In Nature, most known objects can perform their functions only when in supramolecular self-assembled from, e.g. protein complexes and cell membranes. Here, a dendritic polymer is presented that inhibits severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with an irreversible (virucidal) mechanism only when self-assembled into a Two-dimmensional supramolecular polymer (2D-SupraPol). Monomeric analogs of the dendritic polymer can only inhibit SARS-CoV-2 reversibly, thus allowing for the virus to regain infectivity after dilution. Upon assembly, 2D-SupraPol shows a remarkable half-inhibitory concentration (IC(50) 30 nM) in vitro and in vivo in a Syrian Hamster model has a good efficacy. Using cryo-TEM, it is shown that the 2D-SupraPol has a controllable lateral size that can be tuned by adjusting the pH and use small angle X-ray and neutron scattering to unveil the architecture of the supramolecular assembly. This functional 2D-SupraPol, and its supramolecular architecture are proposed, as a prophylaxis nasal spray to inhibit the virus interaction with the respiratory tract.