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.

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The COVID-19 pandemic continues to spread worldwide. To protect and control the spread of SARS-CoV-2, varieties of subunit vaccines based on spike (S) proteins have been approved for human applications. Here, we report a new subunit vaccine design strategy that functions as both an antigen carrier and an adjuvant in immunization to elicit high-level immune responses. The complex of 2-hydroxypropyl-trimethylammonium chloride chitosan and amylose entangles Au nanoparticles (HTCC/amylose/AuNPs) forming 40 nm nanocarriers with a positive charge. The obtained positively charged nanoparticles reveal many merits, including the larger S protein loading capacity in PBS buffer, higher cellular uptake ability, and lower cell cytotoxicity, supporting their potential as safe vaccine nanocarriers. Two functionalized nanoparticle subunit vaccines are prepared via loading full-length S proteins derived from SARS-CoV-2 variants. In mice, both prepared vaccines elicit high specific IgG antibodies, neutralize antibodies, and immunoglobulin IgG1 and IgG2a. The prepared vaccines also elicit robust T- and B-cell immune responses and increase CD19+ B cells, CD11C+ dendritic cells, and CD11B+ macrophages at the alveoli and bronchi of the immunized mice. Furthermore, the results of skin safety tests and histological observation of organs indicated in vivo safety of HTCC/amylose/AuNP-based vaccines. Summarily, our prepared HTCC/amylose/AuNP have significant potential as general vaccine carriers for the delivery of different antigens with potent immune stimulation.