receptor interaction but also inducing viral aggregation, thereby allowing for inhibiting the virus entry and facilitating the phagocytosis of viruses. The nanoparticles exhibit potent and broad‐spectrum antiviral efficacy to multiple pseudoviruses, including severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) and its major variants (D614G, N501Y, N439K, Δ69‐70, Delta, and Omicron; lentiviruses expressing only the spike proteins), as well as other vital viruses (human immunodeficiency virus 1 and Lassa virus), with apparent EC50 values around the 10−9 m level. Significantly, the broad‐spectrum inhibition of authentic viruses of both wild‐type SARS‐CoV‐2 and Delta variants is confirmed. Therefore, this hypervalent glycan‐shield targeting strategy opens new access to broad‐spectrum viral inhibition.